RxPG News : Neurochemistry

Signs of aging may be linked to undetected blocked brain blood vessels

Thu, 01 Sep 2011 04:00:00 PST

( from http://www.rxpgnews.com ) Many common signs of aging, such as shaking hands, stooped posture and walking slower, may be due to tiny blocked vessels in the brain that can't be detected by current technology.

"This is very surprising," said Aron S. Buchman, M.D., lead author of the study and associate professor of neurological sciences at Rush University Medical Center in Chicago. "There is a very big public health consequence because we're not capturing this 30 percent who have undiagnosed small vessel disease that is not picked up by current technology. How would you even get them on your radar? We need additional tools in our toolkit."

In 1994, the researchers began conducting annual exams of 1,100 older nuns and priests for signs of aging. The participants also donated their brains for examination after death. This study provides results on the first 418 brain autopsies (61 percent women, average 88 years old at death).

Although Parkinson's disease occurs in only 5 percent of older people, at least half of people 85 and older have mild symptoms associated with the disease.

Before the study, researchers believed that something more common, such as microscopic blocked vessels, might be causing the physical decline. The study's autopsies found the small lesions could only be seen under a microscope after participants died.

The lesions couldn't be detected by current scans.

During the annual exams of the nuns and priests, researchers used the motor skills portion of a Parkinson's disease survey to assess their physical abilities.

"Often the mild motor symptoms are considered an expected part of aging," said Buchman, who is also a member of the Rush Alzheimer's Disease Center. "We shouldn't accept this as normal aging. We should try to fix it and understand it.

If there is an underlying cause, we can intervene and perhaps lessen the impact."

3-D movie shows, for the first time, what happens in the brain as it loses consciousness

Fri, 10 Jun 2011 04:00:00 PST

( from http://www.rxpgnews.com ) Amsterdam, The Netherlands: For the first time researchers have been able to watch what happens to the brain as it loses consciousness. Using sophisticated imaging equipment they have constructed a 3-D movie of the brain as it changes while an anaesthetic drug takes effect.

Brian Pollard, Professor of Anaesthesia at The University of Manchester (UK), will tell the European Anaesthesiology Congress in Amsterdam that the real-time 3-D images seemed to show that losing consciousness involves a change in electrical activity deep within the brain, changing the activity of certain groups of nerve cells (neurons) and hindering communication between different parts of the brain.

He said the findings appear to support a hypothesis put forward by Professor Susan Greenfield, of the University of Oxford, about the nature of consciousness itself. Prof Greenfield suggests consciousness is formed by different groups of brain cells (neural assemblies), which work efficiently together, or not, depending on the available sensory stimulations, and that consciousness is not an all-or-none state but more like a dimmer switch, changing according to growth, mood or drugs. When someone is anaesthetised it appears that small neural assemblies either work less well together or inhibit communication with other neural assemblies.

Our findings suggest that unconsciousness may be the increase of inhibitory assemblies across the brain's cortex. These findings lend support to Greenfield's hypothesis of neural assemblies forming consciousness, said Prof Pollard.

The team use an entirely new imaging method called functional electrical impedance tomography by evoked response (fEITER *), which enables high speed imaging and monitoring of electrical activity deep within the brain and is designed to enable researchers to measure brain function.

The new device was developed by a multidisciplinary team drawn from the Schools of Medicine and Electrical and Electronic Engineering at The University of Manchester (UK) led by Professor Hugh McCann and with support from a Wellcome Trust Translation Award.

The machine itself is a portable, light-weight monitor, which can fit on a small trolley. It has 32 electrodes that are fitted around the patient's head. A small, high-frequency electric current (too small to be felt or have any effect) is passed between two of the electrodes, and the voltages between other pairs of electrodes are measured in a process that takes less than one thousandth of a second.

An electronic scan is thus carried out and the machine does this whole procedure 100 times a second. By measuring the resistance to current flow (electrical impedance), a cross sectional image of the changing electrical conductivity within the brain is constructed. This is thought to reflect the amount of electrical activity in different parts of the brain. The speed of the response of fEITER is such that the evoked response of the brain to external stimuli, such as an anaesthetic drug, can be captured in rapid succession as different parts of the brain respond, thus tracking the brain's processing activity.

We have looked at 20 healthy volunteers and are now looking at 20 anaesthetised patients scheduled for surgery, said Prof Pollard. We are able to see 3-D images of the brain's conductivity change, and those where the patient is becoming anaesthetised are most interesting.

We have been able to see a real time loss of consciousness in anatomically distinct regions of the brain for the first time. We are currently working on trying to interpret the changes that we have observed. We still do not know exactly what happens within the brain as unconsciousness occurs, but this is another step in the direction of understanding the brain and its functions.

The team at Manchester is one of many worldwide teams investigating electrical impedance tomography (EIT), but this is its first application to anaesthesia. Prof Pollard said that a huge amount of research still needed to be done to fully understand the role EIT could play in medicine.

If its power can be harnessed, then it has the potential to make a huge impact on many areas of imaging in medicine. It should help us to better understand anaesthesia, sedation and unconsciousness, although its place in medicine is more likely to be in diagnosing changes to the brain that occur as a result of, for example, head injury, stroke and dementia.

The biggest hurdle is working out what we are seeing and exactly what it means, and this will be an ongoing challenge, he concluded.

UT Dallas' Moller receives teaching award

Fri, 20 May 2011 04:00:00 PST

( from http://www.rxpgnews.com ) Dr. Aage Moller of UT Dallas is known throughout the world for his innovative research on sensory systems and neural plasticity. But back at The University of Texas at Dallas, he's known to many students simply as a terrific teacher.

Moller received the President's Teaching Excellence Award for Tenure-Track Faculty during the annual Honors Convocation on May 13. He was selected from among more than 100 eligible faculty members who were nominated by undergraduate students. The award carries a stipend of $5,000.

Moller holds the Margaret Fonde Jonsson Endowed Chair in the School of Behavioral and Brain Sciences. He and his wife, Margareta, also are donors to UT Dallas, helping establish scholarships and professorships at the school.

Moller said he enjoys working with students and is pleased that his time in the classroom and labs helps move their education forward.

I am naturally greatly honored by this award, he said. I love teaching, and my students are great - I learn a lot from them. It is very rewarding to be able help young people get the best possible start in a professional or academic life.

While Moller is invited to lecture around the world on his research, he still derives a great deal of satisfaction from working side-by-side with students and sharing what he has learned during a long career.

He offers the following advice to young faculty members: Provide your very best in making the topic you teach interesting. Have respect for your students, and remember that we as teachers work for the students. They have paid dearly and suffered many sacrifices to get our help in learning the basis for a professional or academic life.

Moller received another honor recently, when he was chosen to present BBS' first Distinguished Lecture in Behavioral and Brain Sciences. Slated to be an annual event, this lecture will be the final talk in the school's annual colloquium series. He will present the lecture in April 2012.

The distinguished lecture is designed to recognize the careers of faculty members and to enable faculty members to hear the talks their colleagues regularly deliver to audiences around the world.

Moller said his lecture will focus on neural plasticity, a feature of the brain important for childhood development, new skill acquisition and recovery after strokes and other injuries. He recently published a new book, A New Epidemic: Harm in Health Care.

Among Moller's most important contributions to neuroscience is his development of methods to reduce the risk of serious complications from brain operations. The technique is used worldwide and known as intraoperative neurophysiological monitoring.

Dr. Bert Moore, dean of BBS, praised the teaching and research accomplishments of Moller.

These parallel honors reflect the contributions that Aage Moller makes as a scientist, scholar and instructor, he said. We are very proud of his winning the President's Teaching Award, and also the recognition that our most distinguished researchers are also some of our most esteemed classroom teachers.

Following trail of cell death in epilepsy patients to find ways to preserve brain health

Thu, 05 May 2011 04:00:00 PST

( from http://www.rxpgnews.com ) Scientists have known for years that seizures in patients with epilepsy cause progressive cell death in the brain. What they did not know was why this was happening.

That may change with a new line of research led by Professor Wilma Friedman of the Department of Biological Sciences at Rutgers University, Newark. The research is funded by a recently awarded, four-year, $2 million grant from the National Institutes of Health.

Researchers have identified a likely culprit in this post-seizure damage, and its name is P75, says Friedman, professor of cellular neurobiology. P75 is a receptor for a specific type of chemical in the brain called a growth factor. Growth factors can regulate the normal functions of a cell, or they can tell a cell to self-destruct.

When a growth factor called ProNGF binds to the P75 receptor on damaged nerve cells following a seizure, it causes them to die, Friedman says. Understanding this process can help researchers determine how to prevent cell death from happening.

This research has the potential not only to benefit people with epilepsy, but also those who suffer seizures as a consequence of traumatic brain injuries and strokes. In addition, it may shed some light on how to prevent cell death in degenerative conditions such as Alzheimer's disease.

Friedman and her team of Rutgers researchers are working in an ongoing collaboration with Barbara Hempstead, MD, Ph.D., at Weill Cornell Medical College in New York City. They have also recently developed a working relationship with Helen Scharfman, Ph.D., Nathan S. Kline Institute for Psychiatric Research, who is associated with New York University's Langone Medical Center.

A key to learning how the ProNGF growth factor works with the P75 receptor is following it through the brain after a seizure. Similar in concept to how the migration of birds is monitored with tagging, scientists will biologically tag the proNGF growth factor in mice. That will allow them to follow where the growth factor goes in the brain, what it does, and how it functions in the cell-death process. Once the process is better understood, researchers will test various molecules, already approved by the Federal Drug Administration, in hopes of finding one that blocks the P75 receptors and thereby prevents cell death.

Friedman has worked at the Department of Biological Sciences at Rutgers University, Newark, for nearly a decade. She has been involved in neurobiological research for more than 30 years at several prestigious institutions including Columbia University, the University of Medicine and Dentistry of New Jersey, Karolinska Institute in Sweden, and the Rockefeller University in New York. She is a graduate of The Rockefeller University (Ph.D.) and Oberlin College (B.A.).

I find research on the brain to be one of the most fascinating fields of scientific study, Friedman says. There's still so much we don't know and need to discover. It's a mystery that is constantly being unraveled bit by bit. The more we know about it, the more potential there is for the development of new therapeutic treatments. That's very exciting.

Early indications of Parkinson's disease revealed in dream sleep

Mon, 28 Mar 2011 04:00:00 PST

( from http://www.rxpgnews.com ) During a large-scale study of the socioeconomic costs of this neurodegenerative disease, Danish researchers, some from the University of Copenhagen, discovered that very early symptoms of Parkinson's disease may be revealed in dream or REM sleep.

Parkinson's disease is a brain disease best known for the trembling it causes. It is an incurable, chronic disease and gradually affects the muscles and mental capacity, seriously afflicting the lives if the patient and his or her immediate relatives.

In the study we saw that eight years before diagnosis, Parkinson's sufferers exhibited work and health indications that something was wrong, says Poul Jennum, professor of clinical neurophysiology at the Center for Healthy Ageing, University of Copenhagen, and the Sleep Centre at Glostrup Hospital.

Among the very early symptoms is the sleep disorder RBD, or REM sleep behaviour disorder. REM is a particular stage of sleep in which we dream, and our eyes flicker rapidly behind our eyelids, hence the term REM, or Rapid Eye Movement. To prevent us from actually acting out our dreams the body usually shuts down our muscle movement during REM sleep, but in RBD it is still active, and REM sleepers with RBD display a range of behaviours from simple arm and leg spasms to kicking, shouting, seizing or jumping out of bed.

In some cases their behaviour may be violent and result in injuries to the patients or their partners, Professor Jennum explains.

Our hypothesis is that the very earliest stages of Parkinson's disease show up as various other diseases such as RBD, Jennum says.

In recent years, great advances have been made in the treatment of Parkinson's disease, but we still do not have therapies to mitigate the later symptoms, costs and increased mortality of the disease.

This may become possible if we are able to intervene earlier, and if we are able to find clear indications of Parkinson's disease eight years sooner than we are now, this may give us an important tool. The question is of course whether we can actually say that RBD is always a very early marker for Parkinson's disease. That is what we are now investigating at the Sleep Centre at Glostrup Hospital, says Jennum.

Not surprisingly the study showed that Parkinson's sufferers are more often in contact with all sections of the health service, more often unemployed, more often on benefits, and on average cost the health service DKK 50,000 a year more than healthy control subjects.

For the study, researchers used the National Patient Register to identify all the patients diagnosed with Parkinson's disease between 1997 and 2007. 13,700 patients were compared to 53,600 healthy patients of the same sex, social class, educational background etc.

The study was carried out by researchers from the Center for Healthy Ageing, the Danish Center for Sleep Medicine, University of Copenhagen, Glostrup Hospital, Bispebjerg Hospital and the Danish Institute of Health Research, and was published in the

Miniature 'wearable' PET scanner ready for use

Sun, 13 Mar 2011 05:00:00 PST

( from http://www.rxpgnews.com ) UPTON, NY - Scientists from the U.S. Department of Energy's (DOE) Brookhaven National Laboratory, Stony Brook University, and collaborators have demonstrated the efficacy of a wearable, portable PET scanner they've developed for rats. The device will give neuroscientists a new tool for simultaneously studying brain function and behavior in fully awake, moving animals.

The researchers describe the tool and validation studies in the April 2011 issue of Nature Methods.

Positron emission tomography (PET) is a powerful tool for studying the molecular processes that occur in the brain, said Paul Vaska, head of PET physics at Brookhaven with a joint appointment at Stony Brook, who led the development of the portable scanner together with Brookhaven colleagues David Schlyer and Craig Woody. PET studies in animals at Brookhaven and elsewhere have helped to uncover the molecular underpinnings of conditions such as drug addiction.

But studying animals with PET has required general anesthesia or other methods to immobilize the animals. Immobilization and anesthesia make it impossible to simultaneously study neurochemistry and the animals' behavior - the actions resulting from what goes on in the brain, Schlyer said. Our approach was to eliminate the need for restraint by developing a PET scanner that would move with the animal, thus opening up the possibility of directly correlating the imaging data with behavioral data acquired at the same time.

After several years of development, the scientists have arrived at a design for a miniature, portable, donut-shaped PET scanner that can be worn like a collar on a rat's head for simultaneous studies of brain function and behavior. Weighing only 250 grams, the device - dubbed RatCAP, for Rat Conscious Animal PET - is counterbalanced by a system of springs and motion stabilizers to allow the animal significant freedom of movement. Measurements of the rats' stress hormones indicated only moderate and temporary increases.

Rats wearing the device appear to adapt well and move freely about their environment, Woody said.

To validate the use of the wearable scanner for simultaneous studies of brain function and behavior, the scientists conducted tests with 11C-raclopride, a commonly used PET radiotracer, which incorporates a radioactive, positron-emitting isotope of the element carbon. When the positrons interact with electrons in ordinary matter, they immediately annihilate one another, emitting back-to-back gamma rays. Detectors in the circular PET scanner pick up the signals from these back-to-back gamma rays to identify the location and concentration of the tracer in the body.

The tracer 11C-raclopride binds to receptors for dopamine, a brain chemical involved in movement, reward, and memory formation. A higher signal from the tracer means that less natural dopamine is in that particular part of the brain; a low signal indicates that that particular part of the brain has released dopamine (which binds to its receptors, thus blocking the tracer from binding).

The main test was to see if the wearable scanner could be used to correlate dopamine levels with behavior - in this case, the rats' activity (i.e., movement) within their chambers. Surprisingly the level of activity was inversely related to dopamine levels - that is, the more active the animals were, the lower the level of dopamine (as indicated by a stronger tracer signal).

This is perhaps a counterintuitive result because behavioral activation is typically associated with an increase in dopamine release, said Daniela Schulz, a Brookhaven behavioral neuroscientist and lead author of the paper. So our method provides data which may challenge traditional paradigms and ultimately improve our understanding of the dopamine system.

But regardless of the direction, the results clearly demonstrate that RatCAP can correlate brain function measurements with behavioral measures in a useful way, she said.

The scientists also present results comparing RatCAP-wearing rats moving freely about their cages with animals that had been anesthetized, as well as comparisons of two methods of administering the tracer - injecting it all at once and in a steady infusion to maintain a constant concentration in the blood.

These measurements will help us further refine the technique and aid in our assessment of results obtained with RatCAP in comparison with other study techniques, Schulz said.

The researchers' next step will be to use RatCAP to explore distinct behavioral expressions that can be correlated with simultaneously acquired PET data.

Genes of the immune system are associated with increased risk of mental illness

Mon, 07 Feb 2011 05:00:00 PST

( from http://www.rxpgnews.com ) Genes linked to the immune system can affect healthy people's personality traits as well as the risk of developing mental illness and suicidal behaviour, reveals a thesis from the University of Gothenburg, Sweden.

Inflammation is part of the immune system and is responsible for defending humans against infection as well as fascilitating the healing of injuries, and is therefore vital for our survival. Research has demonstrated that inflammatory processes also have other roles to play as inflammatory substances produced by the body influence mechanisms in the brain involving learning and memory.

Inflammatory substances produced in moderate quantities in the brain can be beneficial during the formation of new brain cells, for example. However, an increase in the levels of these substances as is the case during illness, can result in damage to the brain.

Previous studies have shown that individuals suffering from various mental illnesses have an increased peripheral inflammation, but the reason behind this increase is not known, says Petra Suchankova Karlsson, who wrote the thesis. It has been suggested that the stress that goes with mental illness activates the body's immune system, but it is also possible that inflammation in the body affects the brain, which in turn results in mental illness.

Previous studies have focused on how environmental and psychological factors affect the immune system's impact on the brain. Suchankova's thesis presents, for the first time, results that suggest that several different genes linked to the immune system are associated with healthy people's personality traits. It also demonstrates that some of these genes are associated with an increased risk of developing schizophrenia or suicidal behaviour.

One of the things we studied was a gene variant that increases impulsiveness in people who carry it, says Suchankova. We already knew that the risk of attempting suicide is higher in impulsive people and therefore analysed this gene variant in a group of patients who had attempted to take their life. We found that these patients more often carried the particular gene variant when compared to the general population which meant that this variant was not only associated with increased impulsiveness in healthy individuals but also with increased risk of suicidal behaviour.

The change in the levels of inflammatory substances in the blood of patients suffering from a mental illness as previously noted may have been caused by inflammation-related genes affecting the risk of mental illness, rather than the illness itself leading to a change in levels, as is traditionally believed.

It could well be that some variants of the genes play a role in the development of mental illness by controlling how the brain is formed, perhaps during the embryonic stage, or by affecting the transfer of signal substances, says Suchankova.

The results of this thesis support the proposed role of the immune system in mental illness, and could be used as a basis for further studies that, it is hoped, will lead to the development of new treatment methods.

The thesis has been successfully defended.

Academy of Science-St. Louis announces recipients of Outstanding St. Louis Scientist Awards

Thu, 13 Jan 2011 05:00:00 PST

( from http://www.rxpgnews.com ) ST. LOUIS, JANUARY 12, 2011: The 17th annual Academy of Science-St. Awards dinner, honoring top scientists and engineers from the St. Louis region, will be held at the Chase Park Plaza on April 13, 2011.

The academy's Peter H. Raven Lifetime Award recognizes local scientists with a distinguished career in science, engineering or technology. The 2011 prize goes to Marcus E. Raichle, MD, Professor of Radiology, Neurology, Neurobiology, BioMedical Engineering and Psychology at the Washington University School of Medicine. Dr. Raichle has an exceptional body of leading-edge research work inHuman cognitive neuroscience and neuroimaging.

Dr. Raichle has profoundly influenced biomedical science by discovering and then creatively applying methods of image human brain function. His PET studies in the late 1980's and early 1990's on language, attention and memory were the turning point for the field of human cognitive neuroscience.

Over the past three decades, Raichle and his colleagues have pioneered a revolution in brain science using noninvasive neuroimaging methods to study human brain function. His specific contributions include advances in the methodology of imaging and groundbreaking work in elucidating cognitive aspects of human brain function. The PET experiments of Raichle and his colleagues on the manner in which the brain processes single words is among the most emulated and cited studies in the functional neuroimaging literature. His impact is evident in myriad fields of study, including memory, emotion, personality differences, depression, anxiety and blindness.

The Science Leadership Award honors an individual or organization that has played an important leadership role in the development of science and scientists in the region. This year's honorees are Emerson and Timothy Eberlein, MD, Director of the Siteman Cancer Center at Barnes-Jewish Hospital.

An innovative technology leader, St. Louis-based Emerson has been recognized by FORTUNE as a Global 500 Company and one of the World's Most Admired Companies.

Thanks to strong global technological innovations, such as the modernization of 100 hydroelectric turbine generators in Ukraine; power inverters and plant-wide controls for what will be California's largest photovoltaic facility; climate technologies that preserve globally transported fruit and vegetables; and scroll compressor heating technology is now being used by major heat pump manufacturers in Asia.

Emerson is a global leader in bringing technology and engineering together to provide innovative solutions for customers in industrial, commercial, and consumer markets through its network power, process management, industrial automation, climate technologies, and appliance and tools businesses. With more than 500 new products per year, Emerson just ended 2010 with net sales of $21 billion.

Timothy Eberlein, MD is the Bixby Professor and Chairman of the Department of Surgery at Washington University School of Medicine. He also serves as the Olin Distinguished Professor and Director of the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University Medical Center. Dr. Eberlein serves as the Surgeon-in-Chief at Barnes-Jewish Hospital.

Dr. Eberlein was the founding Director of the Siteman Cancer Center, a NCI Comprehensive Cancer Center and member of the National Comprehensive Cancer Network. Under his leadership, the Center has become one of the largest clinical cancer centers in the country with integrated research programs involving all Departments of the School of Medicine, as well as the Schools of Engineering, Social Work and Arts and Sciences. The Center treats more than 40,000 cancer patients each year and just received a $23 million research grant from the NCI.

Eberlein has held a series of national leadership positions, currently serves as editor-in-chief of the Journal of the American College of Surgeons and is President-Elect of the American Surgical Association.

The James B. Eads Award for outstanding achievement in technology or engineering will be presented to Alexander Rubin, PhD, Senior Technical Fellow, Boeing Research and Technology, The Boeing Company, and Ettigounder (Samy) Ponnusamy, PhD, Principal Scientist, Sigma-Aldrich.

UIC Distinguished University Professor named AAAS Fellow

Tue, 11 Jan 2011 05:00:00 PST

( from http://www.rxpgnews.com ) Mark M. Rasenick, Distinguished University Professor in physiology and biophysics and psychiatry and founding director of the Neuroscience Program at the University of Illinois at Chicago College of Medicine, has been named a Fellow by the American Association for the Advancement of Science.

Election as a Fellow is an honor bestowed upon AAAS members by their peers.

Rasenick was cited for distinguished contributions advancing our understanding of neurotransmitter signaling and the biology of mood-disorders and for his and advocacy for science policy.

Mark has been a leader in the neuroscience efforts of the department and was instrumental in obtaining a neuroscience-oriented training grant and in making neuroscience a degree granting program, said R. John Solaro, Distinguished University Professor and head of physiology and biophysics at UIC. Rasenick pioneered the establishment of a role of cytoskeletal elements in G protein signaling, Solaro said, which is now widely recognized to be a significant element in signaling cascades.

In his study of G protein signaling and the interaction with structural proteins in the brain, Rasenick and his colleagues found evidence that a change in the location of this protein could serve as a biomarker for depression, suggesting molecular and cellular targets for antidepressant treatment. A biomarker could make it possible to identify patients with depression with a simple laboratory test and to determine whether therapy was providing a successful response.

Rasenick has worked to use science as a tool of diplomacy and outreach all over the world. During 1999 and 2000, Rasenick worked on the staff of the late Senator Edward M. Kennedy as a Robert Wood Johnson Fellow. In addition he serves on the advocacy committees of several scientific societies -- neuroscience, biochemistry and molecular biology, and neuropsychopharmacology.

Rasenick received his B.A. from Case Western Reserve University in biology and political science and a Ph.D. in developmental biology from Wesleyan University. After post-doctoral research at Yale Medical School, Rasenick joined the faculty of the UIC College of Medicine as an assistant professor in 1983. He was named Distinguished University Professor in 2006. In addition to his research and teaching, Rasenick worked to develop UIC's interdisciplinary graduate program in neuroscience, which he directs along with Simon Alford and Daniel Corcos.

The tradition of AAAS Fellows began in 1874. This year 503 Fellows were named for their scientifically or socially distinguished efforts to advance science or its applications. They will be honored Feb. 19 at the AAAS annual meeting in Washington.

The high price of sleep disorders

Fri, 17 Dec 2010 05:00:00 PST

( from http://www.rxpgnews.com ) Danish sleep researchers at the University of Copenhagen and the Danish Institute for Health Services Research have examined the socio-economic consequences of the sleep disorder hypersomnia in one of the largest studies of its kind. The sleep disorder has far-reaching consequences for both the individual and society as a whole.

Hypersomnia is characterised by excessive tiredness during the day. Patients who suffer from the disorder are extremely sleepy and need to take a nap several times a day. This can occur both at work, during a meal, in the middle of a conversation or behind the steering wheel.

- Hypersomnia is often a symptom of sleep disorders such as narcolepsy, sleep apnoea, restless leg syndrome, violent snoring and/or obesity-related breathing difficulties, explains Professor of Clinical Neurophysiology Poul Jennum from the Center for Healthy Aging at the University of Copenhagen. The professor also leads the Danish Center for Sleep Medicine at Glostrup Hospital, which each year treats patients from across the country.

- Previous studies have indicated that these sleep disturbances affect people's quality of life to a considerable degree both socially and economically. Our studies show that people who e.g. snore violently but especially those who suffer from sleep apnoea, narcolepsy and obesity-related breathing difficulties use the health services more frequently, take more medicine, and are more frequently unemployed. The more serious the sleep disorder the higher the socio-economic cost.

Each person who snores violently, suffers from narcolepsy or hypersomnia is calculated to cost Danish society an annual figure of EURO 10,223 and EURO 2190 respectively. The figures refer to the direct cost of frequent doctor's visits, hospital admissions or medicine expenses and indirect costs in the form of lost working hours. In addition to this, costs are also incurred in the form of state benefits. The researchers demonstrated that hypersomnia patients received state benefits more often than healthy subjects and took state subsidised medicine more frequently. The study has highlighted the high costs that have arisen, especially those born by society and which is largely due to frequent absence from the work force and lower incomes among the sick.

Our study is the first to show the actual socio-economic consequences of untreated hypersomnia, explains Poul Jennum and refers to the fact that last year he and his colleagues carried out a similar study on the socio-economic consequences of the sleep disorder, narcolepsy. Here they also found an increase in the intake of medication, a higher rate of hospital admissions, and 30% more unemployment when the disease went undiagnosed and untreated. There is, however, significant potential for better diagnosis and treatment.

We have gotten better in the last few years at diagnosing and treating hypersomnia and the underlying diseases, explains Poul Jennum. This can be a help to patients because we know that there are a lot of people who go around incredibly tired during the day who do suffer from hypersomnia, but have never been diagnosed or discovered the reason for their tiredness. The question is whether their tiredness is owing to narcolepsy or is the fact that they sleep badly at night owing to some other reason?

It's clear to us that those who suffer from hypersomnia are more often ill and where hypersomnia is chronic, the economic costs to society can be quite considerable. That's why it is essential that people with the disorder have access to a system of treatment - otherwise the illness can affect their education, ability to work and thus their economic circumstances and health.

Ion channel responsible for pain identified by UB neuroscientists

Fri, 17 Dec 2010 05:00:00 PST

( from http://www.rxpgnews.com ) BUFFALO, N.Y. -- University at Buffalo neuroscience researchers conducting basic research on ion channels have demonstrated a process that could have a profound therapeutic impact on pain.

Targeting these ion channels pharmacologically would offer effective pain relief without generating the side effects of typical painkilling drugs, according to their paper, published in a recent issue of The Journal of Neuroscience.

Pain is the most common symptom of injuries and diseases, and pain remains the primary reason a person visits the doctor, says Arin Bhattacharjee, PhD, UB assistant professor of pharmacology and toxicology in the School of Medicine and Biological Sciences, director of the Program in Neuroscience and senior author on the paper.

Fifty million Americans suffer from chronic pain, costing between $100-200 billion a year in medical expenses, lost wages and other costs, says Bhattacharjee. The need to understand pain mechanisms remains paramount for human health and for society.

Inflammatory pain can result from penetration wounds, burns, extreme cold, fractures, arthritis, autoimmune conditions, excessive stretching, infections and vasoconstriction.

There are efficacious treatments for inflammatory pain, such as corticosteroids and non-steroidal anti-inflammatory drugs, says Bhattacharjee, but the adverse side effects associated with these drugs limit their long-term use and compromise patient compliance. As a result, there is a great need to understand the cellular processes involved in inflammatory pain to create less toxic, less addictive, analgesic drugs.

Pain-responsive nerve cells, known as nociceptors, are electrical cells that normally respond to pain stimuli. Nociceptors then relay information to the central nervous system, indicating the location, nature and intensity of the ensuing pain. Nociceptors are sensitized during inflammation, their ionic properties are altered and their firing characteristics changes. This sensitization causes a state of hyperalgesia, or increased sensitivity to pain.

Merely touching the inflamed area can be very painful, notes Bhattacharjee. The ionic mechanisms that are chiefly responsible for this inflammatory-mediated change in nociceptive firing had not been clearly identified.

We were able to demonstrate that a certain class of potassium channels is removed from the surface of nociceptive cells during inflammatory signaling. The removal of these ion channels is linked to the hypersensitivity of these nerve cells. We demonstrated that reducing the expression of these channels by gene interference techniques produced a similar nociceptor hyperexcitability.

Bhattacharjee says his team plans to extend their ion channel trafficking studies to in vivo models, using peptide inhibitors to try to prevent the removal of the potassium channels from the surface of nociceptors during inflammation.

We expect to show that maintaining these channels at the surface during inflammation will be effective for pain relief. Successful completion of our studies will provide the impetus for direct human clinical trials.Megan O. Nuwer, PhD, and Kelly E. Picchione, PhD, both in the neuroscience program, are co-authors on the paper.

Laboratory studies show promise for new multiple sclerosis treatment

Thu, 18 Nov 2010 05:00:00 PST

( from http://www.rxpgnews.com ) Successfully treating and reversing the effects of multiple sclerosis, or MS, may one day be possible using a drug originally developed to treat chronic pain, according to Distinguished Professor Linda Watkins of the University of Colorado at Boulder.

Watkins and her colleagues in CU-Boulder's department of psychology and neuroscience discovered that a single injection of a compound called ATL313 -- an anti-inflammatory drug being developed to treat chronic pain -- stopped the progression of MS-caused paralysis in rats for weeks at a time.

Lisa Loram, a senior research associate who spearheaded the project in Watkins' laboratory, presented the findings at the Society for Neuroscience's annual meeting held in San Diego this week.

MS is an inflammatory disease where the body's immune system attacks a protective sheath called myelin that encompasses nerves in the spinal cord and brain. As the disease progresses, the myelin develops lesions, or scars, that cause permanent neurological problems.

What happens now with MS drugs is they slow or stop the progression of MS, but they don't treat it, Watkins said. They don't take people back to normal because the lesions caused by MS don't heal.

Watkins, Loram and their colleagues hope to use spinal cord and brain-imaging technology to extend their studies to determine if lesions are being healed in rats that received an ATL313 injection.

If we have a drug that is able to heal these lesions, this treatment could be a major breakthrough in how we treat the symptoms of MS in the future, she said.

The new findings were quite a surprise to Watkins. The team had originally wanted to look at the drug's potential in treating pain associated with MS, because about 70 to 80 percent of MS patients suffer from chronic pain that is not treatable.

What we had originally thought about this class of compounds is that they would calm down glial cells in the spinal cord because their pro-inflammatory activation is what causes pain, she said.

Under normal circumstances glial cells are thought to be like housekeepers in the nervous system, Watkins said, essentially cleaning up debris and providing support for neurons. Recent work by Watkins and others has shown that glial cells in the central nervous system also act as key players in pain enhancement by exciting neurons that transmit pain signals.

What's become evident is that glial cells have a Dr. Jekyll and Mr. Hyde personality, Watkins said. Under normal circumstances they do all these really good things for the neurons, but when they shift into the Mr. Hyde formation they release a whole host of chemicals that cause problems like neuropathic pain and other chronic pain conditions.

They discovered that ATL313 appears to reset the glial cells from an angry activated state to a calm anti-inflammatory state that may heal MS lesions.

Why estrogen makes you smarter

Wed, 17 Nov 2010 05:00:00 PST

( from http://www.rxpgnews.com ) CHICAGO --- Estrogen is an elixir for the brain, sharpening mental performance in humans and animals and showing promise as a treatment for disorders of the brain such as Alzheimer's disease and schizophrenia. But long-term estrogen therapy, once prescribed routinely for menopausal women, now is quite controversial because of research showing it increases the risk of cancer, heart disease and stroke.

Northwestern Medicine researchers have discovered how to reap the benefits of estrogen without the risk. Using a special compound, they flipped a switch that mimics the effect of estrogen on cortical brain cells. The scientists also found how estrogen physically works in brain cells to boost mental performance, which had not been known.

When scientists flipped the switch, technically known as activating an estrogen receptor, they witnessed a dramatic increase in the number of connections between brains cells, or neurons. Those connections, called dendritic spines, are tiny bridges that enable the brain cells to talk to each other.

We created more sites that could allow for more communication between the cells, said lead investigator Deepak Srivastava, research assistant professor in neuroscience at Northwestern University Feinberg School of Medicine. We are building more bridges so more information can go from one cell to another.

The findings will be presented Nov. 17 at Neuroscience 2010 in San Diego. Peter Penzes, associate professor of physiology and of psychiatry and behavioral sciences at the Feinberg School, is the senior investigator.

Previous research has shown an increase in dendritic spines improves mental performance in animals. In humans, people who have Alzheimer's disease or schizophrenia often have a decrease in these spines.

We think there is a strong link between the number of dendritic spines and your mental performance, Srivastava said. A major theory is if you increase the number of spines, it could be a way to treat these significant mental illnesses.

Northwestern scientists also found strong clues that estrogen can be produced in cortical brain cells. They identified aromatase, a critical protein needed to produce estrogen, to be in precisely the right spot in the brain cell to make more dendritic spines.

We've found that the machinery needed to make estrogen in these brain cells is near the dendritic spines, Srivastava said. It's exactly where it's needed. There's a lot of it in the right place at the right time.

Next, Srivastava said, he wants to further identify the key molecules involved in the dendritic spine production and target them in the same way as the estrogen receptor in order to ultimately be able to treat schizophrenia and other mental disorders.

Nick Brandon, head of psychiatry at Pfizer Inc., whose group collaborated with the Penzes lab for this work, added, We are very excited by the emerging data in this area. There is a great deal of literature and precedent for a role of estrogen and estrogen signaling in major mental illnesses. This adds to our understanding of the specific neuronal functions. As we understand the effects of these specific estrogen receptor beta compounds in preclinical models, we are discovering effects on specific neuronal functions, which could be relevant for the treatment of cognitive disorders, depression and schizophrenia.

Rett Syndrome research gets 'SMART' with Pepsi Challenge funding

Thu, 28 Oct 2010 04:00:00 PST

( from http://www.rxpgnews.com ) Cincinnati, OH - The International Rett Syndrome Foundation (IRSF) believes that accelerating the pace of meritorious research, supporting families, and raising awareness are the minimum effort necessary to successfully search for treatments and a cure for one of the most devastating neurological diseases to affect young girls. On October 1, IRSF became the recipient of a $250,000 grant from the Pepsi Refresh contest that was officially confirmed later in the month. The contest was a highly-publicized and competitive online grant program to benefit non-profit organizations. In March 2010, IRSF entered the challenge when Donna Wright contacted IRSF's Director of Family Support, Paige Nues, to discuss the competition on behalf of her granddaughter, Naomi, who suffers from Rett syndrome.

The Pepsi Challenge funds will be put to immediate use in part, to launch the Selected Molecular Agents for Rett Therapeutics (SMART) Initiative - a new Rett syndrome-specific drug development program. The SMART Initiative was the outcome of an intensive two day meeting convened in March, where IRSF brought together a blue ribbon panel of advisors to discuss the development of new medicines for reversing the symptoms of Rett syndrome. The panel drew on the expertise of leading clinicians and researchers working on Rett syndrome, experts drawn from the biotech and pharma industries together with advisors from the FDA and the NIH.

The SMART Initiative will be directed by two leading medicinal chemists: Professor Alan Kozikowski and Dr. Irina Gaisina at the University of Illinois, Chicago, in consultation with external advisors Drs. John McCall and Clark Eid--key participants at the March meeting. The new consortium's first task will be to assemble a collection of brain-specific drugs which target select biological mechanisms important in Rett syndrome. The research team in Chicago will select compounds on the basis of their mechanism of action, and their drug-like qualities. They will create an electronic database of all of the drugs that are procured or synthesized, and keep records ensuring their purity. The database will also obtain information on all drugs that are assayed. Rett researchers from around the globe will have access to the compound collection upon written request to facilitate studies of these selected agents.

Commenting on the SMART Initiative, Dr. Kozikowski said, In the first phase of this program, the consortium will be highly selective in choosing the most appropriate drugs for testing. As the identification of effective therapeutics requires a strong marriage between chemistry and biology, we believe that this initiative will help advance the development of new drugs for Rett syndrome. Dr. Kozikowski added, The chemistry group in Chicago is extremely grateful to the grass roots effort that played a key role in obtaining the Pepsi Challenge funding on behalf of IRSF.

Dr. McCall, said, Drug discovery is often driven by access to compounds that target specific mechanisms. The consortium will provide valuable tools allowing researchers to efficiently explore new approaches to treatment. We often talk about looking for keys under the street lamp - we intend to provide the street lamp, he added.

To win the Pepsi Refresh competition, IRSF launched an intensive grassroots effort, mobilizing thousands of volunteers who voted every day for four months until the Foundation was chosen as the winner on the eve of Rett Syndrome Awareness Month. Ms. Nues, whose daughter Katie has Rett syndrome, commented, The true win goes to our girls and women who wait patiently while our researchers work diligently for new treatments and an eventual cure for this devastating disease.

Experimental treatments for cocaine addiction may prevent relapse

Thu, 26 Aug 2010 04:00:00 PST

( from http://www.rxpgnews.com ) Doctors have used the drug disulfiram to help patients stay sober for several decades. It interferes with the body's ability to metabolize alcohol, giving a fierce hangover to someone who consumes even a small amount of alcohol.

More recently, disulfiram was shown to be effective in treating cocaine addiction as well, even though alcohol and cocaine affect the nervous system in different ways.

Now, researchers at Emory University School of Medicine have identified how disulfiram may exert its effects, and have shown that a newer drug with fewer side effects works by the same mechanism.

The results are published online this week by the journal Neuropsychopharmacology. Research assistant professor Jason Schroeder, PhD, and graduate student Debra Cooper are co-first authors of the paper, and the research also involved collaborations with P. Michael Iuvone, PhD, director of research at the Emory Eye Center, Gaylen Edwards, DVM, PhD, head of the department of physiology and pharmacology at the University of Georgia's College of Veterinary Medicine, and Philip Holmes, PhD, professor of psychology at the University of Georgia.

Disulfiram has several effects on the body: it interferes with alcohol metabolism, but it inhibits several other enzymes by sequestering copper, and can also damage the liver, says senior author David Weinshenker, PhD, associate professor of human genetics at Emory University School of Medicine. We wanted to figure out how disulfiram was working so we could come up with safer and potentially more effective treatments.

In treating cocaine addiction, there are several challenges: not only getting people to stop taking the drug, but also preventing relapse. Cocaine boosts the levels of several neurotransmitters, including dopamine and norepinephrine, at the junctions between nerve cells by blocking the machinery the brain uses to remove them.

Under normal conditions, dopamine is important for the sensation of pleasure produced by natural rewards such as food or sex, Weinshenker says. Cocaine hijacks the dopamine system, which plays a large role in addiction. Similarly, norepinephrine has a role in attention and arousal, but its overactivation can trigger stress responses and relapse, he says.

Weinshenker's team showed that disulfiram prevents rats from seeking cocaine after a break, a model for addicts tempted to relapse. At the same time, it doesn't stop them from taking cocaine when first exposed to it, or from enjoying their food.

Disulfiram appears to work by inhibiting dopamine beta-hydroxylase, an enzyme required for the production of norepinephrine. A dose of disulfiram that lowers the levels of norepinephrine in the brain by about 40 percent is effective, while doses that do not reduce norepinephrine have no effect on relapse-like behavior in rats.

To confirm that the beneficial effects of disulfiram were because of dopamine beta-hydroxylase inhibition, the researchers turned to a drug called nepicastat, which was originally developed for the treatment of congestive heart failure in the 1990s.

Nepicastat is a selective dopamine beta-hydroxylase inhibitor that does not sequester copper or impair a host of other enzymes like disulfiram, Weinshenker says. We reasoned that if disulfiram is really working through dopamine beta-hydroxylase, then nepicastat might be a better alternative.

Researchers at the University of Texas Medical Branch at Galveston have recently completed a Phase I safety trial studying nepicastat for the treatment of cocaine addiction in human subjects.

15 new US patents awarded this past year to NJIT researchers

Mon, 23 Aug 2010 04:00:00 PST

( from http://www.rxpgnews.com ) NJIT researchers were awarded 15 new U.S. patents this past year, increasing the total number of issued patents for NJIT to 97. More than 150 applications are in process. With projected research expenditures greater than $90 million for 2010-11, NJIT ranks as a leader in size and growth of research programs among technological universities. The patents were awarded from July 1, 2009-June 30, 2010. Specifics follow.

Yeheskel Bar-Ness, distinguished professor of electrical and computer engineering and Foundation Chair of the Center for Communication and Signal Processing Research, received a patent for Equal BER Power Control for Uplink MC-CDMA with MMSE Successive Interference Cancellation, a system designed to increase efficiency and reduce interference in wireless telecommunications.

Ken Chin, professor of physics, gained a patent for an Aligned Embossed Diaphragm Based Fiber Optic Sensor which can be used in optical, mechanical, pressure, temperature, chemical, biometric or acoustic sensing. One specific application is the detection of on-line acoustic signatures of sparking and arcing in a multitude of applications including: large electric utility transformers, auto-transformers, tap-changers, phase angle regulators, voltage regulators, reactors, circuit breakers, pipe-type high- voltage cables, and other oil insulated utilities.

Ivan Dentcho, research professor in biomedical engineering and director of the NJIT Microelectronics Fabrication Center, earned a patent in collaboration with Joseph R. Madsen, associate professor of neurosciences at Harvard Medical School, for a Waveform Sensing and Regulating Fluid Flow Valve that is used to drain excess cerebrospinal fluid from the brain in hydrocephalus patients.

Anthony East and Michael Jaffe, research professors of biomedical engineering, were awarded a patent for Thermoset Epoxy Polymers from Renewable Resources, a substance made from sugar derived from corn that can be used commercially in adhesives and coatings.

Reginald Farrow, research professor of physics, was awarded a patent for Method of Forming Nanotube Vertical Field Effect Transistor, a new technique to make nanoscale transistors that are oriented vertically from the surface of a silicon wafer.

Sergiu M. Gorun, associate professor of chemistry, was awarded a patent, Functional Coating Compositions of Perfluoroalkyl Perfluoro-Phthalocyanine Compounds, disclosing a new self-contained subclass of molecules. These new materials are comprised of organic scaffolds with metal centers, which can be applied as either an opaque or transparent hydrophobic coating.

Professors Yehoshua Perl and James Geller, of computer science, were awarded a patent for Intersection Ontologies for Organizing Data, a method for organizing sets of data into forms that are more easily usable.

Robert Pfeffer, professor emeritus of chemical engineering, gained patents for System and Method for Nanoparticle and Nanoagglomerate Fluidization, as well as a filter composed of nanoparticles, Fractal Structured Nanoagglomerates as Filter Media.

Nuggehalli Ravindra, professor of physics, received a patent for Method of Assembly Using of Programmable Magnets, a new technique for assembling integrated circuits.

Yun-Qing Shi, professor of electrical and computer engineering, received four patents for his work in data hiding. The patents included: Method For Identifying Marked Content, Such as By Using a Class-Wise Non-Principal Component Approach; System and Method for Data Hiding Using Inter-Word Space Modulation; System and Method for Robust Lossless Data Hiding and Recovering From the Integer Wavelet Representation; and System and Method for Reversible Data Hiding Based on Integer Wavelet Spread Spectrum.

Proof that a gut-wrenching complaint -- irritable bowel syndrome -- is not in your head

Thu, 19 Aug 2010 04:00:00 PST

( from http://www.rxpgnews.com ) Irritable bowel syndrome makes life miserable for those affected -- an estimated ten percent or more of the population. And what irritates many of them even more is that they often are labeled as hypochondriacs, since physical causes for irritable bowel syndrome have never been identified. Now, biologists at the Technische Universitaet Muenchen (TUM) have shed new light on the matter: They have discovered mini-inflammations in the mucosa of the gut, which upset the sensitive balance of the bowel and are accompanied by sensitization of the enteric nervous system.

Flatulence, constipation and diarrhea, nausea and stomach cramps: Irritable bowel syndrome (IBS) can turn digestion into a nightmare. Frequent visits to the bathroom are often accompanied by sleep disturbances, headaches, and backaches. In Germany alone, some seven million people are affected by the disorder -- and by the fact that their irritable bowel syndrome is often deemed psychosomatic. This is because the organic trigger of the disease has never been discovered, and consequently the various therapeutic interventions are disappointing for both the patients and their doctors. That may soon change, however, because now, for the first time, biologists in Munich have nailed down hidden physical causes of this bowel disorder.

Professor Michael Schemann's research team at the TUM Department for Human Biology has managed to demonstrate that micro-inflammations of the mucosa cause sensitization of the enteric nervous system, thereby causing irritable bowel syndrome. Using ultrafast optical measuring methods, the researchers were able to demonstrate that mediators from mast cells and enterochromaffin cells directly activate the nerve cells in the bowel. This hypersensitivity of the enteric nervous system upsets communication between the gut's mucosa and its nervous system, as project leader Prof. Schemann explains: The irritated mucosa releases increased amounts of neuroactive substances such as serotonin, histamine and protease. This cocktail produced by the body could be the real cause of the unpleasant IBS complaints.

The TUM researchers in human biology are blazing a trail as they follow this lead. Their current focus is to what extent nerve sensitization correlates with the severity of symptoms. Working with colleagues from Amsterdam, they have already substantiated the clinical relevance of their results: Irritable bowel symptoms improved after treatment with an antihistamine known for its immune-stabilizing effect in the treatment of allergic reactions such as hay fever. Thanks to funding from the German Research Foundation (DFG), the scientists are now investigating whether the improved symptoms are accompanied by a normalization of nerve activity.

Successful identification of the active components could enable the development of effective drugs to treat irritable bowel syndrome. Even now, though, the TUM team have made life easier for many IBS patients, in that they have shown that the chronic disorder does have physical causes and is not merely in their heads.

Virus 'explorers' probe inner workings of the brain

Mon, 28 Jun 2010 04:00:00 PST

( from http://www.rxpgnews.com ) Imagine an exceedingly complex circuit board. Wires often split -- seemingly at random -- and connect in strange and unexpected ways.

This is how Princeton University researchers developing a new method for studying brain connectivity see the brain.

Because of its intricate organization, figuring out the wiring diagram that explains how the billions of neurons in the brain are connected, and determining how they work together, remains a formidable task. But success in this endeavor could transform the field of neuroscience, offering a map toward increased knowledge of how the brain works, with implications for learning more about conditions ranging from depression and schizophrenia to Alzheimer's and Parkinson's disease.

Funded by a $993,000 National Institutes of Health Challenge Grant through the American Recovery and Reinvestment Act, Lynn Enquist, a professor in Princeton's Department of Molecular Biology and in the Princeton Neuroscience Institute, is leading an effort to use genetically engineered viruses as explorers that travel throughout the nervous system, tracing the connections between neurons and reporting on their activity along the way.

Over the years, the understanding of how cells in the brain are connected has been a major problem, said Enquist, Princeton's Henry L. Hillman Professor in Molecular Biology. How can this blob of tissue do everything? We're missing a lot of information about how the brain works.

The NIH-funded project hinges on the creation and use of a genetically engineered virus that causes neurons to produce colorful fluorescent proteins. As the virus spreads, it leaves a colorful path through the brain in its wake. Some of the engineered viruses are designed to make the neurons glow brightly when they are active, like an On Air sign in the brain.

These DNA-based technologies allow us to put little labels on neurons that tell who they are connected to, said team member Samuel Wang, an associate professor in the Department of Molecular Biology and in the Princeton Neuroscience Institute. It's as if you could immediately tell on Facebook the difference between 'friends' and 'friends of friends.' And when we add proteins that get brighter when neurons are active, now our little labels tell us not only where a neuron is, but what it is doing. Combined with microscopy, it's like seeing all your Facebook friends' status updates at once, in real time -- basically watching the whole conversation at once.

Chemicals exist that can be used to trace brain connectivity, including certain molecules from the horseradish plant and the cholera toxin, but they become increasingly dilute as they spread throughout the brain, just as a drop of food coloring disperses in a cup of water. Other chemicals can change brightness or color when a neuron is active, but they label all cells indiscriminately, leading to a murky image. Because viruses replicate, they are self-amplifying and do not become less concentrated as they move away from their entry point into the brain, making them a promising tool for researchers seeking to probe the hidden depths of the brain. Viruses also can target subsets of neurons, making them glow -- and therefore stand out -- in sharp relief. Enquist and his collaborators presently are conducting laboratory experiments in test tubes and mice as they seek to increase fundamental knowledge about neural connectivity, which has significant implications for understanding the human brain.

The Princeton-led team's virus of choice is pseudorabies virus (PRV), which normally infects pigs but can also attack a variety of other organisms, including chickens and rodents. PRV does not infect people, but it is a member of the alpha herpes virus family, which includes the viruses that cause chicken pox and cold sores in humans.

To make the virus capable of coloring brain cells as it infects them, team member Oren Kobiler, a postdoctoral research fellow in Enquist's lab, is incorporating into its genetic material a cell-marking technique known as Brainbow. The technology was developed at Harvard University by a research team led by Jean Livet, Joshua Sanes and Jeff Lichtman, and first reported in a 2007 issue of the journal Nature. Brainbow works by inserting into neurons three genes that direct the production of blue, green and red fluorescent proteins. There are some 90 possible hues that can be made from different combinations of the blue, green and red proteins, and the color of a given neuron is determined by the specific amount of each color being made by the cell.

The Brainbow technique also incorporates into neurons a genetic mechanism that randomly mixes and matches the genes that direct the production of the blue, green and red proteins. This shuffling system is activated by the presence of a protein called CRE, which causes neurons that produce CRE to turn different colors from other neurons around them.

By inserting Brainbow into a virus, the research team is hoping to design a viral tracer with capabilities that exceed conventional viral tracers being used today, he explained. Current tracers are able to map out entire circuits, but they cannot distinguish among different sections within a given circuit.

Enquist and his collaborators are using genetic engineering techniques to direct certain neurons, such as those that control a particular body function, to produce CRE. When the neurons that have been engineered to make CRE are infected by the new viral tracer, they will be different colors from infected neurons that are not making CRE. This will allow the researchers to see different subcircuits in the brain, Enquist explained.

For example, he is working with J. Patrick Card, a neuroscientist at the University of Pittsburgh, to make neurons in the brainstem involved in blood pressure regulation in mice produce CRE. When the mice are then infected with the Brainbow virus, the neural circuits that control blood pressure should be different colors from the rest of the circuits in the brain, he said.

For a minute, think of the brain like a car battery, Enquist said. The Brainbow virus will let us label all of the wires in the car that connect to the battery, but to label those that connect to the radio in a different color from the rest of the circuit.

In addition to the Brainbow technology, the research team is adding genetic instructions to the virus that tell cells to produce a special fluorescent protein that gets brighter in the presence of calcium, the levels of which rise inside neurons when they are sending signals. This technology, which is being refined in Wang's lab, will allow the researchers to mark neural circuits and watch them work, according to Enquist.

To continue the analogy, our viral tracer should not only label the wires to the radio in a different color, but also cause them to glow as power travels through them, he said.

Beyond using the Brainbow virus to study the structure and function of neural circuits in living mice, the researchers intend to investigate simple neural circuits built in the lab to understand how they function in a less complicated environment. Jason Puchalla, a faculty member in Princeton's physics department, is fabricating microfluidic devices on which the researchers will grow neurons and explore how they function. This will provide opportunities for the scientists to learn more about how alpha herpes viruses spread, which has implications for treatment of these infectious diseases. At the same time, increasing the fundamental understanding of how neurons connect to one another may generate new insights into neurological disorders, which can arise when normal neural circuitry is disturbed.

The Brainbow project is characteristic of Lynn Enquist's ability to see beyond the horizon and generate an experimental plan that merges, and advances, scientific disciplines, in this case virology and neuroscience, Card said. Successful completion of the experiments funded through this grant will represent a huge advance in the power of technology. The collaborative studies with Sam Wang are particularly important in that they not only define the synaptic organization of neural circuits but also promise to provide insights into the functional activity of the circuit under study. The novel insights into brain organization and function that are likely to emerge from those investigations cannot be overestimated.

SSRIs and cardiovascular health

Mon, 26 Apr 2010 04:00:00 PST

( from http://www.rxpgnews.com ) A class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) may provide a boost to cardiovascular health by affecting the way platelets, small cells in the blood involved in clotting, clump together, say researchers at the Loyola University Medical Center in Maywood, Ill.

In a study of 50 adults, the researchers found that platelets were slower to clump together, or aggregate, in participants who were taking an SSRI to treat depression. As depression is associated with an increased risk of cardiovascular disease, this finding could indicate a beneficial side effect for people who take SSRIs to treat depression, said Evangelos Litinas, MD, Research Associate in the Center's Pathology Department. Dr. Litinas will present the team's research at the American Physiological Society's annual Experimental Biology 2010 conference being held in Anaheim, CA from April 24-28.

SSRIs and Platelet FunctionSSRIs function to modulate the effect of serotonin in the brain. Neurotransmitters, like serotonin, are messages sent across the gap called the synapse between nerve cells in the brain. The cell sending the message, called the pre-synaptic cell, releases serotonin into the synapse. The serotonin is taken in by the receiving, post-synaptic cell, or be taken back by the pre-synaptic cell.

In a depressed patient, the post-synaptic cell doesn't take in enough serotonin and the message gets lost. To treat the depression, SSRIs decrease the ability of the pre-synaptic cell to reuptake the serotonin, leaving the message in the synapse longer and giving the post-synaptic cell a better chance of receiving the serotonin.

However, this blocking activity of SSRIs may have an effect on other cells in the body that require serotonin uptake. Small cells called platelets, which are involved in blood clotting, absorb serotonin only once and use it for their activation in response to injury.

When a blood vessel is injured in a healthy patient, their platelets are exposed to proteins that normally reside beneath the endothelium, the thin layer of cells lining blood vessel walls. These proteins activate the platelets and prompt them to send out finger-like projections that grab onto each other. This also activates the clotting system so that a clot will form at the wound site. This kind of platelet activation also occurs when blood vessel walls become inflamed in atherosclerosis (hardening of the arteries).

Once activated, the platelets release the contents of small packages that they carry called delta granules. These packages contain calcium, various energy-containing molecules, and serotonin. When the delta granules are released by activated platelets, the serotonin and other molecules work in the injured area to amplify the coagulation response.

However, Dr. Litinas and his team believe that in depressed patients who have an associated risk of cardiovascular problems, the blocking activity of SSRIs may have a side-effect of preventing the serotonin uptake by platelets, making them less responsive to aggregation and may thereby improving the patients' cardiovascular health.

To test their hypothesis, the researchers recruited 50 volunteers, 25 who were healthy and were not taking antidepressant medications and 25 who were being treated for depression with an SSRI. The team collected blood samples from each volunteer at the beginning of the protocol and again at the study's fourth week and eighth week. After each round of blood-drawing, the team separated the blood into its components to obtain the platelet-rich plasma for study.

The researchers then treated all of the samples with platelet-activating substances and with saline, which does not activate platelets. They observed platelet activity and quantified the amount of aggregation in each sample by using an aggregometer, a machine that aims light into liquid samples. Cells that do not aggregate tend to prevent light from getting all the way through a sample to the other side, whereas cells that aggregate form large clusters that sink down out of the way, allowing the light to shine through.

When the platelets from healthy volunteers were treated with platelet-activating substances at the 4-week time point, 95% of the cells aggregated. In contrast, the platelets of participants taking an SSRI showed only 37% aggregation, indicating that the SSRI had somehow inhibited or changed the platelets' ability to clump together.

As the study progressed, the researchers noticed something peculiar: The platelets taken from SSRI-treated patients at the 8-week mark aggregated more than those drawn at the 4-week mark. This suggested that SSRIs have the greatest impact on preventing platelet activation early on in treatment. Dr. Litinas and his team believe this may be because the body takes several weeks to start modulating SSRIs in the body. The team has extended the study to include samples drawn at the 12-week mark. They will also conduct a study using another brand of SSRI.

The reason we're doing this is to better the lives of depressed patients, said Dr. Litinas. There is clear evidence that depressed patients have a higher risk of cardiovascular disease, and we want to eliminate that. Since depression can be treated with an SSRI, maybe the cardiovascular disease risk can also be decreased. We want our patients to live longer and happier lives, without depression or the risk of heart problems.

Dr. Litinas' colleagues for this study are Dr. Jawed Fareed and Dr. Omer Iqbal, both of whom are affiliated with the Department of Pathology, Loyola University Medical Center, Maywood, IL; and Erin Tobin, Dr. John Piletz, Dr. Edwin Meresh, and Dr. Angelos Halaris, all of the Department of Psychiatry, Loyola University Medical Center.

Neurons growing in line

Thu, 15 Apr 2010 04:00:00 PST

( from http://www.rxpgnews.com ) In order to be able to understand complex organs such as the brain or the nervous system, simplified model systems are required. A group of scientists led by the Frankfurt brain researcher Erin Schuman has successfully developed a novel method to grow cultured neurons in order to investigate basic mechanisms of memory. The researchers grew two separate populations of neurons in microfluidic platforms. These neurons extended their processes through tiny grooves, to meet each other and form synaptic connections. Perpendicular to the grooves, a perfusion channel was constructed that allows the researchers to manipulate very small populations of synapses with drugs or neurotransmitters. The chambers are amenable to imaging, allowing researchers to visualize the dynamics of synapses, the movement of molecules within the neurons.

Studying cultured neurons makes it possible to reduce the complex three-dimensional network in living organisms to two dimensions. However, even in the laboratory, cell growth is totally disorganized, which makes a systematic study difficult. Neurons consist of a nucleus whose signals are transmitted to adjacent cells through a long extension (axon). Shorter extensions (dendrites) absorb the incoming signals. While the stimulus transfer along the axon and dendrites occurs electrically, the contact points between two neurons, the synapses, are bridged by biochemical signals. To understand how synapses are formed and which neurotransmitters play a part in their formation is not only an interesting topic for brain research, but may also aid the development of new pharmaceutical agents.

After demonstrating that functional synapses were formed in the approximately 150 microgrooves of the chamber, the brain researchers developed the device further in order to be able to stimulate the synapses directly. Here, they made use of the fact that cultured dendrites have a characteristic length so that the contact points with the axons of the neighboring cell populations could develop in about the same compartment of the microgrooves. There, the group implemented another small perfusion channel pervading the relevant area perpendicular to the neuronal channels. This supply channel enables a direct manipulation of the synapses via solute substances.

A further refinement of the test arrangement was reached by restricting the biochemically effective fluid in the supply channel from infiltrating the channels containing the nerve fibers. Schuman and her collaborators managed to do so by letting in a solution on both sides of the main stream shielding the main stream. The three parallel fluid streams have the additional advantage that the perfusate may be exactly dosed by varying the width of the middle stream.

Besides, the amount of the perfusate is also subject to increased temporal control: The supply can be turned on and off within one minute. It is thus possible to imitate the short duration signals that are the language of the nervous system.

Erin Schuman who relocated several months ago from the renowned California Institute of Technology (Caltech) to the Max Planck Institute for Brain Research in Frankfurt is interested in the function of synapses in the context of memory. How do synapses change during the storage of memory? And what happens during these processes at the molecular and cellular level? Years ago, her group discovered that dendrites can make the proteins required to change the functional capacity of synapses. The nucleus transcribes the required information as messenger RNA (mRNA), which is then sent out to the dendrites. When certain signals arrive, the dendrites translate the mRNA into protein using ribosomes present in the dendrite.

Frankfurt is not only appealing to the native-born Californian because of the possibility to run the Max Planck Institute for Brain Research together with her husband, brain researcher Gilles Laurent (the other director is Wolf Singer). The cooperation with scientists of the excellence cluster Macromolecular Complexes at Goethe University with which Schuman is associated as Principle Investigator also promises many interesting collaborations, for example with the Paul-Ehrlich-Young Academics awardee Amparo Acker-Palmer or with the Heisenberg-Professor Alexander Gottschalk. With respect to the new building of the MPI for Brain Research, the mother of two daughters at the age of ten and seven already has a plan: Many employees of the institute have children who come into contact with science already at an early age through their parents. We also want to make the new institute family-friendly. We hope to organize Science Saturdays for our kids to see how exciting it is to explore something on their own.

New studies reveal that age-related nerve decline is associated with inflammation, differs by gender

Wed, 14 Apr 2010 04:00:00 PST

( from http://www.rxpgnews.com ) New research investigating neurological decline in a population of super healthy elderly subjects found that the decline in neurological function of the peripheral nervous system attributed to aging may be related to metabolic factors, such as blood sugar levels, even if these factors are within the normal range.

In a related study of peripheral nerve function, the same group found that aging affects the nerves of men more than women later in life.

The findings imply, the researchers say, that age-related declines in peripheral nerve function may not be the consequence of the aging process alone but instead the consequence of aging, gender, plus metabolic factors that may be modifiable. The peripheral nerves are the nerves in the limbs that connect to the central nervous system (brain and spinal cord).

Outcomes from the two studies were presented today by UCSF researchers during the annual American Academy of Neurology scientific meeting in Toronto.

Reduced sensation from a decline of nerve function may contribute to overall morbidity and reduced quality of life in the elderly, said Ari Green, MD, co-lead investigator, assistant director of UCSF's Multiple Sclerosis Center and director of the Neurodiagnostics Center. The medical community considers this decline a consequence of aging. Our findings suggest that low levels of inflammation and impairment in glucose metabolism may accelerate the decline of nerve function.

Both studies involved a unique population of healthy elderly individuals between the ages of 65-90 called the Myelin and Aging Cohort. As part of this work, subjects underwent extensive neurological, laboratory and physical testing, and had to be free of any major chronic illnesses such as diabetes, hypertension, cognitive impairment, neuropathy and cardiovascular disease. For this project, researchers focused on the results from peripheral nerve conduction studies and laboratory findings.

We know that the function of peripheral nerves declines with age but wondered whether other biologic processes were at play and if we could eventually predict this decline, said John W. Engstrom, MD, co-lead investigator and clinical chief of the UCSF Neurology Service. These findings provide an opportunity to identify risk factors for the decline in peripheral nerve function.

In the first study, the team assessed conduction velocity, or the speed at which information traveled along peripheral nerves using nerve conduction studies. They found an association between age and slower nerve conduction in elderly men only.

Everyone ages differently; there are different levels of normal, said co-investigator Chris Songster, a specialist in the UCSF Department of Neurology. We want to understand if there are modifiable risk factors that, if addressed, could help people age well.

In the second study, the research team measured blood levels for highly sensitive C-reactive protein (hs-CRP) and hemoglobin A1c, which are standard tests for diabetes and systemic inflammation. Using the same conduction studies but evaluating the amplitude of the response to an electrical stimulus rather than its speed, the researchers found decline even in subjects with mild elevations in hs-CRP and hemoglobin A1c. The subjects' levels were within the normal, non-diabetic range for those measures.

Even within 'normal ranges' for measures of inflammation and glucose metabolism, we are seeing an accelerated aging process that could contribute to progressive neuropathy, said Green. These findings suggest that age, mild inflammation and mildly impaired glucose metabolism may be bad for nerve cells. Perhaps in the future, we can investigate whether a therapeutic intervention could delay the effect of age on peripheral nerve function. This may just be the tip of the iceberg. We have a lot to learn from this study population.

Both studies are important elements of a broad UCSF effort to learn how nerves age, developed in a groundbreaking collaboration between the UCSF Memory and Aging Center (Drs. Bruce Miller and Joel Kramer), the UCSF Multiple Sclerosis Center (Drs. Stephen Hauser, Ari Green and Jorge Oksenberg) and the UCSF Nerve Injury Clinic (Drs. John Engstrom and Amy Lee). The work was developed in advance of these groups moving together to the new Neurosciences Laboratory and Clinical Research Building at Mission Bay. Laboratory measures were performed in collaboration with the UC Davis Department of Pathology (Drs. Ralph Green and Josh Miller).

The UCSF team is looking at many factors related to how aging effects the connections between nerves and plans many future research studies with this population.

An important next step is to test whether modification of risk factors like inflammation has an impact on nerve function, Green said.

Depression associated with sustained brain signals

Tue, 06 Apr 2010 04:00:00 PST

( from http://www.rxpgnews.com ) Depression and schizophrenia can be triggered by environmental stimuli and often occur in response to stressful life events. However, some people have a higher predisposition to develop these diseases, which highlights a role for genetics in determining a person's disease risk. A high number of people with depression have a genetic change that alters a protein that cells use to talk to each other in the brain. Imaging of people with depression also shows that they have greater activity in some areas of their brain. Unfortunately, the techniques that are currently available have not been able to determine why stress induces pathological changes for some people and how their genetics contribute to disease.

A new mouse model may provide some clues about what makes some people more likely to develop depression after experiencing stress. A collaborative group of European researchers created a mouse that carries a genetic change associated with depression in people. This model has good validity for understanding depression in the human, in particularly in cases of stress-induced depression, which is a fairly widespread phenomenon says Dr. Alessandro Bartolomucci, the first author of the research published in the journal, Disease Models and Mechanisms (DMM).

The scientists made genetic changes in the transporter that moves a signaling protein, serotonin, out of the communication space between neurons in the brain. The changes they made are reminiscent of the genetic changes found in people who have a high risk of developing depression.

There is a clear relationship between a short form of the serotonin transporter and a very high vulnerability to develop clinical depression when people are exposed to increasing levels of stressful life events. says Dr. Bartolomucci, This is one of the first studies performed in mice that only have about 50% of the normal activity of the transporter relative to normal mice, which is exactly the situation that is present in humans with high vulnerability to depression.

Mice with the genetic change were more likely to develop characteristics of depression and social anxiety, which researchers measure by their degree of activity and their response to meeting new mice. The work from this study now allows researchers to link the genetic changes that are present in humans with decreased serotonin turnover in the brain. It suggests that the genetic mutation impedes the removal of signaling protein from communication areas in the brain, which may result in an exaggerated response to stress.

Dr. Bartolomucci points out that many of the chemical changes they measured occurred in the areas of the brain that regulate memory formation, emotional responses to stimuli and social interactions, which might be expected. What we were surprised by was the magnitude of vulnerability that we observed in mice with the genetic mutation and the selectivity of its effects.

UC Berkeley social scientists build case for 'survival of the kindest'

Tue, 08 Dec 2009 05:00:00 PST

( from http://www.rxpgnews.com ) Researchers at UC Berkeley are challenging long-held beliefs that human beings are wired to be selfish. In a wide range of studies, social scientists are amassing a growing body of evidence to show we are evolving to become more compassionate and collaborative in our quest to survive and thrive.

In contrast to every man for himself interpretations of Charles Darwin's theory of evolution by natural selection, Dacher Keltner, a UC Berkeley psychologist and author of Born to be Good: The Science of a Meaningful Life, and his fellow social scientists are building the case that humans are successful as a species precisely because of our nurturing, altruistic and compassionate traits.

They call it survival of the kindest.

Because of our very vulnerable offspring, the fundamental task for human survival and gene replication is to take care of others, said Keltner, co-director of UC Berkeley's Greater Good Science Center. Human beings have survived as a species because we have evolved the capacities to care for those in need and to cooperate. As Darwin long ago surmised, sympathy is our strongest instinct.

Keltner's team is looking into how the human capacity to care and cooperate is wired into particular regions of the brain and nervous system. One recent study found compelling evidence that many of us are genetically predisposed to be empathetic.

The study, led by UC Berkeley graduate student Laura Saslow and Sarina Rodrigues of Oregon State University, found that people with a particular variation of the oxytocin gene receptor are more adept at reading the emotional state of others, and get less stressed out under tense circumstances.

Informally known as the cuddle hormone, oxytocin is secreted into the bloodstream and the brain, where it promotes social interaction, nurturing and romantic love, among other functions.

The tendency to be more empathetic may be influenced by a single gene, Rodrigues said.

While studies show that bonding and making social connections can make for a healthier, more meaningful life, the larger question some UC Berkeley researchers are asking is, How do these traits ensure our survival and raise our status among our peers?

One answer, according to UC Berkeley social psychologist and sociologist Robb Willer, is that the more generous we are, the more respect and influence we wield. In one recent study, Willer and his team gave participants each a modest amount of cash and directed them to play games of varying complexity that would benefit the public good. The results, published in the journal American Sociological Review, showed that participants who acted more generously received more gifts, respect and cooperation from their peers and wielded more influence over them.

The findings suggest that anyone who acts only in his or her narrow self-interest will be shunned, disrespected, even hated, Willer said. But those who behave generously with others are held in high esteem by their peers and thus rise in status.

Given how much is to be gained through generosity, social scientists increasingly wonder less why people are ever generous and more why they are ever selfish, he added.

Such results validate the findings of such positive psychology pioneers as Martin Seligman, a professor at the University of Pennsylvania whose research in the early 1990s shifted away from mental illness and dysfunction, delving instead into the mysteries of human resilience and optimism.

While much of the positive psychology being studied around the nation is focused on personal fulfillment and happiness, UC Berkeley researchers have narrowed their investigation into how it contributes to the greater societal good.

One outcome is the campus's Greater Good Science Center, a West Coast magnet for research on gratitude, compassion, altruism, awe and positive parenting, whose benefactors include the Metanexus Institute, Tom and Ruth Ann Hornaday and the Quality of Life Foundation.

Christine Carter, executive director of the Greater Good Science Center, is creator of the Science for Raising Happy Kids Web site, whose goal, among other things, is to assist in and promote the rearing of emotionally literate children. Carter translates rigorous research into practical parenting advice. She says many parents are turning away from materialistic or competitive activities, and rethinking what will bring their families true happiness and well-being.

I've found that parents who start consciously cultivating gratitude and generosity in their children quickly see how much happier and more resilient their children become, said Carter, author of Raising Happiness: 10 Simple Steps for More Joyful Kids and Happier Parents which will be in bookstores in February 2010. What is often surprising to parents is how much happier they themselves also become.

As for college-goers, UC Berkeley psychologist Rodolfo Mendoza-Denton has found that cross-racial and cross-ethnic friendships can improve the social and academic experience on campuses. In one set of findings, published in the Journal of Personality and Social Psychology, he found that the cortisol levels of both white and Latino students dropped as they got to know each over a series of one-on-one get-togethers. Cortisol is a hormone triggered by stress and anxiety.

Meanwhile, in their investigation of the neurobiological roots of positive emotions, Keltner and his team are zeroing in on the aforementioned oxytocin as well as the vagus nerve, a uniquely mammalian system that connects to all the body's organs and regulates heart rate and breathing.

Both the vagus nerve and oxytocin play a role in communicating and calming. In one UC Berkeley study, for example, two people separated by a barrier took turns trying to communicate emotions to one another by touching one other through a hole in the barrier. For the most part, participants were able to successfully communicate sympathy, love and gratitude and even assuage major anxiety.

Researchers were able to see from activity in the threat response region of the brain that many of the female participants grew anxious as they waited to be touched. However, as soon as they felt a sympathetic touch, the vagus nerve was activated and oxytocin was released, calming them immediately.

Sympathy is indeed wired into our brains and bodies; and it spreads from one person to another through touch, Keltner said.

The same goes for smaller mammals. UC Berkeley psychologist Darlene Francis and Michael Meaney, a professor of biological psychiatry and neurology at McGill University, found that rat pups whose mothers licked, groomed and generally nurtured them showed reduced levels of stress hormones, including cortisol, and had generally more robust immune systems.

Overall, these and other findings at UC Berkeley challenge the assumption that nice guys finish last, and instead support the hypothesis that humans, if adequately nurtured and supported, tend to err on the side of compassion.

This new science of altruism and the physiological underpinnings of compassion is finally catching up with Darwin's observations nearly 130 years ago, that sympathy is our strongest instinct, Keltner said.

Life and death in the living brain

Mon, 10 Aug 2009 04:00:00 PST

( from http://www.rxpgnews.com ) Like clockwork, brain regions in many songbird species expand and shrink seasonally in response to hormones. Now, for the first time, University of Washington neurobiologists have interrupted this natural annual remodeling of the brain and have shown that there is a direct link between the death of old neurons and their replacement by newly born ones in a living vertebrate.

The scientists introduced a chemical into one side of sparrow brains in an area that helps control singing behavior to halt apoptosis, a cell suicide program. Twenty days after introduction of the hormones the researchers found that there were 48 percent fewer new neurons than there were in the side of the brain that did not receive the cell suicide inhibitor.

This is the first demonstration that if you decrease apoptosis you also decrease the number of new brain cells in a live animal. The next step is to understand this process at the molecular level, said Eliot Brenowitz, a UW professor of psychology and biology and co-author of a new study. His co-author is Christopher Thompson, who earned his doctorate at the UW and is now at the Free University of Berlin.

The seasonal hormonal drop in birds may mimic what is an age-related drop in human hormone levels. Here we have a bird model that is natural and maybe similar genes have a similar function in humans with degenerative diseases such as Alzheimer's and Parkinson's, as well as strokes, which are associated with neuron death.

The research involved Gambel's white-crowned sparrows, a songbird subspecies that winters in California and migrates to Alaska in the spring and summer to breed and raise its young. The sparrow's brain regions, including one called the HVC, which control learned song behavior in males, expand and shrink seasonally. Thompson and Brenowitz previously found that neurons in the HVC begin dying within four days hours after the steroid hormone testosterone is withdrawn from the bird's brains. Thousands of neurons died over this time.

In the new work, the UW researchers received federal and state permission to capture 10 of the sparrows in Eastern Washington at the end of the breeding season. After housing the birds for three months, they castrated the sparrows and then artificially brought them to breeding condition by implanting testosterone and housing them under the same long-day lighting conditions that they would naturally be exposed to in Alaska. This induced full growth of the song control system in the birds' brains.

Next the researchers transitioned the birds to a non-breeding condition by reducing the amount of light they were exposed to and removing the implanted testosterone. They infused the HVC on one side of the brain with chemicals, called caspase inhibitors, that block apoptosis, and two chemical markers that highlight mature and new neurons. Twenty days later the birds were euthanized and sections of their brains were examined under a microscope.

These procedures were done with the approval of the UW's Institutional Animal Care and Use Committee and the National Institute of Mental Health. The latter funded the research.

The HVC straddles both hemispheres of the brain but the two sides are not directly connected. When Thompson counted the number of newly born neurons that had migrated to the HVC, he found only several hundred of them among the hundreds of thousands of mature neurons he examined. And there were nearly half the number of new neurons in the side of the HVC where brain cell death was inhibited compared with the other, untreated side of the HVC. This shows there is some direct link between the death of old neurons and the addition of new cells that were born elsewhere in the brain and have migrated, said Brenowitz. What allows new cells to be incorporated into the brain is the big question. This is particularly true on a molecular level where we want to know what is the connection between cell death and neurogenesis and which genes are responsible.

UnMASCing diseases of the brain

Tue, 19 May 2009 04:00:00 PST

( from http://www.rxpgnews.com ) Scientists at the Wellcome Trust Sanger Institute have discovered a set of brain proteins responsible for some of the most common and devastating brain diseases. The proteins underlie epilepsy, depression, schizophrenia, bipolar disease, mental retardation and neurodegenerative diseases including Alzheimer's and Huntington's diseases.

The reason such a remarkable number of diseases are relevant to this set of proteins is that these proteins are at the heart of how brain cells function, explains Professor Seth Grant, Director of the Genes to Cognition Programme at the Wellcome Trust Sanger Institute.

Rather than taking traditional methods for studying just one protein at a time, the researchers developed a method that finds whole sets of proteins that bind to each other and form microscopic molecular machines. They were hunting for the 'engine room' of nerve cells, which is known to be inside the connections between nerve cells called synapses.

Synapses join the billions of nerve cells together in the brain and they are the location where learning and memory and many other behaviours are controlled.

We developed a new method, which led to this discovery, says Dr Jyoti Choudhary, leader of the Proteomic Mass Spectrometry team, which collaborated with Professor Grant's team on the study, and it should be equally useful in finding the basis of many other diseases in other cells and tissues of the body.

To find this key set of proteins - called MASCs (a scientific acronym for MAGUK Associated Signaling Complexes and pronounced 'mask') - the researchers adapted a method that had previously been used in yeast cells.

The method involved making a 'molecular hook' and attaching it to one protein inside brain cells of mice. They then caught the hook and pulled it out and found it brought along another 100 proteins. The set contained dozens of disease causing proteins.

This points to the new concept that the molecular machines are defective in the diseases and that they present new ways to approach therapy, says Dr Choudhary.

Not only were there many disease proteins within the molecular machines but also proteins that control the communication between nerve cells and the mechanisms of learning and memory.

This research is an important convergence of basic and clinical science, says Professor Grant. Our findings are exciting because they suggest that the molecular machine itself is at the root of many important brain diseases. This was a blue-skies research project seeking the basic mechanisms of learning and memory and it has led us into some of the inner workings of the brain.

This is a key step toward new ways to fight mental illness.

New therapy based on magnetic stimulation shows promise for non-drug treatment for migraine

Wed, 29 Apr 2009 04:00:00 PST

( from http://www.rxpgnews.com ) A new UCSF study examining the mechanism of a novel therapy that uses magnetic pulses to treat chronic migraine sufferers showed the treatment to be a promising alternative to medication.

The therapy is called transcranial magnetic stimulation, or TMS. Study findings were presented today (April 29, 2009) during the annual American Academy of Neurology scientific meeting in Seattle.

In a previous randomized controlled clinical study by Ohio State University Medical Center, TMS was used to treat patients who suffer from migraine with aura, a condition in which a variety of mostly visual sensations come before or accompany the pain of a migraine attack. The study showed that TMS treatment was superior to the placebo given to the control group. Patients were pain-free at follow-up intervals of 2, 24 and 48 hours.

In the new study, conducted in rats, UCSF researchers focused on understanding the mechanism of action of TMS therapy -- how the treatment interacted with the brain to produce the pain-free outcomes of patients in the previous study.

The UCSF research identified potential opportunities to enhance treatment strategies in patients. One example, the study team noted, was that factors such as time and peak intensity of stimulation may be important components in the brain's response to TMS.

The data demonstrate a biological rationale for the use of TMS to treat migraine aura, said Peter Goadsby, MD, PhD, lead investigator of the study, professor and director of the UCSF Headache Center. We found that cortical spreading depression, known as CSD and the animal correlate of migraine aura, was susceptible to TMS therapy, with the wave of neuronal excitation blocked on over 50 percent of occasions.

The study findings showed that migraine aura responds to magnetic stimulation because TMS therapy blocks the wave of neuronal excitation, which is a biological system through which neurons become stimulated to fire. TMS creates a focused magnetic pulse that passes noninvasively through the skull, inducing an electric current to disrupt the abnormal brain waves believed to be associated with migraine, including CSD. CSD in humans precedes migraine with aura.

The American Academy of Neurology estimates that over 30 million Americans suffer from migraine, a syndrome characterized by recurrent, often excruciating headaches. The National Headache Foundation estimates that migraine causes 157 million lost workdays each year due to pain and associated migraine symptoms, resulting in a $13 billion burden to American employers.

Further research is needed, the UCSF team said, but the findings give neurologists a potential new treatment option for migraine sufferers unable to tolerate medication, which can cause stomach bleeding and other painful side effects.

USC partners with French drug discovery company on computer modeling effort

Fri, 24 Apr 2009 04:00:00 PST

( from http://www.rxpgnews.com ) A single neurotransmitter, the amino acid L-glutamate, regulates countless biological systems in animals ranging from worms and insects to human beings.

But even though scientists have known for decades that glutamate functions as a neurotransmitter, and have found that numerous diseases, including possibly schizophrenia, are linked to glutamatergic transmission malfunctions, no drugs to treat these malfunctions yet exist, despite intense efforts.

Researchers on an interdisciplinary private-academic study hope to learn enough to change this situation by using large-scale computer modeling to predict synergistic interactions within glutamate systems that might be targets for new drugs.

Two University of Southern California faculty members and the drug discovery company Rhenovia Pharma of Mulhouse, France, have been awarded a Biomedical Research Partnership (BRP) by NINDS of the NIH.

Michel Baudry, a professor in the USC department of biological sciences is the PI of the project. Theodore Berger, from the USC Vtierbi School's department of biomedical engineering is the Co-PI. They will work with Dr. Serge Bischoff, the CEO of Rhenovia Pharma.

Successful funding of this proposal is a notable achievement in the sense of the uniqueness of the structure of the research team, and in terms of the novelty of the scientific approach, says Baudry. The grant will support joint research by the three partners for four years, with the total amount of funding reaching $2.3M.

Berger says the research effort is to develop a new technology of mathematical modeling and computer simulation tools to systematically explore molecular processes underlying glutamatergic synaptic transmission, and the effects of those synaptic processes on multi-synaptic cellular dynamics, and ultimately, a small network of hippocampal neurons.

This approach will not only provide an intimate understanding of the contribution of specific molecular events to synaptic plasticity and ultimately overall systems function, but also will facilitate the design of better and safer therapeutic strategies for learning and memory impairments.

While the ultimate goal is to enable effective development of drugs, the research proposed is basic understandings, according to Baudry. The problem with glutamate in terms of pharmaceuticals is that this molecule is absolutely ubiquitous throughout the body. What is therapeutic in one area can be toxic in another. The trick is to find out a way to home in on the specific neural cells you want to affect, without disturbing the others.

One target the group will focus on is the hippocampal region, critical to learning and memory. Additionally, several neurological conditions, e.g., schizophrenia, are believed to be related to regulatory disruption of the glutamatergic system, says Berger.

The research to be conducted by the USC and French research teams is centered on a detailed model of glutamatergic synaptic transmission, called EONS, first developed by Jean-Marie Bouteiller, a Research Assistant Professor working in Dr. Berger's laboratory.

Bouteiller and Berger's research on EONS was, and still is, supported by the USC Biomedical Simulations Resource (BMSR), a Center in the Biomedical Engineering Department of the Viterbi School of Engineering, dedicated to the development of new methods for mathematically modeling physiological systems.

Thus, says Baudry, the collaboration was a natural, and represents an example of the new emphasis on translational science, realized through collaborations that extend to, and include, industry, including researchers at USC, the University Louis Pasteur in Strasbourg, not far from the Mulhouse home of Rhenovia, and engineering and scientific staff at Rhenovia Pharma itself.

Coordination and management are accomplished through weekly conference calls, e-mail, and travel to and from Mulhouse, where the group recently held its first meeting.

The following 'thinking points' define the strategy the USC-Rhenovia team will follow:

1. Pharmaceutical companies are realizing more and more that treatments for diseases of interest are not going to come in the form of a silver bullet -- a single drug that acts directly on the primary receptor and that suddenly cures everything.

2. Receptors have so many regulatory sites that it is clear that there are many, many places on the primary receptors that can be used to alter receptor function; perhaps several of these sites need to be occupied by drugs to produce the desired effect; these modulatory sites evolved for a reason.

3. An increasing number of studies are finding that agents that bind to these modulatory sites often can have little or no effect when used alone, but when used in combinations they can have large effects. These synergistic effects may represent the key to how to restore appropriate functioning of neural systems that are malfunctioning due to disease or aging. In other words, several of the regulatory sites need to be occupied simultaneously, and re-establishing normal synaptic transmission will require finding appropriate levels of activation (drug concentration) of those multiple sites simultaneously.

4. Finally, and critically: finding such synergistic effects would be very difficult if not impossible to achieve experimentally. But while computationally intensive, computer simulations could potentially create a map to guide experimenters. This will require a comprehensive model, with most of the sites for regulating both the input (presynaptic mechanisms) and the output (postsynaptic mechanisms) of key neurotransmitter systems identified correctly, lots of computing power, and expertise with the systems.

Standardized test battery to aid those with Down syndrome

Mon, 12 Jan 2009 05:00:00 PST

( from http://www.rxpgnews.com ) Researchers at The University of Arizona are developing a set of standardized tests that could improve the lives of people with Down syndrome.

The condition, which occurs once in every approximately 800 to 1,000 live births, is signaled by the presence of an extra 21st chromosome. Those with Down syndrome often have mild to severe developmental disabilities, and other health issues that include heart defects and the early onset of Alzheimer's dementia. New research also suggests connections between chromosome 21 and other genes point to some of these problems.

For the past 25 years, Lynn Nadel has been studying the cognitive aspects of Down syndrome. Nadel, a Regents' Professor in the UA psychology department, has spent the bulk of his career studying the hippocampus, the area located deep within the brain that is associated with memory and spatial navigation.

Nadel said while some researchers may be involved with Down syndrome, he was drawn to it as an interesting scientific problem. The hippocampus develops later than other parts of the brain, including after birth, and is susceptible to disruptions. Nadel became interested in the possible implications of environmental impacts such as fetal alcohol syndrome, autism, lead and mercury poisoning and others.

A lot of things that happen early in life have an impact on the development of this structure because it is still plastic and developing, Nadel said.

Since the hippocampus is one of the later developing parts of the nervous system, it made sense to think there might be some connection between this late development story and cognitive problems in Down syndrome.

Starting in the mid-1980s, Nadel began to speculate on the possibility that problems with hippocampal development might also contribute to cognitive problems in Down syndrome. He said the existing literature and later research added to the mounting evidence connecting the two. His own neuropsychological work and cognitive testing supported the case.

In the early 1990s, Nadel and his colleagues in Denver decided that in order to make any further progress, they would need a very accurate profile of the cognitive deficits in children with Down syndrome. For a while, their research slowed until Roger Reeves, a heart specialist at Johns Hopkins who had worked on heart problems in Down syndrome, asked about Nadel's research.

Like the hippocampus, there are anatomical features in the heart that develop very late, like the closing of the valves. Reeves wondered if children with Down syndrome were more likely to have late-developing heart problems. On one of his heart projects, Reeves related the probability of heart defects not just to chromosome 21, but other genes that interact with the extra chromosome 21, and had shown the feasability of using that as a predictor.

Nadel thought he could do that for cognitive function, and suggested they team up to determine the best way to profile cognitive deficits to use in combination with genetic and intervention studies. This could be a way to determine what else contributes to the exact outcome to any particular child with Down syndrome.

Nadel and Reeves brought in genetics experts from Emory University to complete the team.

We're also planning to bring in researchers in Pittsburgh and setting up two or three sites around the country to increase the sample size to get even more exact data on how to make a direct link between the genetic profile of a given child with Down syndrome and their cognitive outcome. You want to predict as early as possible their likely trajectory, and which kids you should intervene with more aggressively, Nadel said.

Most researchers assume that the range of variability in children with Down syndrome is no different than for the rest of the population. There is a very large range in typically developing children, everything from high-functioning to low-functioning. And there is every reason to assume the same in Down syndrome.

We're trying to figure out how to most accurately assess as early as possible, within the first year or two of life. What is the likely trajectory. The kids at age 1 you could already predict by looking at their genetic makeup and a few cognitive tests that we're trying to work out that would be sensitive to cognitive function in the first year or two of life.

An accurate assessment of a child's learning trajectory would enable parents and medical and education specialists time to develop appropriate strategies for learning and possible drug therapies.

The earlier we can make the prediction, the better advice we can give to parents about what they need to do to optimize their kids' development, Nadel said.

The key to finding out where people with Down syndrome are cognitively, he said, is through the use of standardized tests.

We're working on developing a standardized battery for 8 to 18 year olds, the adolescent range that is easiest to develop tests that have adequate controls for in the developing population. Once we have that figured out for that age range, we want to move in both directions.

That includes tests for much younger children, but also for those in the 25-35 age range. Until a few decades ago, many with Down syndrome died in their 30s and 40s, usually from heart problems. Medical advances have helped stave off heart-related deaths, but it exposed another health risk for this group.

By age 35, and certainly by age 40, just about everyone with Down syndrome has characteristic neuropathology associated with Alzheimer's, Nadel said. Every individual with Down syndrome who has died past that age all have this pathology.

What we also know is that for individuals with Down syndrome who are alive past age 35, about 35 to 40 percent actually seem to have early Alzheimer's. They all have mental retardation, either high or low functioning, but they don't seem to have dementia of the Alzheimer's type. This itself presents another interesting scientific question. Why do they have what appears to be the pathology associated with Alzheimer's disease, but don't have it? Given that they all have the neuropathology, we need another indicator, like behavior testing, to find out which ones have dementia or are more likely to get it.

Developing tests requires a large number of subjects. Several dozen have been tested in Tucson, Baltimore and Atlanta. Nadel is creating a fixed battery of nine or 10 tests that can be useful worldwide.

The test battery has to be precise in its ability to tell researchers about a particular brain structure. Three of these tests are targeted as assays, like blood tests that detect the presence of blood sugar. Performance on a cognitive test indicates how well the subject's hippocampus or the prefrontal cortex, another structure thought to be compromised in Down syndrome, are functioning.

The battery has to be designed to be quite specific to only assay one particular structure and not be affected by the function of other structures, Nadel said.

They have to be targeted and precise. They also have to be fairly short. All kids have a short attention span, so we want tests that are precise and targeted and short. They typically are computer based, but not always.

They also are portable. We want to be able to test not only on kids or individuals who can make it into a university or hospital laboratory, but in schools and homes, he said.

Nadel said a number of criteria constrain the development of this battery but the goal is to have something that is repeatable, to test subjects initially and then bring it back a month later and still get reliable results.

Down syndrome also cuts across languages and cultures, so tests have to work the same way anywhere in the world.

Luckily, we're based in Tucson, where there is a substantial Hispanic population. A number of students working on the project speak both English and Spanish fluently, so they were able to help us navigate testing kids who come from Spanish-speaking families. So we've been able to jump that hurdle, Nadel said.

Nadel and his group are now establishing contacts with colleagues in Barcelona, Spain. One of his students is going to do her study-abroad semester in Argentina and will look into what is happening there. The family of another student runs a home for kids with developmental disabilities in Indonesia.

There are cultural differences in how people with developmental disabilities are treated. But worldwide Down is emerging from the closet and kids are being mainstreamed and treated as educable and worth doing something for. That's happened over the last 20 or so years as a function of what we're learning about it.

Nadel said the test battery is near completion, likely in 2009, after a year and a half in development and presentations at meetings. A journal article is near as well.

We're pretty much there, and should have a finished product that we will be happy to share with others doing the same thing around the world who want to use this standardized approach. People are pretty much waiting on us to finish.

Standardized tests, he said, will also aid other researchers working on drug treatments and other kinds of early stimulation, especially for clinical trials that require before-and-after comparisons.

Nadel also has found popular support from the parents of children with Down syndrome. The research testing was developed so that the children would enjoy it. There are boring parts, but Nadel said they try to work around those.

The parents in Tucson and Denver and wherever I've worked with these groups are enormously positive and cooperative about the work. Most of our research is from private foundations that get their money from families with kids with Down syndrome and want to see this research go forward.

What it will make possible is a way of assessing kids, but also for assessing the efficacy of clinical trials. That's been missing. There's always been lots of anecdotal stories about the value of ginkgo or vitamin E. What has been lacking in the field has been some sort of solid scientific way of assessing the virtues of and value of things. So, parents are very excited that we're getting close to having this kind of measurement tool.

The research has also drawn interest from UA students. Nadel said this avenue of research is an area where the rewards are obvious.

One of the most exciting things is how many students want to work on this project. Six or seven right now. It's been an immediate hit. This is good and interesting science and connects to the real world and they can sink their teeth into it and make a difference. It's been a magnet for undergraduate students who want to get involved in research, in something connected to the world.

This one of those perfect examples of how teaching and research mesh completely. In the classroom you talk about brain development and cognition and how it goes right and how it goes wrong. Here is the opportunity for undergrads to actually go in and discover something about that process and make a difference.

Mayo Clinic finds it generally safe to withdraw anti-seizure medication in children with epilepsy

Sun, 07 Dec 2008 05:00:00 PST

( from http://www.rxpgnews.com ) ROCHESTER, Minn. - A new Mayo Clinic study found that it is generally safe to withdraw anti-seizure medications in children with epilepsy who have achieved seizure-freedom while on the medication. Researchers found that these children were not at high risk of subsequently developing intractable epilepsy. The study will be presented on Sunday, Dec. 7, at the American Epilepsy Society's annual meeting in Seattle.

Epilepsy is a disorder characterized by the occurrence of two or more seizures. It affects more than 3 million Americans. Approximately 10 percent of affected children have intractable epilepsy, a condition in which medications alone do not control seizures and seizures have a disabling effect on quality of life.

It is often recommended that children with epilepsy who become seizure-free on anti-seizure medications be withdrawn from the drugs to avoid side effects of long-term use. Those potential side effects include cognitive slowing, incoordination, weight change, behavioral decline, and liver damage, says Katherine Nickels, M.D., a Mayo Clinic pediatric neurologist and an author of this study. However, few previous studies had examined the risk of intractable epilepsy following withdrawal of anti-seizure medication, and the reported risks varied widely.

Dr. Nickels and a team of Mayo Clinic researchers set out to determine the frequency of intractable epilepsy in children who withdrew from anti-seizure medication after a period of seizure-freedom. The team reviewed the records of 241 children, ages 1 month to 16 years, who were diagnosed with new-onset epilepsy between 1990 and 2000. They identified 152 children who were diagnosed and treated with anti-seizure medication and had at least five years of follow-up. Of those, 56 children (37 percent) achieved seizure-freedom and were withdrawn from the medication. After an average follow-up of eight years, 20 children (36 percent) experienced at least one seizure recurrence. Fifteen of these children re-started the anti-seizure medication, and eight (53 percent) achieved seizure-freedom within one year, two (13 percent) achieved seizure-freedom after two years and only three (20 percent) developed intractable epilepsy. Overall, only 5 percent of the 56 children who withdrew from anti-seizure medication following seizure-freedom developed intractable epilepsy.

The risk of children developing intractable epilepsy after withdrawal of anti-seizure medication was only 5 percent, which is similar to the risk of intractable epilepsy at the time of initial diagnosis of epilepsy in children, says Dr. Nickels. Therefore, the children who achieve seizure-freedom on anti-seizure medication should be considered for withdrawal without high risk of intractable epilepsy.

Japanese encephalitis virus causes 'double trouble' to brain

Mon, 07 Jul 2008 04:00:00 PST

( from http://www.rxpgnews.com ) Japanese encephalitis (JE), commonly known as brain fever, is one of the prevalent mosquito-borne encephalitis in India and entire South East (SE) Asia. Besides resulting in thousand fatalities each year, JE virus (JEV) infection causes prominent neurological sequelae in approximately one-third of the survivors. Even those patients in the good recovery group commonly encounter psychiatric problems, which include mental retardation, learning disabilities, speech and movement disorders and behavioural abnormalities.

Recent research in National Brain Research Center, Manesar, India by Dr. Anirban Basu and his graduate student, Sulagna Das have shown that JE virus damages the brain in two ways, by not only killing brain cells but by preventing the birth of new cells from neural stem/progenitor cells (NPC) and depleting the NPC pool in the brain. It's a double hit to the brain, the JE virus causes brain injury by killing neurons as well as prevents its repair lead researcher and the senior author of the work Anirban Basu said in a statement.

The children are more vulnerable targets of this virus, which causes massive neuronal loss in the Central Nervous System. Children are at a dynamic stage of brain development, hence infection at this stage can have devastating effects on mental functions later in life. Our study has tried to explore how JEV infection leads to development of long-term cognitive deficits in the survivors, says Dr. Anirban Basu who has been working in the neurobiology of JEV infection for the past 4 years. These findings have been published online in a paper in Journal of Neurochemistry for inclusion in a future issue of the journal.

The breakthrough here is that the JE virus prevents neural stem and progenitor cells in the brain from dividing; it hangs them up, Basu said. It's the first time that a mosquito-borne virus has ever been shown to affect neural stem cells. The progressive infection in these cells eventually results in decrease in proliferation ability, providing a possible explanation for their diminished pool upon infection, said Basu. He also went on to state, The neurological and cognitive deficits in the JE survivors could be related to the drop in NPC cells in the neurogenic region of the brain called the subventricular zone.

Neural stem/progenitor cells are the saviours of the brain following any insult or infection and via the process of neurogenesis help the recovery process. These cells have the ability to self-renew over lifetime and generate both neurons and glia, which make up the CNS. The initial work with neural stem cells in cell culture dishes interestingly showed that unlike neurons, these stem cells are a resilient population and do not undergo robust cell death upon JEV infection. Instead, the virus lowers the NPC pool by disrupting the growth kinetics and the proliferative ability of these cells. The study was extended in mouse models of JE, where a significant decrease in the actively proliferating NPCs was observed in the subventricular zone or the primary niche of post-natal neurogenesis.

The possible mechanism by which JEV reduces the proliferating NPC pool was also worked out by the scientists utilising the cell cycle studies. Sustained proliferation is a key feature of NPCs, which have to pass through various cell cycle checkpoints and phases of division. Upon JEV infection, these cells halt at the resting phase and fail to proceed to the dividing S-phase. Both cell culture and animal studies indicate that JEV inhibits the DNA synthesis in these cells during progressive infection and induces cycle arrest in them. The researchers went on to show that the virus leads to increased expression of certain checkpoint proteins that block the transition of cells to S-phase, thus preventing the NPCs from multiplying.

Over the years, JE has become a major cause of mortality and morbidity in wide areas of SE Asia. The very high incidence of permanent and disabling neurological sequelae has considerable socioeconomic impact. Knowing the mechanism, we can start to approach this therapeutically Basu said. This indicates that we might eventually treat this form of neurological and psychiatric problems by either ramping up brain repair or protecting the repair mechanism, Das added.

Study identifies brain pathway that shuts down seizures

Sun, 08 Jun 2008 04:00:00 PST

( from http://www.rxpgnews.com ) Researchers at the University of Iowa and the Veterans Affairs Iowa City Health Care System have uncovered a brain pathway that shuts down seizures.

The multidisciplinary team of scientists pieced together information from clinical observations made in the first half of the 20th century with knowledge from modern genetics and molecular biology to show that an acid-activated ion channel in the brain reacts to a drop in pH (increased acid) in a way that shuts down seizure activity.

The link between low pH in the brain and seizure termination was first hinted at nearly 80 years ago when clinical experiments showed that breathing carbon dioxide, which makes brain tissue more acidic, helps stop epileptic seizures. Subsequent studies in the 1950s found that seizures themselves reduce brain pH. However, it was the modern discovery of an acid-activated ion channel (ASIC1a) in the brain that provided the key to the UI discovery, which is reported in Nature Neuroscience Advance Online Publication on June 8.

We found that ASIC1a does not seem to play a role in how a seizure starts, but as the seizure continues and the pH is reduced, ASIC1a appears to play a role in stopping additional seizure activity, said Adam Ziemann, a student in the Medical Scientist Training Program at the UI and co-lead author of the study.

Specifically, the study shows that mice without the ASIC1a gene have more severe and longer seizures than mice with the gene. In addition, chemically blocking ASIC1a increases the severity and duration of seizures in mice with the gene. Conversely, increasing the expression of ASIC1a in mice protects the animals from severe seizures.

The team also showed that reducing the pH in slices of brain tissue expressing ASIC1a reduced seizure activity, but acid had no effect on seizures in tissue without the protein.

When the team measured pH in mouse brains, they showed that seizures lower the pH to levels that can activate ASIC1a channels. They also found that breathing carbon dioxide causes an additional rapid drop in brain pH, and that breathing 10 percent carbon dioxide was sufficient to protect mice with the ASIC1a protein from lethal seizures.

In seizures, ASIC1a appears to be activating inhibitory neurons, explained John Wemmie, M.D., Ph.D., senior study author and assistant professor of psychiatry in the UI Roy J. and Lucille A. Carver College of Medicine, and a staff physician and researcher at the VA Iowa City Health Care System. This is the first study to show that ASIC1a activation can have an inhibitory effect.

One of the most exciting aspects of the work is that it highlights the potent anti-epileptic effects of acid in the brain -- effects that have been recognized for nearly 100 years but until recently have been poorly understood -- and it identifies ASIC1a as a key player in mediating the anti-epileptic effect of low pH, Ziemann said.

We don't know yet, but presumably there might be examples where the seizures don't stop because of a deficit in this pathway, Wemmie added.

Seizures involve abnormal synchronous firing of groups of neurons, which can cause physical symptoms such as spasms or convulsions and, in the most serious cases, altered control of vital bodily functions, like breathing. Approximately 2 to 4 percent of people will have a seizure at some point in their lives. People who have epilepsy experience repeated seizure activity.

Although the vast majority of seizures are self-limiting and stop by themselves, seizures that don't stop can develop into a life-threatening condition called status epilepticus with a mortality rate of up to 20 percent.

The discovery helps explain why breathing carbon dioxide stops seizures, which might stimulate the use of carbon dioxide for stopping seizures, Wemmie said. However, although this work provides insight into how seizures normally stop and might help us learn more about how to terminate those seizures that don't stop, it will take more work to turn the finding into a new therapeutic approach. We will be working with colleagues in neurology and neurosurgery to try and translate the findings to treatments.

Ziemann noted that a particular strength of neuroscience research at the UI is the close interaction between faculty doing cutting-edge human studies and those pursuing basic science.

Repeated methamphetamine use causes long-term adaptations in brains of mice, researchers find

Wed, 09 Apr 2008 04:00:00 PST

( from http://www.rxpgnews.com ) Repeatedly stimulating the mouse brain with methamphetamine depresses important areas of the brain, and those changes can only be undone by re-introducing the drug, according to research at the University of Washington and other institutions. The study, which appears in the April 10 issue of the journal Neuron, provides one of the most in-depth views of the mechanisms of methamphetamine addiction, and suggests that withdrawal from the drug may not undo the changes the stimulant can cause in the brain.

The researchers set out to determine what sort of changes happen in the brain because of repeated use of the stimulant methamphetamine, and to better understand addiction-related behaviors like drug craving and relapse. Methamphetamine, also known as simply meth, is one of the most popular illegal drugs in the United States, and abuse of the drug can cause severe addiction.

Scientists have believed that abuse of drugs like meth can cause changes to the neurons in the brain and the synapses and terminals that control transmission of information in the brain. In this project, researchers focused on the mouse brain, and how it was affected by methamphetamine over 10 days, which is the mouse equivalent of chronic use in humans.

They found that the long administration and withdrawal of the drug depressed the neural terminals controlling the flow of signals between two areas of the brain, the cortex and striatum. Even a long period of withdrawal -- the equivalent of years in humans -- did not return the terminals to normal activity level. Re-introducing the drug, however, reversed the changes in the brain.

The areas affected by the drug are called pre-synaptic terminals, and are related to the flow of information from the cortex to the striatum. When a person sees something new in their environment, the scientists explained, she focuses attention on that item. At the neuron level, that process stimulates the release of dopamine, a chemical involved in transmitting signals in the brain. As the person sees the new item over and over again, the dopamine response drops, and synapses in the brain adapt to the no-longer-new item.

What happens with methamphetamine use is that the drug makes the nervous system release dopamine, which helps a user focus a lot of attention on a particular goal. Scientists believe that meth allows dopamine in the striatum to filter information coming from the cortex through the pre-synaptic terminals. The filtering of some of the terminals would help someone ignore other things and focus on that one goal or task.

After chronic use of methamphetamine, the filtering process eventually becomes a permanent depression in the activity of those terminals in the brain, the scientists found. And the only thing that can help the pre-synaptic terminals recover in mice, they found, was re-administering the drug.

What we found is that the repeated use of methamphetamine causes adaptations in the brain, and that only re-introducing the drug can reverse that, said Dr. Nigel Bamford, UW assistant professor of neurology and pediatrics and a physician at Seattle Children's Hospital. We think these changes in the brain may account for at least some of the physiological components of meth addiction.

If the mechanism turns out to be similar in people, Bamford said, this could have big effects on the treatment and management of methamphetamine addiction. One treatment for drug addiction is to give people smaller and smaller amounts of the drug to wean them from it and reduce the effects of withdrawal. Unfortunately, that method would not affect the adaptation of the neural terminals in the brain.

Now that we have some understanding of the mechanism through which meth addiction occurs, we may be able to develop other approaches to treating addiction, explained Bamford. We might be able to target some of the chemical receptors in the brain to reset the system and get rid of this depressed state in the pre-synaptic terminals.

Though scientists believe that other stimulants, like methylphenidate, may have similar effects on the brain, they caution against applying these findings to other situations. These synaptic changes may not occur in patients with underlying conditions that require treatment with stimulants, the scientists said.

Scientists find a key culprit in stroke brain cell damage

Thu, 27 Mar 2008 04:00:00 PST

( from http://www.rxpgnews.com ) Researchers have identified a key player in the killing of brain cells after a stroke or a seizure. The protein asparagine endopeptidase (AEP) unleashes enzymes that break down brain cells' DNA, scientists at Emory University School of Medicine have found.

The results are published in the March 28 issue of the journal Molecular Cell.

Finding drugs that block AEP may help doctors limit permanent brain damage following strokes or seizures, says senior author Keqiang Ye, PhD, associate professor of pathology and laboratory medicine at Emory.

When a stroke obstructs blood flow to part of the brain, the lack of oxygen causes a buildup of lactic acid, the same chemical that appears in the muscles during intense exercise. In addition, a flood of chemicals that brain cells usually use to communicate with each other over-excites the cells. Epileptic seizures can have similar effects.

While some brain cells die directly because of lack of oxygen, others undergo programmed cell death, a normal developmental process where cells actively destroy their own DNA.

The mystery was: how do the acidic conditions trigger DNA damage? Ye says. This was a very surprising result because previously we had no idea that AEP was involved in this process.

AEP is a protease, a class of enzymes that cuts other proteins. AEP is also called legumain because of its relatives in plants, and is found at its highest levels in the kidney, says Ye.

He and his co-workers had suspected that another class of proteases called caspases, involved in programmed cell death, controlled DNA damage after a stroke.

At first, he and postdoctoral fellow Zhixue Liu, PhD, thought the results of a critical experiment that led them to AEP were an aberration because the experiment was performed under overly acidic conditions.

But if you can repeat the mistake, it's not a mistake, Dr. Ye says, adding that follow-up work allowed them to set aside caspases as suspects and focus on AEP.

The researchers began by looking for proteins that stick to another protein called PIKE-L, which they previously had studied because of its ability to interfere with programmed cell death in brain cells.

They discovered that PIKE-L sticks to SET, a protein that other scientists had found regulates DNA-eating enzymes involved in programmed cell death. In addition, PIKE-L appears to protect SET from attack by AEP.

Liu and Ye found that a drug scientists use to mimic the acidic overload induced by stroke activates AEP, driving it to break down DNA in brain cells. In mice genetically engineered to lack AEP, both the drug and an artificial stroke resulted in reduced DNA damage and less brain cell death than in regular mice.

This outcome suggests that AEP might be the major proteinase mediating this devastating process, the authors wrote.

Cocaine's effects on brain metabolism may contribute to abuse

Mon, 18 Feb 2008 05:00:00 PST

( from http://www.rxpgnews.com ) UPTON, NY - Many studies on cocaine addiction - and attempts to block its addictiveness - have focused on dopamine transporters, proteins that reabsorb the brain's reward chemical once its signal is sent. Since cocaine blocks dopamine transporters from doing their recycling job, it leaves the feel-good chemical around to keep sending the pleasure signal. Now a new study conducted at the U.S. Department of Energy's Brookhaven National Laboratory suggests that cocaine's effects go beyond the dopamine system. In the study, cocaine had significant effects on brain metabolism, even in mice that lack the gene for dopamine transporters.

In dopamine-transporter-deficient mice, these effects on metabolism are clearly independent of cocaine's effects on dopamine, said Brookhaven neuroscientist Panayotis (Peter) Thanos, who led the research. These metabolic factors may be a strong regulator of cocaine use and abuse, and may also suggest new avenues for addiction treatments. The study will appear in the May 2008 issue of the journal Synapse, and will be available online on Monday, February 18, 2008.

The scientists used positron emission tomography, or PET scanning, to measure brain metabolism in dopamine-transporter deficient mice (known as DAT knockouts) and in littermates that had normal dopamine transporter levels. In this technique, the scientists administer a radioactively labeled form of sugar (glucose) - the brain's main fuel - and use the PET scanner to track its site-specific concentrations in various brain regions. They tested the mice before and after cocaine administration, and compared the results to mice treated with saline instead of the drug.

Before any treatment, mice lacking dopamine transporters had significantly higher metabolism in the thalamus and cerebellum compared with normal mice. This elevated metabolism may be linked to chronically high levels of dopamine in the DAT knockout mice. It also suggests that dopamine levels may play an important role in modulating glucose levels in these brain areas, which play important roles integrating sensory information, learning, and motor function.

Interestingly, DAT knockout mice have been suggested as an animal model for attention-deficit hyperactivity disorder (ADHD). Elevated metabolism due to persistent elevated dopamine levels may be a factor contributing to the symptoms of ADHD, Thanos said.

After the scientists administered cocaine, whole brain metabolism decreased in both groups of mice, but more significantly in normal mice than in DAT knockouts. The scientists were able to detect this reduction in metabolism in a wide range of brain regions in the normal mice, suggesting that these decreases in metabolism are somehow associated with the blockade of dopamine transporters by cocaine.

The scientists also observed a reduction in metabolism in the thalamus region in the DAT knockout mice. This effect may likely be due to the effect of cocaine on other neurotransmitter systems, for example, norepinepherine or serotonin.

In summary, cocaine exposure has an effect on regional brain activity, which is mostly driven by dopamine action and to a secondary degree norepinephrine or serotonin. These results also support the idea that the thalamus and the cerebellum play key roles in cocaine's mechanism of effect on sensory input, learning, and motor function. This is particularly of interest in better understanding the mechanism of cocaine addiction as well as the neurobiology of ADHD.

New devices to boost nematode research on neurons and drugs

Tue, 05 Feb 2008 05:00:00 PST

( from http://www.rxpgnews.com ) A pair of new thin, transparent devices, constructed with soft lithography, should boost research in which nematodes are studied to explore brain-behavior connections and to screen new pharmaceuticals for potential treatment of parasitic infections in humans, report 10 scientists at three institutions.

The tools -- an artificial soil device and a waveform sampler device, both of which can be held easily in a human hand -- are detailed in a paper appearing online ahead of regular publication by the Journal of Neurophysiology.

The devices take advantage of a microfluidic fabrication technique, which allows for the presence of channels, chambers or ports, for gas permeability and transparency and for using fluids to deliver stimuli with precision. The major improvement over previous tools is that these new ones are agarose-free, using micron-scale channels and pillars that mimic real soil particles.

The newly reported devices provide a near natural environment for soil-dwelling roundworms (Caenorhabditis elegans, or C. elegans) that measure barely a millimeter in length. The nematodes move normally, but slightly compressed so that highly sensitive microscopes can be used to monitor individual fluorescent-injected neurons in real time during experiments.

There is a commonality between these devices that is really going to help us understand how the nervous system works, said lead researcher Shawn Lockery, a professor of biology and member of the Institute of Neuroscience at the University of Oregon.

The artificial soil device consists of a hexagonal array of microscopic pillars sandwiched between a glass cover slip and a bulk material from which the pillars protrude, Lockery said. The worm wanders around in a one-centimeter square area as a river of mostly water flows through it. We can change the solution the nematode is exposed to in ways that are relevant to the research that is being conducted.

For instance, researchers can manipulate the levels of sodium chloride and oxygen in the water being injected into the devices.

As a proof of principle, researchers had to show that the behavior of the nematodes is essentially normal in the new devices, meaning that the worms crawl like they do on an agar surface. But nematodes don't live on exposed agar surfaces in real life, Lockery said. Instead, they are found within soil and easily collected in the wild in rotting fruit.

The beauty of this system is that it reproduces standard laboratory behavior, but it does so in a context that is probably more normal in terms of the worms' real-life environment, he said. You get forward and reverse locomotion, and the nematodes also do the omega turn, in which a worm's head bends around to touch the tail during forward locomotion, forming a shape like the Greek omega.

The waveform device features 18 different channels, with each divided into domains with unique amplitudes and wavelengths to manipulate how a nematode moves. Instead of using posts to mimic real soil, depressions or channels provide natural areas -- even some that don't occur in nature -- for the nematodes to crawl through. This ability to change the channels but still allow the worms to move about proved the principle in this case, Lockery said. What we found from this is that these animals are remarkably adaptable to a wide range of situations.

The artificial soil device, Lockery said, will help to study how brains generally process sensory information and for high-through-put screening of new drugs for their biological effects. Such research, he said, could lead to new treatments for some two billion people infected annually by parasitic nematodes, as well as new tools to reduce nematode-caused losses in world agriculture.

The waveform device could enhance research on brain-behavior connections. C-elegans have only 302 neurons, compared to 100 billion neurons in the human brain, Lockery said. At least 50 percent of the proteins in the nematode brain are identical to those in human brains. C. elegans is the only animal for which we have a complete anatomical reconstruction of the nervous system -- a complete wiring diagram of the brain. This greatly accelerates analyses of brain function in this organism, he said.

Gene protects adults abused as children from depression

Mon, 04 Feb 2008 05:00:00 PST

( from http://www.rxpgnews.com ) Some forms of a gene that controls the body's response to stress hormones appear to protect adults who were abused in childhood from depression, psychiatrists have found.

People who had been abused as children and who carried the most protective forms of the gene, called corticotropin-releasing hormone receptor one (CRHR1), had markedly lower measures of depression, compared with people with less protective forms, the researchers found in a recent study.

The findings could guide doctors in finding new ways to treat depression in people who were abused as children, says senior author Kerry Ressler, MD, PhD, assistant professor of psychiatry and behavioral sciences at Emory University School of Medicine.

We know that childhood abuse and early life stress are among the strongest contributors to adult depression, and this study again brings to light the importance of preventing them, Dr. Ressler says. But when these tragic events do occur, studies like this one ultimately can help us learn how we might be able to better intervene against the pathology that often follows.

The results of the study, performed on two separate racially and economically distinct groups from the Atlanta area, were published in the February 4 issue of the Archives of General Psychiatry.

The first and second authors of the study are Rebekah Bradley, PhD, at the Atlanta Veterans Affairs Medical Center and Elisabeth Binder, MD, PhD, at Emory University and the Max Planck Institute for Psychiatry in Munich, Germany. Dr. Ressler, who also is a scientist at Emory's Yerkes National Primate Research Center and a member of the Center for Behavioral Neuroscience, and Joseph Cubells, MD, PhD, associate professor of human genetics at Emory University School of Medicine, are co-senior authors.

The team's research illustrates how life events and genetic influences can combine in complex ways, leading to depression or protection from it. Almost 15 million U.S. adults have major depression, according to the National Institute of Mental Health.

The study also supports previous evidence that corticotropin-releasing hormone (CRH) and related hormones play a role in depression. Other studies have found increased levels of CRH and altered levels of its receptor in the brains of patients with depression.

Some pharmaceutical firms are testing compounds that block CRHR1 as potential medications for depression.

The receptor for a hormone acts like a receiver or radar dish for messages sent between cells. CRH stimulates the pituitary gland to release another hormone, adrenocorticotropin, which in turn induces the release of cortisol from the adrenal cortex.

Extreme stress in childhood can over-activate this cascade of hormones, increasing the risk of depression in adulthood, Dr. Ressler says.

Our results suggest that genetic differences in signals mediated by CRH may amplify or soften the developmental effects that childhood abuse can have -- effects that can raise the risk of depression in adults, he says.

In the study, scientists began by interviewing more than 470 adults and testing their DNA, looking for alternative spellings or SNPs (single nucleotide polymorphisms) in several parts of the CRHR1 gene.

This first group was mostly black and a majority had a monthly income less than $1,000. The researchers measured their symptoms of depression and had them answer questionnaires about childhood trauma. Their responses were categorized as low, mild, moderate and severe.

Overall, people with a history of moderate or severe child abuse had depression symptoms that averaged about double the level of those with low or mild child abuse scores.

Roughly 30 percent of the group had variations in the CRHR1 gene that together appeared to be protective if moderate to severe abuse had occurred. People who had inherited two copies of the most protective forms of the gene, or haplotypes, had average depression symptoms that were about half those of people who had not inherited those haplotypes. A haplotype comprises several SNPs that frequently appear together.

These differences in depression symptoms were only seen in people with histories of moderate to severe abuse; depression levels were not significantly different in people with low to mild abuse.

The most significant SNPs appear in the part of the gene preceding the region that encodes the receptor protein, suggesting that the variations may affect its regulation rather than the composition of the protein, the authors say.

The findings were strengthened when the researchers repeated the study in 199 white, middle-income adults and came up with similar results, suggesting that the genetic variations act in a way that is independent of ethnic background or economic status.

Naked mole-rats bear chili pepper heat

Mon, 28 Jan 2008 05:00:00 PST

( from http://www.rxpgnews.com ) Pity the tiny naked mole-rat. The buck-toothed, sausage-like rodent lives by the hundreds in packed, oxygen-starved burrows some six feet under ground. It is even cold-blooded -- which, as far as we know, is unique among mammals.

You can feel their pain. But, they can't feel ours.

Evolution has benefited naked mole-rats by ridding them of a body chemical called Substance P, a neurotransmitter released by pain fibers that send signals to the central nervous system in mammals after making contact with things that cause long-lasting, achy pain.

A better understanding of how Substance P works in the strange rodents may lead to new analgesic drugs for people with chronic pain who do not respond well to current medication, according to Thomas Park, associate professor of biological sciences at the University of Illinois at Chicago, and Gary Lewin of the Max-Delbrück Center for Molecular Medicine in Berlin, principal authors of a study appearing Jan. 29 in the free-access journal PLoS Biology.

Park, Lewin and their laboratory teams in Chicago and Berlin used a modified herpes cold sore virus to carry genes for Substance P to the rodents' nerve fibers.

We were able to rescue their ability to feel pain, said Park. His research group restored Substance P and the naked mole-rats' ability to sense the burning sensation other mammals feel when subjected to capsaicin, the active ingredient in chili peppers.

The restored sensitivity was limited to just one rear foot of each tested rodent. They'd pull their foot back and lick it, in response to the stimulus, said Park. Other feet were impervious to the sting of capsaicin.

Capsaicin is very specific for exciting the fibers that normally have Substance P, said Park. They're not the fibers that respond to a pin prick or pinch, but the ones that respond after an injury or burn and produce longer-lasting pain.

But the researchers found that mole-rats remained completely insensitive to acids, indicating a fundamental difference in how their nerves respond to this stimulus.

Acid acts on the capsaicin receptor and on another family of receptors called acid-sensitive ion channels, Park said. Acid is not as specific as capsaicin. The mole-rat is the only animal that shows completely no response to acid.

Park said the research adds to knowledge about the neurotransmitter Substance P.

This is important specifically to the long-term, secondary-order inflammatory pain. It's the pain that can last for hours or days when you pull a muscle or have a surgical procedure, he said.

Park said naked mole-rats provide a new model system that is different from all other animals he has studied.

We're learning which nerve fibers are important for which kinds of pain, so we'll be able to develop new strategies and targets.

Naked mole-rats, native to east-central Africa, developed a protective reaction to acids through evolution. Living in tight underground quarters, the mole-rats exhale high levels of carbon dioxide, which becomes acid when it touches skin and mucous tissue in the nose, eyes and mouth. But the mole-rats have evolved to become desensitized to the stinging pain of acid.

The UIC biologist plans to study other animals, both closely related and unrelated -- such as Alaskan marmots that burrow in high CO2 environments -- to examine how they have evolved similar strategies to cope with acid-rich living conditions.

Weill Cornell team discovers how brain's own tPA helps regulate blood flow to neurons

Thu, 17 Jan 2008 05:00:00 PST

( from http://www.rxpgnews.com ) NEW YORK (Jan. 17, 2008) -- The human brain contains its own store of a powerful enzyme (and stroke drug) called tissue plasminogen activator (tPA), which appears to be a key regulator of blood flow to brain cells, a team at the Weill Cornell Medical College in New York City reports.

We found that this natural tPA boosts blood flow to brain cells via its influence on nitric oxide synthase, which is essential to the production of nitric oxide (NO). NO is a well-known vasodilator -- a drug or chemical that widens blood vessels -- so, more NO means better blood flow to neurons as they become more active, explains study senior author Dr. Costantino Iadecola, the George C. Cotzias Distinguished Professor of Neurology and Neuroscience at Weill Cornell Medical College, and chief of the Division of Neurobiology at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

The findings have just been published in this week's online issue of Proceedings of the National Academies of Science.

Besides elucidating the role of naturally produced tPA in neuronal blood flow, the new findings could have implications for the study of stroke and Alzheimer's disease. Both conditions are associated with marked declines in natural brain levels of tPA.

TPA has become a star of sorts in cardiovascular research over the past two decades, ever since scientists discovered its remarkable ability to break up clots.

Essentially, tPA, a powerful protease enzyme, cleaves a protein called plasminogen into plasmin, an enzyme that quickly 'eats up' clots, notes study lead author Dr. Laibaik Park, instructor in neuroscience at Weill Cornell. For that reason, doctors often administer a shot of tPA to stroke patients within minutes or hours of an attack.

But other research had also detected tPA occurring naturally in the human brain, with levels of the enzyme rising as brain cell activity increased.

What really piqued our interest was the finding from recent studies that tPA somehow modulates the activity of a protein lying on the surface of neurons called the NMDA receptor, Dr. Iadecola explains. This receptor serves as a gateway of communication between adjoining neurons, with glutamate being the 'currency' of exchange. Fluctuating levels of tPA seemed to influence just how much of that currency got through as brain cells became more or less active.

Exploring this mechanism further, Dr. Iadecola's team utilized a genetically engineered knockout mouse that lacked neuronal tPA. They tweaked the mouse's whiskers and watched blood flow in the area of the rodent's brain linked to whisker sensitivity.

In the knockout mouse, blood flow in that area did not change as much upon whisker stimulation -- confirming that tPA is necessary to boosting local blood flow, Dr. Iadecola says.

But how was tPA working, exactly? The prevailing theory -- that the enzyme impacted directly on the NMDA receptor -- was quickly proven wrong. We found that tPA was not acting as any kind of direct 'choke' on the NMDA receptor to allow more or less glutamate into the cell, says Eduardo Gallo, a graduate student in the Department of Neurology and Neuroscience, who played a key role in the study.

So, the team looked elsewhere at other rate-limiting mechanisms that might explain tPA's effects.

One of the end-products of NMDA receptor activity is nitric oxide (NO), a powerful vasodilator, Gallo notes. In our experiments, we discovered that tPA helps control how much NO can be made by activation of the NMDA receptor. TPA does so by boosting the ability of neuronal nitric oxide synthase (nNOS) -- an enzyme -- to produce NO. More tPA means more active nitric oxide synthase -- and more of this enzyme means more vessel-widening NO. The end result: a localized boost in blood flow to brain cells.

Questions remain, however. TPA exists outside the brain cell, but the nNOS activity and NO production goes on inside the neuron, Dr. Iadecola points out. That means there's some kind of biochemical chain connecting external tPA to these internal mechanisms, he says. Identifying the key players in that pathway will be a key part of our research going forward.

The new discoveries will have exciting implications for brain research, he says.

More and more, we are realizing that alterations in the availability of blood to brain cells is crucial to stroke and post-stroke recovery, and in the debilitating loss of neuronal function that underlies Alzheimer's disease and other dementias, Dr. Iadecola says.

It is possible that drugs or other interventions that manipulate the brain's natural supply of tPA could help preserve neurological function after stroke or Alzheimer's, or even help reverse some of the damage, he says. Those types of treatments are still a long way off, but our new understanding how tPA works to keep neurons healthy and active is a crucial first step in that research.

Overweight people may not know when they've had enough

Wed, 09 Jan 2008 05:00:00 PST

( from http://www.rxpgnews.com ) UPTON, NY - Researchers at the U.S. Department of Energy's Brookhaven National Laboratory have found new clues to why some people overeat and gain weight while others don't. Examining how the human brain responds to satiety messages delivered when the stomach is in various stages of fullness, the scientists have identified brain circuits that motivate the desire to overeat. Treatments that target these circuits may prove useful in controlling chronic overeating, according to the authors. The study is published online and will appear in the February 15, 2008 issue of NeuroImage.

By simulating feelings of fullness with an expandable balloon we saw the activation of different areas of the brain in normal weight and overweight people, said lead author Gene-Jack Wang of Brookhaven Lab's Center for Translational Neuroimaging. The overweight subjects had less activation in parts of the brain that signal satiety in normal weight subjects. The overweight subjects were also less likely than normal weight subjects to report satiety when their stomachs were moderately full. These findings provide new evidence for why some people will continue to eat despite having eaten a moderate-size meal, said Wang.

Wang and colleagues studied the brain metabolism of 18 individuals with body mass indices (BMI) ranging from 20 (low/normal weight) to 29 (extremely overweight/borderline obese). Each study participant swallowed a balloon, which was then filled with water, emptied, and refilled again at volumes that varied between 50 and 70 percent. During this process, the researchers used functional magnetic resonance imaging (fMRI) to scan the subjects' brains. Subjects were also asked throughout the study to describe their feelings of fullness. The higher their BMI, the lower their likelihood of saying they felt full when the balloon was inflated 70 percent.

One notable region of the brain - the left posterior amygdala - was activated less in the high-BMI subjects, while it was activated more in their thinner counterparts. This activation was turned on when study subjects reported feeling full. Subjects who had the highest scores on self-reports of hunger had the least activation in the left posterior amygdala.

This study provides the first evidence of the connection of the left amygdala and feelings of hunger during stomach fullness, demonstrating that activation of this brain region suppresses hunger, said Wang. Our findings indicate a potential direction for treatment strategies - be they behavioral, medical or surgical -- targeting this brain region.

The scientists also looked at a range of hormones that regulate the digestive system, to see whether they played a role in responding to feelings of fullness. Ghrelin, a hormone known to stimulate the appetite and cause short-term satiety, showed the most relevance. Researchers found that individuals who had greater increases in ghrelin levels after their stomachs were moderately full also had greater activation of the left amygdala. This indicates that ghrelin may control the reaction of the amygdala to satiety signals sent by the stomach, said Wang.

This study was funded by the Office of Biological and Environmental Research within the U.S. Department of Energy's Office of Science, the National Institute on Drug Abuse (NIDA), the National Institute of Diabetes and Digestive and Kidney Diseases, the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the General Clinical Research Center at University Hospital Stony Brook. DOE has a long-standing interest in research on brain chemistry gained through brain-imaging studies. Brain-imaging techniques such as MRI are a direct outgrowth of DOE's support of basic physics and chemistry research.

The current study is part of a major focus of research at Brookhaven Lab on the neurobiology of eating disorders and obesity and their treatment. Earlier studies at the Lab have:

Cognitive, genetic clues identified in imaging study of alcohol addiction

Tue, 25 Dec 2007 05:00:00 PST

( from http://www.rxpgnews.com ) People with clinical addictions know first-hand the ravages the disease can take on almost every aspect of their lives. So why do they continue addictive behaviors, even after a period of peaceable abstinence

Some answers appear rooted in regions of the brain active during decision making.

It's perhaps not just that people are slaves to pleasure, but that they have trouble thinking through a decision, said Charlotte Boettiger, an assistant professor of psychology at the University of North Carolina at Chapel Hill, and lead author of a study in the December issue of the Journal of Neuroscience that took a novel tack in addiction imaging research.

Our data suggest there may be a cognitive difference in people with addictions, Boettiger said. Their brains may not fully process the long-term consequences of their choices. They may compute information less efficiently.

The study also found that a variant of the COMT gene, which controls the level of the neurotransmitter dopamine in the cortex, was associated with a tendency to make impulsive decisions and with high activity in certain brain areas during decision making.

Current medications for addictions are not universally effective; many either mimic the addictive substance to help people get through withdrawal periods or block the substance to prevent its effects. For stimulants, such as methamphetamines, there are no therapies yet, Boettiger said.

What's exciting about this study is that it suggests a new approach to therapy. We might prescribe medications, such as those used to treat Parkinson's or early Alzheimer's disease, or tailor cognitive therapy to improve executive function, said Boettiger, who led the study as scientist at the University of California, San Francisco's Gallo Clinic and Research Center.

I am very excited about these results because of their clinical implications, said Dr. Howard Fields, a professor of neurology at UCSF and an investigator in the Gallo Center.

The genetic findings raise the hopeful possibility that treatments aimed at raising dopamine levels could be effective treatments for some individuals with addictive disorders, said Fields, who is senior author of the study.

Most addiction imaging studies have focused on the brain response to drug-related stimuli.

Boettiger used functional magnetic resonance imaging (fMRI), which shows brain activity while a subject performs a function, to see what happened inside their heads when sober alcoholics and people in a non-alcoholic control group made decisions between immediate and delayed rewards.

Boettiger recruited 24 subjects; 19 provided fMRI data, nine were recovering alcoholics in abstinence and 10 had no history of substance abuse. Another five were included in the genotyping analysis.

At the fMRI research facility at the University of California, Berkeley, the subjects were asked to decide between receiving a small monetary award immediately or wait for a larger payoff. The scenarios were hypothetical, but the tasks measured rational thinking and impulsivity; sober alcoholics chose the now reward almost three times more often than the control group, reflecting more impulsive behavior.

While decisions were being made the imaging detected activity the predicted individual choice in regions associated with decision making -- the posterior parietal cortex, the dorsal prefrontal cortex, the anterior temporal lobe and the orbital frontal cortex.

People who sustain damage to the orbital frontal cortex generally suffer impaired judgment; they manage money poorly and act impulsively. Boettiger's study revealed reduced activity in the orbital frontal cortex in the brains of subjects who preferred nowover later, most of whom had a history of alcoholism.

The orbital frontal cortex activity may be a neural equivalent of long-term consequences. Think of the orbital frontal cortex as the brakes, Boettiger said. With the brakes on, people choose for the future; without the brakes they choose for the short-term gain.

The dorsal prefrontal cortex and the parietal cortex often form cooperative circuits, and this study found that high activity in both is associated with a bias toward choosing immediate rewards.

The frontal and parietal cortex are also involved in working memory -- being able to hold data in mind over a short delay. When asked to choose between $18 now or $20 in a month, the subjects had to calculate how much that $18 (or what it could buy now) would be worth in a month and then compare it to $20 and decide whether it would be worth the wait.

The parietal cortex and the dorsal prefrontal cortex were much more active in people unwilling to wait. This could mean, Boettiger said, that the area is working less efficiently in those people.

The COMT gene has two common variants with a single amino acid difference at position 158; valine (Val) or methionine. The Val form of the gene is associated with lower dopamine levels, and Boettiger's study showed that people with two copies of the Val allele (resulting in the lowest dopamine levels) had significantly higher frontal and parietal activity and chose now over later significantly more often.

We have a lot to learn, Boettiger said. But the data take a significant step toward being able to identify subtypes of alcoholics, which could help tailor treatments, and may people who are at risk for developing addictions and provide earlier intervention.

The bigger picture, Boettiger said, is that her study provides more evidence that addiction is a disease, something even some of her peers do not yet believe.

It's not unlike chronic diseases, such as diabetes, she said. There are underlying genetic and other biological factors, but the disease is triggered by the choices people make.

It wasn't that long ago that we believed schizophrenia was caused by bad mothers and depression wasn't a disease. Hopefully, in 10 years, we'll look back and it will seem silly that we didn't think addiction was a disease, too.

Biocapture surfaces produced for study of brain chemistry

Thu, 13 Dec 2007 05:00:00 PST

( from http://www.rxpgnews.com ) A research team at Penn State has developed a novel method for attaching small molecules, such as neurotransmitters, to surfaces, which then are used to capture large biomolecules. By varying the identity and spacing of the tethered molecules, researchers can make the technique applicable to a wide range of bait molecules including drugs, chemical warfare agents, and environmental pollutants. Ultimately, the researchers also hope to identify synthetic biomolecules that recognize neurotransmitters so that they can fabricate extremely small biosensors to study neurotransmission in the living brain.

In the brain, dozens of different small signaling molecules interact with thousands of large receptive proteins as part of the fundamental communication process between nerve cells. This cacophony of specific interactions is highly dependent on nanoscale molecular structure. One key to advancing our understanding of how the brain works is to identify the nature of the association between neurotransmitters and their binding partners. The technique of producing these high-affinity materials will be published in January 2008 in the journal Advanced Materials by a research team headed by Anne Milasincic Andrews, associate professor of veterinary and biomedical sciences, and including Paul S. Weiss, distinguished professor of chemistry and physics.

The process starts with a self-assembled monolayer (SAM), a single-molecule-thick layer that organizes itself on a surface. The molecules that make up the SAM terminate in and expose oligoethyleneglycol units that are known to prevent adhesion of proteins and other large biomolecules. Next, tether molecules are inserted into the defects that naturally occur in the SAM. Finally, a small molecule, in this case the neurotransmitter serotonin, is chemically linked to the tether molecules. Since the defects in the SAM occur at irregular but controllable intervals, serotonin molecules are prevented from clumping together. This is key to their being recognized by the correct proteins.

When the surface is exposed to a solution containing many different proteins, only those with high affinities for the tethered small molecule selectively attach to the surface. The bound protein molecules can then be identified in place or removed for characterization. The tethered neurotransmitter acts like a fishing pole, says Andrews. When the small molecule 'bait' is correctly placed on the surface, it captures much larger molecules that interact with it in a biologically specific way.

As a result of this inherent selectivity, it is possible to identify biomolecules, by function, from a sea of thousands of different types of molecules. Weiss adds, The key to obtaining a highly specific association is producing optimal spacing of the tethered neurotransmitters. The ideal spacing allows large molecules to recognize the functional groups of the small molecule while avoiding nonspecific binding to the surface itself.

Because of their selectivity, these materials are suitable for a variety of investigations in biological systems. Each neurotransmitter can bind to a number of different receptors in the brain, says Andrews. Some of these receptors are known, but there are many more to identify. Also, the numbers of receptors are altered in different disease states and in response to treatment, and these capture surfaces could be used to study how groups of functionally related proteins change in a coordinated fashion.

Dr. Nicholas Schiff receives research award for Innovation in Neuroscience

Thu, 13 Dec 2007 05:00:00 PST

( from http://www.rxpgnews.com ) NEW YORK (Dec. 13, 2007) -- A leading authority on neurological disorders of consciousness, Dr. Nicholas Schiff of NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New York City has received a prestigious Research Award for Innovation in Neuroscience from the Society for Neuroscience, the world's largest organization of physicians and scientists who study the brain and nervous system.

The award -- for imaginative, innovative research that will advance novel ideas and have the potential to lead to significant breakthroughs in the understanding of the brain and nervous system and related diseases, -- was presented at the Society's recent annual meeting in San Diego.

Dr. Schiff was the lead author of a breakthrough study in the Aug. 2 journal Nature, reporting that a 38-year-old man who spent more than five years in a minimally conscious state as a result of a severe head injury is now communicating regularly with family members and recovering his ability to move after having his brain stimulated with pulses of electric current. The findings provide the first rigorous evidence that any procedure can initiate and sustain recovery in such a severely disabled person, years after the injury occurred.

Study investigators included NewYork-Presbyterian/Weill Cornell's Dr. Joseph Fins and physician-scientists at the JFK Johnson Rehabilitation Institute (Edison, N.J.) and the Cleveland Clinic Foundation.

Dr. Schiff is associate professor of neurology and neuroscience at Weill Cornell Medical College and associate attending neurologist at NewYork-Presbyterian/Weill Cornell. He is an inventor at Cornell University of some of the technology used in the study described in Nature and is a paid consultant and advisor to IntElect Medical Inc., to which the technology has been licensed by Cornell University and in which Cornell University has an equity interest. A Conflict Management Plan relating to IntElect and its relationship with Dr. Schiff and Cornell University is in place.

A diplomate of the American Board of Psychiatry and Neurology, he received his medical degree from Cornell University Medical College (now Weill Cornell Medical College). He completed his residency in neurology at The New York Hospital (now NewYork-Presbyterian/Weill Cornell), where he trained with Drs. Fred Plum and Jerome Posner and developed his subspecialty interest in the field of impaired consciousness. He is a co-author of the fourth edition of Dr. Plum and Posner's classic textbook The Diagnosis of Stupor and Coma. Dr. Schiff is an elected member of the American Neurological Association. His long-range goals are to develop strategies and improved diagnostics to treat of chronic cognitive disabilities resulting from brain injuries.

Breakthrough technology observes synapse in real time, supporting theory of vesicular recycling

Thu, 13 Dec 2007 05:00:00 PST

( from http://www.rxpgnews.com ) NEW YORK (Dec. 13, 2007) -- For the first time, scientists at Weill Cornell Medical College in New York City have observed in real time a cellular mechanism that's crucial to how brain cells communicate.

In doing so, they've also laid to rest a competing theory as to how key cellular processes -- called endocytosis and exocytosis -- work.

The scientists published their findings in this week's online edition of Proceedings of the National Academy of Sciences (Dec. 18 print edition).

Healthy neurological function hinges on the efficient passage of information between brain cells via the synapse, and exocytosis/endocytosis is the complex trafficking mechanism that allows this to happen.

At its simplest level, exocytosis involves the packaging, transport and delivery of neurotransmitter chemicals in sac-like structures called vesicles. These vesicles move from the interior of the cell to the cell membrane, where they deliver their information-rich cargo to the synapse. Endocytosis involves a similar function in the reverse direction, with incoming vesicles being transported into the cell's interior.

The vesicles aren't discarded, however. Instead, once they release their cargo they are recycled for use in another go-round. There have been two competing theories about how that recycling occurs -- either the vesicle fragments upon delivering its cargo and must be rebuilt, or it simply empties itself like milk from a bottle which is then resealed.

The vast bulk of the evidence suggests the former theory is actually the correct one, but it's been tempting to think of the 'resealable spout' theory, because it seems so logical and because there's been some ambiguous evidence that it might be true, says the study's co-author Dr. Timothy Ryan, professor of biochemistry at Weill Cornell Medical College.

The trouble is, no one had ever found a way to observe -- accurately and in real time -- synaptic vesicle recycling as it occurs.

That has changed with this new paper. We have taken advantage of recent advances in fluorescent 'tagging' of molecules involved in these cellular processes, as well as new microscopy technologies that give us an incredible new ability to watch all of this, up close and in real-time, says Dr. Ryan.

Specifically, Dr. Ryan used a fluorescent chemical stain called pHluorin and genetically fused it to a vesicular protein called vGlut1. We've used this fluorescent tagging approach before, but with molecules that can exist on either the outside or the inside of the vesicle, Dr. Ryan notes.

VGlut1 gives us a much more precise view, since it only inhabits the inside of the vesicle, he adds. That means that when we see the green fluorescent tag move outside of the vesicle, then the vesicle itself must have ruptured in some way. This gives us a much more accurate picture of the recycling process.

At the same time, the team took advantage of new breakthroughs in optical microscopy that maximize how much of the tag's fluorescent light can be grabbed by the microscope. This approach allowed them, for the first time, to follow how individual synaptic molecules are delivered and retrieved from the synaptic surface.

The result is an accurate view into this hitherto mysterious synaptic phenomenon, Dr. Ryan says.

The resealable spout hypothesis of vesicular recycling (also known as the kiss-and-run theory) may be the first casualty of this new insight.

We observed that, although recycling appears to occur within a set but somewhat variable time-frame, it's still using the same mechanism -- the vesicle falls apart upon delivering its cargo to the cell membrane, and then enzymes go to work re-building it for the next cycle, Dr. Ryan adds. I think this real-time observation really closes the door on the 'kiss-and-run' theory of vesicular recycling.

The new technology used in these experiments should bring scientists much more insight into how the synapse works generally, and that could have real implications for our understanding of neurological health and illness, Dr. Ryan says.

This is all part of the 'shop manual' of neurological function that we are currently putting together, piece by piece, he says. Discoveries like these are adding new pages to the manual every day, and it's that kind of knowledge that will someday save, extend and improve lives.

In fruit flies, homosexuality is biological but not hard-wired

Sun, 09 Dec 2007 05:00:00 PST

( from http://www.rxpgnews.com ) While the biological basis for homosexuality remains a mystery, a team of neurobiologists reports they may have closed in on an answer -- by a nose.

The team led by University of Illinois at Chicago researcher David Featherstone has discovered that sexual orientation in fruit flies is controlled by a previously unknown regulator of synapse strength. Armed with this knowledge, the researchers found they were able to use either genetic manipulation or drugs to turn the flies' homosexual behavior on and off within hours.

Featherstone, associate professor of biological sciences at UIC, and his coworkers discovered a gene in fruit flies they called genderblind, or GB. A mutation in GB turns flies bisexual.

Featherstone found the gene interesting initially because it has the unusual ability to transport the neurotransmitter glutamate out of glial cells -- cells that support and nourish nerve cells but do not fire like neurons do. Previous work from his laboratory showed that changing the amount of glutamate outside cells can change the strength of nerve cell junctions, or synapses, which play a key role in human and animal behavior.

But the GB gene became even more interesting when post-doctoral researcher Yael Grosjean noticed that all the GB mutant male flies were courting other males.

It was very dramatic, said Featherstone. The GB mutant males treated other males exactly the same way normal male flies would treat a female. They even attempted copulation.

Other genes that alter sexual orientation have been described, but most just control whether the brain develops as genetically male or female. It's still unknown why a male brain chooses to do male things and a female brain does female things. The discovery of GB provided an opportunity to understand why males choose to mate with females.

Based on our previous work, we reasoned that GB mutants might show homosexual behavior because their glutamatergic synapses were altered in some way, said Featherstone. Specifically, the GB mutant synapses might be stronger.

Homosexual courtship might be sort of an 'overreaction' to sexual stimuli, he explained.

To test this, he and his colleagues genetically altered synapse strength independent of GB, and also fed the flies drugs that can alter synapse strength. As predicted, they were able to turn fly homosexuality on and off -- and within hours.

It was amazing. I never thought we'd be able to do that sort of thing, because sexual orientation is supposed to be hard-wired, he said. This fundamentally changes how we think about this behavior.

Featherstone and his colleagues reasoned that adult fly brains have dual-track sensory circuits, one that triggers heterosexual behavior, the other homosexual. When GB suppresses glutamatergic synapses, the homosexual circuit is blocked.

Further work showed precisely how this happens -- without GB to suppress synapse strength, the flies no longer interpreted smells the same way.

Pheromones are powerful sexual stimuli, Featherstone said. As it turns out, the GB mutant flies were perceiving pheromones differently. Specifically, the GB mutant males were no longer recognizing male pheromones as a repulsive stimulus.

Featherstone says it may someday be possible to domesticate insects such as fruit flies and manipulate their sense of smell to turn them into useful pollinators rather than costly pests.

Effects of social isolation traced to brain hormone

Wed, 14 Nov 2007 05:00:00 PST

( from http://www.rxpgnews.com ) The anxiety and aggression that result from social isolation have been traced to altered levels of an enzyme that controls production of a brain hormone.

The study, done in mice by researchers at the University of Illinois at Chicago College of Medicine, is reported in this week's online addition of the Proceedings of the National Academy of Sciences.

We use this animal model for human stress because social isolation in both animals and humans can be responsible for a range of psychological effects, including anxiety, aggression and memory impairment, said Dr. Erminio Costa, director of the UIC Psychiatric Institute, professor of biochemistry and one of the authors of the study.

Previous studies had suggested that the neural pathways that underlie aggression, anxiety and fear include activation of specific types of neural circuitry that leads into the amygdala, the region of the brain responsible for emotion.

The researchers looked in these types of neurons for changes in the levels of two enzymes that are needed for the production of allopregnanolone, a brain hormone that acts to reduce stress through regulation of GABA, an important neurotransmitter. They found that the level of one of the enzymes, called 5-alpha-reductase type I, was reduced nearly 50 percent in the lonesome mice. Levels of the other enzyme did not change.

The researchers suggest that the decrease of 5-alpha-reductase type I and the consequent reduction in the hormone may impair the function of circuits leading to the amygdala and explain the aggressive behavior, perhaps related to anxiety, in socially isolated mice.

Humans respond to similar stress in very similar ways, said Dr. Alessandro Guidotti, UIC scientific director and professor of biochemistry in psychiatry. By identifying the mechanism we may be able to identify drugs that can treat these effects of stress.

UIC researchers Roberto Agis-Balboa, Dr. Graziano Pinna, Fabio Pibiri and Dr. Bashkim Kadriu also contributed to the study. The work was supported by grants from the National Institute of Mental Health. Pibiri was supported in part by a postdoctoral fellowship from the Regione Autonoma della Sardegna, Italy.

UIC ranks among the nation's top 50 universities in federal research funding and is Chicago's largest university with 25,000 students, 12,000 faculty and staff, 15 colleges and the state's major public medical center. A hallmark of the campus is the Great Cities Commitment, through which UIC faculty, students and staff engage with community, corporate, foundation and government partners in hundreds of programs to improve the quality of life in metropolitan areas around the world.

Hearing changes how we perceive gender

Wed, 24 Oct 2007 04:00:00 PST

( from http://www.rxpgnews.com ) EVANSTON, Ill. --- Think about the confused feelings that occur when you meet someone whose tone of voice doesn�t seem to quite fit with his or her gender.

A new study by neuroscientists from Northwestern University focuses on the brain�s processing of such sensory information about another�s gender to examine whether hearing fundamentally changes visual experience.

The study concludes that it does, weighing in with findings that contribute to provocative evidence about multi-sensory processing of our world that has been emerging in recent years.

�Auditory-Visual Cross-Modal Integration in Perception of Face Gender,� was published in a recent issue of Current Biology. The study�s co-authors are investigators at Northwestern�s Visual Perception, Cognition and Neuroscience Laboratory: lead author Eric Smith, graduate student, Marcia Grabowecky, research assistant professor of psychology, and Satoru Suzuki, associate professor of psychology.

�Researchers have long thought that one part of the brain does vision and another does auditory processing and that the two really don�t communicate with each other,� said Grabowecky.

�But emerging research suggests that rich information from different senses come together quickly and influence each other so that we don�t experience the world one sense at a time.�

The Northwestern study suggests that sensory interactions are happening at a very early level and tones of voices indeed fundamentally change visual processing.

�For our study, we used simple tones with no explicit gender information to get a window into how vision and audition work together to process gender information,� Grabowecky said. �Unlike stereotypical voices, the tones only hinted at male and female characteristics, and by coupling them with ambiguous faces, we were able to see how processing of various pitches affected vision very early in the sensory process.�

The study builds upon scarce scientific evidence supporting the idea that sounds can alter how masculine or feminine a person looks.

�Our vision can bias our experience of other senses, such as hearing,� said Smith. �We hear, for example, the ventriloquist�s voice coming from the dummy. In this study we wanted to see if hearing could change our visual experience.�

�We learn early on what auditory and visual characteristics accompany female and male voices, starting with our earliest experiences with our mothers and fathers,� said Grabowecky. �The question from the neuroscience perspective is when in the processing of perceptual information do auditory and visual senses interact with each other How does the brain do this�

To test whether a sound can influence perception of a face�s gender, the researchers digitally morphed male and female faces to create androgynous faces not easily categorized as male or female. Study participants were asked to look at the faces while listening to brief auditory tones, which fell within the fundamental speaking frequency range of either male or female voices.

In the initial stage of auditory processing, sounds are decomposed into basic frequency components, the lowest one called the fundamental frequency and higher ones called the harmonics. The fundamental frequency in the human voice typically falls between about 100 to 150 Hz for males and 160 to 300 Hz for females. Roughly speaking, the fundamental frequency determines the perceived pitch (lower for men and higher for women), and the harmonics add timbre (the quality of human voice).

In higher auditory brain areas, these frequencies are put back together to be coded as a human voice. The researchers took advantage of the fact that pure tones can be used to deliver individual frequency components that are registered in early auditory brain areas.

The findings showed that when an androgynous face was paired with a pure tone that fell within the female fundamental-frequency range, people were more likely to report that the ambiguous face was that of a female. But when the same face was paired with a pure tone in the male fundamental-frequency range, people were more likely to see a male face. (The bias did not occur when a face was paired with a pure tone that was too low or too high to be in the typical speaking range.)

�The strength of the study is that pure tones sound like beeps, and they primarily activate early stages of auditory processing,� Grabowecky said. �We think that the effect demonstrates a direct input from early auditory processing to visual perception.�

When people were forced to guess whether the tones were in the male range, the female range or outside of the typical speaking frequency range, their guesses were inaccurate and relative. In other words, when people heard a pair of pure tones, they tended to hear the higher tone to be feminine and the lower tone to be masculine regardless of the actual frequencies of the tones.

�Such relativity is not surprising, because our auditory experience depends on relative, rather than absolute, frequencies as most useful and entertaining auditory information, such as speech and music, is carried by how sound frequencies change over time,� Grabowecky said.

Absolute frequencies do not matter much, as we readily understand speech spoken by people with low and high voices and enjoy songs regardless of the keys in which they are played. In contrast, it is the �neglected� absolute-frequency information that influences visual perception of gender.

�A conscious impression of your voice is not what enhances your look of masculinity or femininity,� said Suzuki. �Sounds seem to influence visual gender in a much more fundamental way on the basis of their absolute frequencies processed in early auditory brain areas.�

The researchers focused on gender perception, because people have such a strong need to categorize people as male or female. �We all know the feeling of meeting a person who is very androgynous,� said Smith. �We simply need to know and will use any information at our disposal to identify a person�s gender. It is probably quite evolutionarily adaptive to be able to accurately tell males from females, as far as propagation of one�s genes is concerned.�

What is on the horizon?

�If sound can implicitly bias visual gender perception, then we need to consider whether other senses, such as smell, might yield similar effects,� said Smith. �Future studies might use masculine and feminine colognes, or even human pheromones to bias people to see androgynous faces as either male or female. With the possibility of other senses biasing the way that we see the world, our visual experience of gender might turn out to be much more than meets the eye.�

Stress: Brain yields clues about why some succumb while others prevail

Thu, 18 Oct 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Results of a new study may one day help scientists learn how to enhance a naturally occurring mechanism in the brain that promotes resilience to psychological stress. Researchers funded by the National Institutes of Health�s National Institute of Mental Health (NIMH) found that, in a mouse model, the ability to adapt to stress is driven by a distinctly different molecular mechanism than is the tendency to be overwhelmed by stress. The researchers mapped out the mechanisms � components of which also are present in the human brain � that govern both kinds of responses.

In humans, stress can play a major role in the development of several mental illnesses, including post-traumatic stress disorder and depression. A key question in mental health research is: Why are some people resilient to stress, while others are not This research indicates that resistance is not simply a passive absence of vulnerability mechanisms, as was previously thought; it is a biologically active process that results in specific adaptations in the brain�s response to stress.

Results of the study were published online in Cell, on October 18, by Vaishnav Krishnan, Ming-Hu Han, PhD, Eric J. Nestler, MD, PhD, and colleagues from the University of Texas Southwestern Medical Center, Harvard University, and Cornell University.

Vulnerability was measured through behaviors such as social withdrawal after stress was induced in mice by putting them in cages with bigger, more aggressive mice. Even a month after the encounter, some mice were still avoiding social interactions with other mice � an indication that stress had overwhelmed them � but most adapted and continued to interact, giving researchers the opportunity to examine the biological underpinnings of the protective adaptations.

�We now know that the mammalian brain can launch molecular machinery that promotes resilience to stress, and we know what several major components are. This is an excellent indicator that there are similar mechanisms in the human brain,� said NIMH Director Thomas R. Insel, MD.

Looking at a specific part of the brain, the researchers found differences in the rate of impulse-firing by cells that make the chemical messenger dopamine. Vulnerable mice had excessive rates of impulse-firing during stressful situations. But adaptive mice maintained normal rates of firing because of a protective mechanism � a boost in activity of channels that allow the mineral potassium to flow into the cells, dampening their firing rates.

Higher rates of impulse-firing in the vulnerable mice led to more activity of a protein called BDNF, which had been linked to vulnerability in previous studies by the same researchers. With their comparatively lower rates of impulse-firing, the resistant mice did not have this increase in BDNF activity, another factor that contributed to resistance.

The scientists found that these mechanisms occurred in the reward area of the brain, which promotes repetition of acts that ensure survival. The areas involved were the VTA (ventral tegmental area) and the NAc (nucleus accumbens).

In a series of experiments, the scientists extended their findings to provide a progressively larger picture of the vulnerability and resistance mechanisms. They used a variety of approaches to test the findings, strengthening their validity.

�The extensiveness and thoroughness of their research enabled these investigators to make a very strong case for their hypothesis,� Insel said.

For example, the researchers showed that the excess BDNF protein in vulnerable mice originated in the VTA, rather than in the NAc. Chemical signals the protein sent from the VTA to the NAc played an essential role in making the mice vulnerable. Blocking the signals with experimental compounds turned vulnerable mice into resistant mice.

The scientists also conducted a genetic experiment which showed that, in resistant mice, many more genes in the VTA than in the NAc went into action in stressful situations, compared with vulnerable mice. Gene activity governs a host of biochemical events in the brain, and the results of this experiment suggest that genes in the VTA of resilient mice are working hard to offset mechanisms that promote vulnerability.

Another component of the study revealed that mice with a naturally occurring variation in part of the gene that produces the BDNF protein are resistant to stress. The variation results in lower production of BDNF, consistent with the finding that low BDNF activity promotes resilience.

The scientists also examined brain tissue of deceased people with a history of depression, and compared it with brain tissue of mice that showed vulnerability to stress. In both cases, the researchers found higher-than-average BDNF protein in the brain�s reward areas, offering a potential biological explanation of the link between stress and depression.

�The fact that we could increase these animals� ability to adapt to stress by blocking BDNF and its signals means that it may be possible to develop compounds that improve resilience. This is a great opportunity to explore potential ways of increasing stress-resistance in people faced with situations that might otherwise result in post-traumatic stress disorder, for example,� said Nestler.

�But it doesn�t happen in a vacuum. Blocking BDNF at certain stages in the process could perturb other systems in negative ways. The key is to identify safe ways of enhancing this protective resilience machinery,� Nestler added.

Genes may make some people more motivated to eat, perhaps overeat

Sun, 14 Oct 2007 04:00:00 PST

( from http://www.rxpgnews.com ) WASHINGTON � Science has found one likely contributor to the way that some folks eat to live and others live to eat. Researchers at the University at Buffalo, The State University of New York, have found that people with genetically lower dopamine, a neurotransmitter that helps make behaviors and substances more rewarding, find food to be more reinforcing than people without that genotype. In short, they are more motivated to eat and they eat more.

The findings appear in the October issue of Behavioral Neuroscience, which is published by the American Psychological Association (APA). Insights into genes and eating could inspire custom-tailored treatment programs for obesity, perhaps including genetically targeted drugs.

Led by Leonard Epstein, PhD, a distinguished professor of pediatrics and social and preventive medicine at the university�s medical school, the team brought 29 obese adults and 45 adults who were not obese into the lab for a controlled study of the relationships among genotype, motivation to eat and caloric consumption.

Epstein�s team was particularly interested in the influence of the Taq1 A1 allele, a genetic variation linked to a lower number of dopamine D2 receptors and carried by about half the population (most of which carries one A1 and one A2; carriers of two A1 alleles are rare). The other half of the population carries two copies of A2, which by fostering more dopamine D2 receptors may make it easier to experience reward. People with fewer receptors need to consume more of a rewarding substance (such as drugs or food) to get that same effect.

Epstein differentiates reinforcing value, defined by how hard someone will work for food, from the �feel good� pleasure people get from food, saying, �They often go together, but are not the same thing.�

Researchers measured participants� body mass, swabbed DNA samples from inside their cheeks, and had them fill out eating questionnaires. There were two behavioral tasks.

In the first task, participants rated various foods � from chips to candy bars � for taste and personal preference. This apparent preference test disguised a task that measured how much participants ate when food was freely available.

In the second task, participants could swivel between two computer stations. Pressing specified keys on one earned points to eat their favorite food; pressing keys on the other earned points to read a newspaper.

The resulting behavioral measures included calories consumed as energy in kilocalories, reflecting both amount and caloric density, and time spent earning food instead of the opportunity to read the news.

Both obesity and the genotype associated with fewer dopamine D2 receptors predicted a significantly stronger response to food�s reinforcing power. Perhaps not surprisingly, participants with that high level of food reinforcement consumed more calories.

The results also revealed a three-rung ladder of consumption, with people who don�t find food that reinforcing, regardless of genotype, on the lowest rung. On the middle rung are people high in food reinforcement without the A1 allele. Atop the ladder are people high in food reinforcement with the allele, a potent combination that may put them at higher risk for obesity.

The reinforcing value of food, which may be influenced by dopamine genotypes, appeared to be a significantly stronger predictor of consumption than self-reported liking of the favorite food. What�s more, obese participants clearly found food to be more reinforcing than non-obese participants. The authors conclude that, �Food is a powerful reinforcer that can be as reinforcing as drugs of abuse.�

Researchers still view reinforcement as one of several factors that motivate eating behavior, but the present study highlights the genetic contribution and role of reinforcement. In theory, people producing less dopamine may, as a result, require more food to reach a certain state of reward or reinforcement that might be reached quicker, after less consumption, by those with a different genotype.

Findings such as these can help obesity experts to pinpoint people at greater risk for obesity and to develop treatments tailored to specific risk factors. �Behavior and biology interact and influence each other,� says Epstein. �The genotype does not cause obesity; it is one of many factors that may contribute to it. I think the factors that make up eating behavior are in part genetic and in part learning history.�

He and his colleagues speculate that, as with other public-health campaigns, it may be better to focus behavior change efforts on those at high risk. �A strategy for someone who is high in food reinforcement would be very different from the strategy for someone who is low in food reinforcement but higher in activity reinforcement,� they wrote. Using overweight men, the group has already found that chemically manipulating dopamine levels alters eating behavior, a finding highly suggestive for pharmaceutical intervention.

Scientists identify brain circuits used in sensation of touch

Wed, 10 Oct 2007 04:00:00 PST

( from http://www.rxpgnews.com ) The ability to tactually recognize fine spatial details, such as the raised dots used in braille, is especially important to those who are blind. With that in mind, a team of researchers has identified the neural circuitry that facilitates spatial discrimination through touch. Understanding this circuitry may lead to the creation of sensory-substitution devices, such as tactile maps for the visually impaired.

The findings appear in the Oct. 10 edition of The Journal of Neuroscience.

The research team, led by Krish Sathian, MD, PhD, professor of neurology in Emory University School of Medicine, included first author Randall Stilla, research MRI technologist at Emory, and Gopikrishna Deshpande, Stephen Laconte and Xiaoping Hu of the Coulter Department of Biomedical Engineering at Georgia Tech and Emory.

Using functional magnetic resonance imaging (fMRI), the researchers found heightened neural activity in a network of frontoparietal regions of the brain when people engaged in fine tactile spatial discrimination. Within this network, the levels of activity in two subregions of the right posteromedial parietal cortex--the right posterior intraparietal sulcus (pIPS) and the right precuneus--were predictive of individual participants' tactile sensitivities.

To determine which areas of the brain were involved in identifying fine spatial details, the researchers asked 22 volunteers to determine only by touch whether the central dot of three vertically arranged dots was offset to the left or to the right of the other two.

Using their right index fingers, the subjects got to feel the dots for one second to determine in which direction the central dot was offset, says Dr. Sathian. We also varied the amount the dot was offset from the other two, which allowed us to quantify people's sensitivity. In other words, we asked what is the minimal offset required to discriminate.

In a separate control task, the subjects were asked to determine how long they were touched by three perfectly aligned dots. Brain activity during that temporal task was contrasted with brain activity during the spatial task. The researchers found that different brain regions showed more activity during either spatial or temporal processing.

What is interesting is that we found the most relevant areas of the brain for spatial processing are on the right side, the same side of the body that was used to feel the stimuli. This is the opposite side to the one that might be expected, says Randall Stilla.

We usually think of the left side of the brain as controlling the right side of the body, which is generally true. But more and more we are finding that the right side of the brain is particularly important in many types of sensory processing, adds Dr. Sathian.

Dr. Sathian's and Dr. Hu's laboratories also collaborated to determine the strength and direction of the connections between the areas of the brain that govern tactile spatial acuity (perception). Such collaboration, explains Dr. Hu, allows the application of cutting-edge image analysis methods to fundamental questions in neuroscience.

We found that there are two pathways into the right posteromedial cortex that not only predict individuals' acuity but also predict the magnitude of neural activation, says Dr. Deshpande, who performed the connectivity analyses. In better performers, the paths predicting acuity converge from the left somatosensory cortex and right frontal eye field (an attentional control center), onto the right pIPS. What's more, these paths are stronger during spatial discrimination than temporal discrimination.

The researchers are not yet sure why this particular neural pathway exists. Dr. Sathian suggests the signal patterns may be a combination of attentional, tactile, and visual processing reflecting the visualization of the spatial configurations. Future research, he says, will attempt to unravel the mechanisms underlying these different component processes.

Evil genes made me do it

Mon, 08 Oct 2007 04:00:00 PST

( from http://www.rxpgnews.com ) While there have been numerous medical studies investigating the physiological and biochemical basis for behavioral disorders such as antisocial personality disorder and borderline personality disorder, there have been virtually no comprehensive studies aimed at providing a physiological explanation of malignant narcissism�a term that characterizes individuals who exhibit malevolent behavior but are still able to function effectively in society.

Inspired both by the dearth of scientific literature on the subject and by her sister�s Machiavellian personality, Barbara Oakley, Associate Professor of Bioengineering at Oakland University in Michigan, set out to conduct an investigation of the physiology of this particular disorder and the impact it has had on human society. The result is Evil Genes: Why Rome Fell, Hitler Rose, Enron Failed, and My Sister Stole My Mother�s Boyfriend (Prometheus Books $28.95), which Harvard professor Steven Pinker praises as �a fascinating scientific and personal exploration of the roots of evil, filled with human insight and telling detail.�

Evil Genes is the first book to tie together the cutting edge neuroscientific and genetic results that explain human evil, showing that some deceitful, manipulative, and even sadistic behavior appears to be programmed genetically. Unlike other popular books about human evil, Evil Genes goes far beyond �explaining� psychopathic behavior using old-fashioned psychological theories or religious dogma. Instead, it centers on what neuroscience and genetics are revealing about not only psychopathy, but also the more subtly devious behavior of seemingly ordinary people. Oakley follows clues from the diary of her late sister�who actually did steal her mother�s boyfriend�and takes the reader inside the heads of malevolent people you know, perhaps all too well, but could never understand�until now.

Starting with psychology as a frame of reference, Oakley uses cutting-edge images of the working brain to provide startling support for the idea that �evil� people act the way they do mainly as the result of certain dysfunctions, some of which have a genetic basis. But there are unexpected fringe benefits to Evil Genes. We may not like them�but we literally can�t live without them. The recent dramatic findings presented in Evil Genes illuminate not only the eerily similar behavior of dictators far afield, such as Hitler, Mao, and Milosevic, but aspects of politics at home, as well as business, religion, and everyday life. As Terrance Deacon, Professor of Biological Anthropology and Neuroscience at UC Berkeley, says, �shining this light on some of the most problematic figures of our era�challenges our assumptions about the roots of terrorism, genocide, crime, corruption�and even the sinister sides of politics, business, and religion.�

In fact, history has been shaped by the strange confluence of genes and environment that science is just now beginning to understand. Oakley links the latest findings of molecular research to a wide array of seemingly unrelated historical and current phenomena, from the harems of the Ottomans and the chummy jokes of �Uncle Joe� Stalin, to the remarkable memory of investor Warren Buffett.

William A. Wulf, President Emeritus, National Academy of Engineering, says, �Oakley deftly moves through psychology, functional brain imagery, and molecular biology to weave a compelling and provocative case for a genetic base for evil. 'Scientific non-fiction' and 'page turner' aren�t two phrases I�d expect in the same sentence, but for the remarkable Evil Genes, they fit.�

Evil Genes is a tour-de-force of popular science writing that brilliantly melds scientific research with intriguing family history and puts both a human and scientific face to evil.

Barbara Oakley, PhD, �a female Indiana Jones,� is one of the few women to hold a doctorate in systems engineering. She chronicled her adventures on Soviet fishing boats in the Bering Sea in Hair of the Dog: Tales From Aboard a Russian Trawler. She also served as a radio operator in Antarctica and rose from private to captain in the U.S. Army. Now an associate professor of engineering at Oakland University in Michigan, Oakley is a recent vice president of the IEEE Engineering in Medicine and Biology Society. Her work has appeared in numerous publications.

USC biomedical team to participate in $6 million low vision project

Fri, 05 Oct 2007 04:00:00 PST

( from http://www.rxpgnews.com ) An interdisciplinary team of biomedical researchers from the USC Viterbi School, the College and the Keck School of Medicine of USC has received a $6-million Bioengineering Research Partnership grant from the National Institutes of Health (NIH) to begin designing visual aids for millions of older adults who suffer from significant vision loss.

The USC team, led by Norberto Grzywacz, professor of biomedical engineering in the Viterbi School and director of the USC Center for Vision Science and Technology, will join other researchers from Harvard Medical School and the University of Houston School of Optometry to address low vision problems caused by neural pathologies, such as macular degeneration and other diseases affecting the retina. Many of these vision problems are prevalent in older adults and cannot be fully corrected with ordinary lenses, medical treatment or surgery.

Aging, injuries and diseases can all cause low vision, but the leading causes among older adults and the elderly are impairments such as age-related macular degeneration (AMD), said Grzywacz, principal investigator on the five-year project, who also directs the USC Neuroscience Graduate Program. �Our dream is to build devices like intelligent glasses or intelligent television displays that can improve these people�s lives.�

AMD is a condition that usually develops in older adults and the elderly, and gradually destroys the central vision of the eye and an individual�s ability to see fine detail. AMD patients quite often lose their ability to read, recognize faces and drive.

With an aging population, the incidence of AMD is on the rise. According to Grzywacz, approximately 3.5 percent of people in industrialized countries over the age of 75 have AMD.

�That percentage rises to a staggering 18.5 percent for people over 85 years old,� he said. �AMD is also responsible for about 50 percent of all cases of registered blindness in industrialized countries.�

The statistics are just as daunting in the United States. According to the National Eye Institute (NEI), approximately 1.7 million Americans have some form of AMD. Mark Humayun, an AMD expert in the USC Viterbi School of Engineering and the Keck School of Medicine of USC, predicts that by 2020, that number will climb to nearly 3 million. At the same time, an additional 8 million people will have clinical signs of AMD.

The NIH project will concentrate on designing visual displays that will help these people, who have lost their central vision and must rely on peripheral vision to see.

�We plan to use some of the techniques of computer vision and computational neuroscience to build visual displays that will enhance certain parts of an image enough so that a person with AMD will be able to digest the visual information better,� Grzywacz said. �We aren�t concerned with the optics of the eye in low vision � that can be corrected with glasses or surgery. Rather, our preoccupation is with the nervous system and the way in which the brain processes information.�

The nervous system has been damaged in people with low vision and lacks some kinds of neurons that process information, he said. In AMD, for example, people lack central photoreceptors, the neurons that transduce light energy into electrochemical signals, the means of brain communication. Grzywacz hopes to design visual displays that will compensate for that neural loss.

As part of the work, engineering faculty in USC�s Center for Vision Science and Technology will improve visual displays in two ways: first, they will enhance contrast in scenes and suppress background �noise� (irrelevant details) that might confuse a visually-impaired person; second, they will design displays that brighten the contours of objects in a scene, creating a �cartoon� of outlines that would be more recognizable by someone with poor eyesight.

Gerard Medioni of the Viterbi School Computer Science Department will lead the first task of building displays with region-specific contrast enhancement display. He will work with DXO Labs to modify and extend an already existing system that was developed for photography, emphasizing visibility rather than aesthetics. In standard photography, a camera adjusts its light sensitivity to the overall luminosity in a scene, so some objects will come out much darker than the brightest object in the picture. In the contrast-enhanced display, all regions of the scene would appear equally well lit, regardless of how dark or light they actually are.

�When you lose your central vision, you lose the ability to use the fovea, which is responsible for the perception of sharp details,� Grywacz said. �This is a region with a high concentration of cone photoreceptors.

�Once that region is damaged, an individual can only see in the peripheral region of the retina, which has far fewer cone photoreceptors and can only deliver information of low resolution to the brain,� he said. �The near periphery is inferior to the fovea and gets confused when too many details appear in the scene; scientists call this the �masking �and �crowding� effects.�

To combat that reduced ability to see sharp details, a second team of researchers will use automatic techniques to outline and simplify the main objects in a scene, as in a cartoon, to increase their visibility and salience. These simplified objects may be more easily recognizable by subjects with low vision, said Bartlett Mel, associate professor of biomedical engineering in the Viterbi School, who will lead the effort.

In the third phase of the study, a team of psychologists and clinicians from the USC College, Keck School of Medicine, Harvard Medical School and University of Houston School of Optometry will develop and administer tests to measure the effectiveness of these new visual display systems. This team has expertise in blindness and low vision, and in the development of visual aids.

They will administer a battery of high-level vision tests to probe psychophysically visual functions, such as recognition of objects, faces and scenes. Other, lower-level tests will help the team determine whether subjects have better visual acuity, contrast sensitivity, visual fields, color vision and reading ability.

The patients will also be trained in techniques of perceptual learning to make the best use of the devices; statistical learning tools built into the devices will adapt automatically to the needs of the patients. Bosco Tjan of the USC College Psychology Department, Susana Chung from the University of Houston, and Eli Peli from Harvard Medical School will lead that effort.

Other USC faculty working on the NIH study include Irving Biederman of the College, who is an expert in object, face, and scene recognition; Zhong-Lin Lu of the College and Viterbi School, who specializes in motion perception and perceptual learning; and AMD specialist Dr. Mark Humayun, who holds joint appointments in the Keck School of Medicine of USC Department of Ophthalmology and the Viterbi School of Engineering.

Vanderbilt nets brain gene research center

Tue, 02 Oct 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Neuroscientists at Vanderbilt University are stepping into the national limelight with the establishment of a Silvio O. Conte Center for Neuroscience Research.

The new center, funded by a $10 million grant from the National Institute of Mental Health (NIMH), will support interdisciplinary studies aimed at understanding the gene networks that control serotonin systems in the brain.

The neurotransmitter serotonin is central to brain biology: it participates in systems that control sleep, aggression, sexual drive, satiety, reward and mood. Serotonin has been implicated in a range of disorders including depression, obsessive-compulsive disorder, schizophrenia and autism, and medications that affect serotonin signaling, such as the SSRI (selective serotonin reuptake inhibitor) antidepressants, are widely prescribed.

The Vanderbilt Conte Center investigators are focusing their efforts on the raphe nuclei, a cluster of serotonin neurons that reside in the brain stem and receive input from and send messages to neurons throughout the rest of the brain.

�This is one of the most medically important cell groups in the nervous system, and the genes that control these neurons and their output are particularly key to our understanding of mental illness risk,� said Randy Blakely, Ph.D., director of the new Conte Center.

�Dr. Blakely has assembled the right team for the job of understanding how genetic variability affects neurotransmitter systems in the developing brain,� said Thomas Insel, M.D., director of the NIMH. �The new Center holds promise for hastening the day when discoveries in the lab will be translated into improved treatments for people with mental illnesses, from mood disorders to autism.�

Conte Centers for Neuroscience Research are a centerpiece of NIMH funding, said Beth-Anne Sieber, Ph.D., chief of the Developmental Biology Program at NIMH. �With these centers, NIMH is looking to the investigators to push their hypotheses forward, create new hypotheses, and find answers relevant to mental health.�

�The Vanderbilt center is the epitome of a Conte Center,� she said. �It really captures the spirit of integration and synergy between investigators.�

The centers are named for the late U.S. Rep. Silvio O. Conte, a longtime advocate for scientific research and organizer of the 1990s �Decade of the Brain� efforts. There are approximately 10 Conte Centers for Neuroscience Research and 10 Conte Centers for the Neuroscience of Mental Disorders � centers with a translational-clinical research emphasis.Blakely said the new center reflects Vanderbilt�s commitment to and investments in neuroscience programming, evident in the growth in research and education here over the last decade.

�This is a defining moment for the neurosciences at Vanderbilt,� said Jeffrey Balser, M.D., Ph.D., associate vice chancellor for Research. �Over the last few years, we have received several forms of external validation that affirm neuroscience at Vanderbilt has become absolutely top tier. An NIH Conte award makes that excellence even more visible to the national and international research community, and at the same time will provide crucial resources for making fundamental progress in mental health research.�

The Vanderbilt Conte Center includes scientists from the School of Medicine and the College of Arts and Science as well as researchers at other institutions. The center investigators will probe the workings of serotonin neurons in the raphe complex from their earliest stages of development to their function in mature animals. The operating hypothesis of the group, Blakely said, is that a rich network of genes establishes and maintains serotonin signaling in the brain and that deficits in the formation or stability of this network in humans underlies risk for mental illness.

The projects make extensive use of specialized mouse models, including mice in which serotonin neurons have been specifically tagged with fluorescent marker proteins or have had selective changes to their serotonin signaling molecules.

�We know that serotonin networks � broadly, all the genes that cooperate to control serotonin assembly and signaling � can be identified and manipulated in the mouse,� Blakely said, �and we feel strongly that the conservation of these networks in humans will allow us to formulate new hypotheses regarding disease-associated genetic variation.�

The Conte Center will also support multiple core facilities that �rest upon the significant technological framework that has been established at Vanderbilt through its shared resources program,� Blakely added.

In addition to its core facilities that will benefit the wider Vanderbilt research community, the Conte Center will administer a pilot grant program targeted to young investigators or established investigators who wish to enter the field of serotonin biology. The center will also host an annual symposium centered on the themes of the Conte program, and Conte Center members will participate in outreach activities that convey to a broader audience the �why� behind the research.

Vanderbilt Conte Center projects and leaders:

Chemical compound found in tree bark stimulates growth, survival of brain cells

Mon, 01 Oct 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Researchers have identified a compound in tree bark that mimics the chemical reactions of a naturally occurring molecule in the brain responsible for stimulating neuronal cell signaling. Neuronal cell signaling plays a crucial role in the growth, plasticity and survival of brain cells.

The tree bark compound, known as gambogic amide, behaves much like Nerve Growth Factor (NGF), a molecule found in the brain. NGF binds to TrkA, a neuronal receptor, and activates neuronal signaling. It is known that the loss of TrkA density correlates with neuronal atrophy and severe cognitive impairment such as that associated with Alzheimer�s disease.

Because gambogic amide also binds to TrKA and activates neuronal signaling, the researchers believe it may have potential as a therapeutic treatment in people affected by neurodegenerative disease, such as stroke, Alzheimer�s disease and peripheral diabetic neuropathies.

Results of the study are published online in the Proceedings of the National Academy of Sciences and will be published in a future print edition.

The research was conducted by Emory University scientists Keqiang Ye, PhD, associate professor of pathology and laboratory medicine; first author Sung-Wuk Jang, PhD, and Masashi Okada, PhD, post-doctoral fellows in Dr. Ye�s lab; Iqbal Sayeed, PhD, instructor; Donald Stein, PhD, Asa G. Candler Professor of Medicine; and Peng Jin, PhD, assistant professor of human genetics; and Dr. Ge Xiao at the Centers for Disease Control and Prevention.

Gambogic amide is derived from gambogic acid, a major ingredient of gamboges, a brownish-orange resin exuded from the Southeast Asian Garcinia hanburryi tree. The resin has been used in that area of the world for thousands of years to treat cancers without any reported toxicity to noncancerous cells.

Humans actually have a naturally occurring molecule in the body, Nerve Growth Factor (NGF), which stimulates the growth and differentiation of certain types of nerve cells. However, NGF has poor pharmocokinetics and bioavailability when synthetically manufactured and used therapeutically, and it is also expensive to produce, Dr. Ye says.

Previous research had focused on copying the chemical structure of NGF, but the cyclopeptide mimetics are not potent enough to use as a therapeutic agent. Instead, we decided that we needed to identify a more robust molecule that would pharmacologically mimic NGF's effect on brain cells by binding to TrkA. What we came up with was gambogic amide. Dr. Ye says.

The researchers are now conducting further pre-clinical research to investigate how the body processes gambogic amide and to confirm that it is in fact non-toxic.

Loss of gene leads to protein splicing and buildup of toxic proteins in neurons

Thu, 27 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) JACKSONVILLE, Fla. -- Researchers at Mayo Clinic in Jacksonville have discovered how loss of a gene can lead to accumulation of toxic proteins in the brain, resulting in a common dementia, and they say this mechanism may be important in a number of age-related neurological disorders.

In the Sept. 26 issue of the Journal of Neuroscience, the scientists demonstrate that absence of a gene known as progranulin leads to errant splicing of a protein that usually operates within the nucleus of a nerve cell (neuron). When cut these proteins move into the body of the cell, and begin to stick together and form a thicket that grows, eventually disrupting the normal functioning of the neuron, the researchers say.

Clumps of this protein, TDP-43, have been found in a number of older age dementias, including Alzheimer�s Disease (AD), Frontal Temporal Dementia (FTD), and in amyotrophic lateral sclerosis (ALS).

Not only does the study potentially explain why TDP-43 pathology is present in a number of neurodegenerative diseases, it also offers new research routes to take in looking for beneficial treatments, says the study�s lead investigator, Leonard Petrucelli, Ph.D. �Our work opens opportunities on possible future therapeutic applications, from approaches to novel drug discovery to the continued exploration of cell survival systems,� he says.

Mayo investigators filled in this piece of the dementia puzzle by exploring possible connections between two recent ground-breaking discoveries. In July, 2006, Mayo researchers reported in Nature that a form of FTD not caused by tau accumulation in neurons was due to mutations in the progranulin gene. Progranulin produces a protein that helps neurons survive, and so far, the research group has found more than 40 different mutations in the gene can directly cause FTD.

The second study, reported in October, 2006, in Science by researchers at the University of Pennsylvania School of Medicine, found that the protein clogging brains of patients with FTD and ALS is TDP-43. The protein was recovered from post-mortem brain tissue and was found only in areas affected by the diseases. For example, in ALS patients it was found in the spinal cord motor neurons which control movement, and in patients with FTD, which is second most common form of dementia in people under age 65, clumps of TDP-43 were found in the frontal and temporal lobes which control the judgment and thought process disrupted in the disease. In its normal state, TDP-43 is believed to help genes produce proteins.

In this study, Mayo researchers investigated whether progranulin is involved in TDP-43 processing. Suppressing progranulin expression in neurons led to accumulation of TDP-43 fragments, they found, and further discovered that this cleavage depends on the caspase 3 enzyme. Caspases cut other proteins and thus play a crucial role in pushing a cell to die when it needs to. It makes sense that these caspase might be activated when progranulin is mutated, Dr. Petrucelli says, because loss of progranulin can activate cell death signaling. �We are now looking into how mutations in progranulin leads to an increase in caspase activity,� he says. �Progranulin could be acting a protective chaperone where it binds to TDP-43, and may protect it from cleavage.�

Theoretically, suppression of caspase 3 might stop the cutting and accumulation of TDP-43, but such a strategy could not work clinically given that caspases are needed throughout the body for normal functioning, Dr. Petrucelli says. �However, it might be possible to identify other compounds that specifically prevent the fragmentation and redistribution of TDP-43, and that is an issue we are now studying.�

At this point, researchers don�t know if progranulin mutations are present in ALS or in AD.

Genes linked to suicidal thinking during antidepressant treatment

Thu, 27 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Specific variations in two genes are linked to suicidal thinking that sometimes occurs in people taking the most commonly prescribed class of antidepressants, according to a large study led by scientists at the National Institutes of Health�s (NIH) National Institute of Mental Health (NIMH). Depending on the particular mix inherited, these versions increased the likelihood of such thoughts from 2- to15-fold, the study found. About 1 percent of adult patients were deemed to be at high genetic risk, 41 percent at elevated risk and 58 percent at lower risk.

If confirmed, the findings may hold promise for genetic testing, as more such markers are identified.

Risk increased proportionately if a participant had two, as opposed to just one of the suspect versions. Both genes code for components of the brain�s glutamate chemical messenger system, which recent studies suggest is involved in the antidepressant response.

Overall, about 6 percent of 1,915 patients with depression reported that they started to have suicidal thoughts while taking an antidepressant. This rate soared to 36 percent among the few patients with both of the suspect gene versions; 59 percent of the patients who had suicidal thoughts had at least one of the versions.

Francis J. McMahon, M.D., Gonzalo Laje, M.D., NIMH Mood and Anxiety Disorders Program, and colleagues at the National Human Genome Research Institute (NHGRI), Mount Sinai School of Medicine, and the University of Texas Southwestern Medical Center, report on their findings in the October, 2007 issue of The American Journal of Psychiatry.

�These data suggest that genetics may soon help us in our quest to individualize treatments for depression,� said NIMH Director Thomas R. Insel, M.D.

�In the future, we hope that genetic testing will help doctors identify those few patients who are at high risk for suicidal thinking during antidepressant therapy and need close monitoring or alternative treatments,� said McMahon. �This should help allay concerns for the vast majority of patients. The best way to prevent suicide is to treat depression.�

In the most comprehensive study of its kind to date, McMahon and colleagues screened genetic material from 1,915 adult participants with major depression in level one of the NIMH-funded STAR*D (Sequenced Treatment Alternatives for Depression) trial. Study participants were treated with the selective serotonin reuptake inhibitor (SSRI) citalopram. The researchers looked for associations between self-reports of suicidal thinking and more than 700 sites in 68 suspect genes where letters in the genetic code vary across individuals, creating different versions of the same gene.

The researchers found that certain versions of two genes that code for glutamate receptors � the receiving stations for the neurotransmitter�s chemical messages � were more prevalent in patients with suicidal thinking. How the newly identified versions affect the workings of glutamate receptors to confer increased risk remains to be discovered. It�s also not yet known whether the findings generalize to other antidepressants.

One percent of the study participants had a version of the kainate receptor gene, GRIK2, that increased the odds for suicidal thinking more than 8-fold. Forty-one percent of participants had a version of the AMPA receptor gene, GRIA3, that raised the odds nearly 2-fold. About one-half of 1 percent of participants had both high risk gene versions, boosting the odds 15 fold � but this was the case for only 11 participants, of whom four developed suicidal thinking.

Neither version was related to self-reported history of suicide attempts. This suggests that the versions are specific to suicidal thoughts that occur during antidepressant treatment, rather than the much more common suicidal thoughts and behavior that occur outside of the treatment setting.

More than 40 percent of those who developed suicidal thoughts lacked either of the two versions, indicating that other genes and environmental factors were also likely involved. But the potential value of predictive testing is increasing as more genes are analyzed. McMahon�s group will report at a genetics conference in October on identification of additional versions that emerged from a scan of the whole genome in STAR*D patients. In July, NIMH funded researchers at Massachusetts General Hospital reported an association between variations in the CREB1 gene and treatment-emergent suicidal thinking among men in the STAR*D sample.

Earlier studies had shown that about 4 percent of youth treated with antidepressants experience suicidal thinking compared with about 2 percent of those taking placebos.

The resultant climate of concern culminated in the 2004 Food and Drug Administration decision requiring that antidepressants carry a black box warning about risk of suicidal thinking for children and adolescents � and later proposing that it be extended to young adults up to age 24. In 2004, the Centers for Disease Control recorded the largest spike in youth suicide rates in 15 years. NIMH-funded researchers recently suggested that this may have been related to a drop in antidepressant prescriptions for youth. By contrast, they note that suicide rates reached a record low in 2004 for adults over 60, for whom antidepressant prescription rates continued to rise; this inverse relationship held with increasing age. A more definitive analysis must await release of 2005 U.S. suicide rate data later this year, researchers say.

However, evidence suggests that neither suicidal thoughts, nor the high-risk gene versions, are necessarily related to actual suicide attempts, according to McMahon. Other studies have shown that the rate of such attempts is higher before antidepressant treatment begins � and suicide attempts are not always preceded by suicidal thoughts. For example, in the current study, one of the two participants who actually attempted suicide carried high-risk versions, but denied experiencing suicidal thoughts.

Even if suicidal thinking does not predict suicidal behavior, it is associated with a poorer response to antidepressant medication, the researchers say. Only 25 percent of patients with suicidal thinking fully recovered from their depression during the initial phase of the STAR*D trail, compared with 42 percent of patients not affected by such thoughts.

McMahon and colleagues hope that the newly identified versions may prove useful in identifying patients who need closer monitoring, alternative treatments and/or specialty care � while reassuring those for whom antidepressants are appropriate.

Scientists identify fundamental brain defect, probable drug target in fragile X syndrome

Mon, 17 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Scientists have discovered how the gene mutation responsible for fragile X syndrome--the most common inherited form of mental retardation--alters the way brain cells communicate. In neurons cultured from laboratory rats, the scientists also were able to reverse the effects of the mutation using a drug targeted to the specific site in an upstream pathway of the defect. The finding could lead to the development of human therapies for this previously untreatable condition.

The research was led by Stephen T. Warren, PhD, Timmie professor and chair of human genetics in Emory University School of Medicine, and Gary J. Bassell, PhD, Emory professor of cell biology. It will be reported in the Proceedings of the National Academy of Sciences (PNAS) the week of Sept. 17. Lead author is Emory genetics postdoctoral fellow Mika Nakamoto.

We have now explained the fundamental defect in the brain in fragile X syndrome and, most importantly, found that we can correct this problem in the laboratory, says Dr. Warren. This is quite exciting, progressing from the identification of the gene in 1991 to now believing we will be able to treat a previously untreatable condition. Our next steps will be to continue screening and identifying the best drugs to try and correct the deficiencies that result from fragile X syndrome.

Fragile X syndrome is caused by a mutation in the FMR1 gene on the X chromosome. A region of the mutated FMR1 gene repeats a trinucleotide sequence of DNA bases--CGG--between 200 and 1,000 times, rather than the normal 6 to 55 repeats in normal individuals. The abnormal trinucleotide repeats cause the absence of the FMR protein normally produced by the gene.

Dr. Warren and his colleagues led an international team that discovered the FMR1 gene in 1991. They later characterized the FMR protein (FMRP) and developed diagnostic tests for fragile X syndrome. Ever since, their research has focused on identifying the specific consequences of FMRP deficiency in the brain and finding targets for drug therapy.

Previously, Dr. Warren, working with scientists at Brown University, discovered that the absence of FMRP in the mouse model of fragile X syndrome leads to an abnormality in synaptic strength, or the degree by which neurons communicate, that suggested an abnormality of AMPAR receptors on the surface of neurons. These receptors are necessary for neurons to connect with each other at synapses, allowing the communication that leads to learning and memory. Drs. Warren and Bassell discovered that in fragile X syndrome, AMPAR receptors move in and out of the surface neuronal cells more frequently and destabilize the synaptic connections. The Emory scientists and others believe this is the ultimate defect in fragile X syndrome.

Using cultured neurons in the laboratory, manipulated to model fragile X syndrome, the Emory scientists were able to target the mGluR5 receptor with an mGluR5 antagonist--MPEP. Since the mGluR5 receptor is upstream of FMRP and has an opposing influence over the neuron, tempering mGluR5 stimulation should normalize the consequence of the loss of FMRP. Indeed, the Emory scientists found the targeted MPEP therapy rescued the abnormal AMPAR receptor movement on the surface of the FMRP-deficient neurons.

By adding a drug that antagonizes the mGluR5 receptor and signal, we were able to normalize the AMPAR receptor trafficking, and presumably allow the neurons to make appropriate synaptic connections, Dr. Warren says. This gives us great hope that we will be able to develop treatments for patients with fragile X syndrome.

Antidepressant shows early promise in treating agitation and psychotic symptoms of dementia

Mon, 10 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Toronto, ONT � Researchers have found surprising evidence that an antidepressant (citalopram) may perform as well as a commonly-prescribed antipsychotic (risperidone) in the alleviation of severe agitation and psychotic symptoms of dementia. Researchers also found that the antidepressant was associated with �significantly lower� adverse side effects.

The study, published in the online American Journal of Geriatric Psychiatry (in advance of the November 2007 issue), is believed to be the first head-to-head comparison of an SSRI (selective serotonin reuptake inhibitor) with one of the more commonly prescribed second generation antipsychotics in older, non-depressed patients.

The findings are exciting because they raise the possibility of a new direction in drug treatment for psychotic disorders related to dementia in the elderly. However, the researchers caution that more studies are needed to replicate their early findings and that second generation antipsychotics continue to be a first-line pharmacological treatment, despite growing scientific evidence that they can be associated with serious side effects, including death.

�We are encouraged by this early data, but we need to learn more in further trials that include a placebo group before we can say with confidence that antidepressants are an effective and safe treatment for agitation and psychosis in patients suffering from dementia,� says lead investigator Dr. Bruce Pollock, who teamed up with colleague Dr. Benoit Mulsant to conduct the study.

Both scientists are internationally recognized for their research in geriatric psychopharmacology � the study of the effects of drugs on mood, behavior and cognition in late life. They are now with leading Toronto-based research institutes � Dr. Pollock with the Rotman Research Institute at Baycrest and the Geriatric Mental Health Program at the Centre for Addiction and Mental Health (CAMH), and Dr. Mulsant with the Geriatric Mental Health Program at CAMH. They also have academic appointments with the Department of Psychiatry, University of Toronto (UofT).

Drs. Pollock and Mulsant conducted a double-blind randomized control trial of citalopram (antidepressant) and risperidone (antipsychotic) to compare the efficacy and safety of the two drugs in 103 patients who were hospitalized with psychiatric disturbances related to dementia at the University of Pittsburgh Medical Centre.

In this 12-week clinical trial, 53 patients were given daily doses of citalopram and 50 received daily doses of risperidone. Overall, 43% of the participants completed the trial: 47% in the citalopram group and 40% in the risperidone group. The dropout rate is typical for this vulnerable population, according to Dr. Pollock, and does not undermine the scientific validity of the findings.

The researchers were surprised to find that citalopram and risperidone had similar efficacy in reducing psychosis (hallucinations, delusions, suspicious thoughts) and agitation. Overall, there was a 32% reduction of symptoms with citalopram and a 35% reduction with risperidone. Citalopram was associated with a significantly lower burden of adverse side effects, such as sedation, tension and apathy. Total side effect burden scores increased 19% for risperidone and decreased by 4% with citalopram.

�We didn�t expect that an antidepressant would have so-called antipsychotic properties,� adds Dr. Mulsant. �It reinforces our belief that psychosis and agitation have a different neurochemistry in older patients with dementia and in younger patients with schizophrenia, even though both groups of patients are currently treated with the same medications (antipsychotics).�

Implantable device designed to detect, stop seizures under study at MCG

Mon, 10 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) A small device implanted in the skull that detects oncoming seizures, then delivers a brief electrical stimulus to the brain to stop them is under study at the Medical College of Georgia.

MCG is among 28 U.S. centers participating in a study to determine if the neurostimulator device can help patients whose seizures are not well controlled by drugs.

�The device constantly monitors electrical activity of the brain, gets accustomed to what is normal for that patient and, when it detects activity that is abnormal, within a few milliseconds, sends out a small electrical stimulus to stop it,� says Dr. Yong Park, MCG pediatric epileptologist and a principal investigator.

At MCG Medical Center, the RNS� System, developed by California-based medical device manufacturer NeuroPace, will be used in about 10 patients age 18-70 who have failed to get their seizures controlled with at least two medications. About 240 patients are expected to enroll nationwide.

Eligible participants must have at least three seizures per month and no more than two seizure foci in the brain. Seizure activity is closely monitored through a diary and monthly doctor visits for three months before patients become eligible.

Participants have a device implanted in the skull, with up to two wires containing electrodes placed near the seizure focus. A modified laptop computer looks at electrical activity picked up by the neurostimulator, then is used to program the device to recognize a patient�s seizure activity. Physicians can continue to fine-tune the detection and stimulation patterns.

During the first month after implant, the RNS� is set for detection only while doctors design a set of parameters that allow it to reliably detect the onset of seizure activity, says Dr. Patty Ray, study coordinator. After one month, half of the patients are set for detection and responsive stimulation, the other half continue with detection only. After four months, all devices are set for detection and responsive stimulation throughout the remainder of the two-year study. After the study, patients will be eligible for a study to continue to use the device until it receives FDA approval, Dr. Ray says.

Participants remain on anti-seizure medication throughout the study, although Dr. Park suspects some patients may eventually be weaned off drugs. During this study, researchers also are collecting data on which drugs work best with the neurostimulator.

MCG participated in a smaller feasibility study of the neurostimulator in 2004 and prior to that was among the first centers in the country to use it as an external, temporary measure to try to stop seizures in hospitalized patients whose seizure activity was being monitored, Dr. Park says.

About 1 in 200 people have seizures and about 1 out of 3 cannot get seizures under control with one or more medications. Some people are not candidates for traditional epilepsy surgery to remove the seizure focus because the location increases the risk of problems or deficits, because there are too many foci or because they simply do not want the surgery, Dr. Park says. Early evidence indicates the RNS� device might be most effective for foci in the medial temporal lobe, an area deep inside the brain involved in memory, where surgery is not an option, he says.

A handful of new drugs, with generally fewer side effects, also have become available in the last few years, giving patients and their doctors more options, he says. MCG has begun studies of three additional anti-seizure medications.

Also on the horizon is a mechanism that delivers a bolus of drug directly to the seizure focus in the brain, which may enhance efficacy and decrease side effects, as well as gene therapy to modify abnormal brain tissue, says Dr. Park, who wants MCG to participate when those studies move to clinical trials.

Embryonic stem cell strategy advanced with UCSF finding

Mon, 10 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) UCSF scientists are reporting what they say is a significant improvement in the technique for genetically reprogramming mouse cells to their embryonic state, a process that transforms the cells, in essence, into embryonic stem cells.

The finding, published on-line as an immediate early publication in �Cell Stem Cell� (Sept. 6, 2007), builds on the strategic breakthrough reported by Shinya Yamanaka, MD, PhD, in 2006, and confirmed in the spring of 2007 both by Yamanaka�s team and, in independent studies, by scientists at MIT, Harvard and UCLA.

The advance by the UCSF team should accelerate research aimed at improving the original strategy, the team says, and increase its potential use for studying disease development and creating patient-specific stem-cell based therapies.

The work is the result of a collaboration between the labs of Miguel Ramalho-Santos, PhD, and Robert Blelloch, MD, PhD, of the UCSF Institute for Regeneration Medicine.

�The new technique removes a major technical hurdle that has likely discouraged many labs around the world from carrying out studies on the strategy,� says senior author Ramalho-Santos, a UCSF Fellow and a member of the Diabetes Center. For separate reasons, he says, removal of the hurdle increases the technique�s potential use in developing patient-specific cellular therapies.

�Now, laboratories will be able to use the approach to study a broad range of normal and diseased cells of interest,� says the first author of the study, Blelloch, an assistant professor of urology. �There will be a much greater ability to precisely dissect the mechanisms of reprogramming and to identify the genes that will be most effective in transforming adult cells.�

Yamanaka�s strategy -- over-expressing certain genes in mouse skin cells to initiate reprogramming � relied on the insertion of a foreign �drug resistance� gene into the mouse skin cells. This gene would �switch on� in those cells that successfully converted to embryonic stem cells, thus providing a means of detecting them. The drawbacks of this technique were that it was technically difficult to carry out and, because it involves a foreign gene, would raise safety concerns that would hinder its use in cell-based therapies.

In the current study, the UCSF scientists developed an alternative to this genetically engineered �switch� technique. They developed serum-free conditions in the cell culture dish that both promoted more successful reprogramming and generated embryonic stem cells that could be detected based on their form and structure, alone.

Scientists are interested in reprogramming because of its potential for developing human embryonic stem cells that contain the genetic makeup of individual patients. In theory, any patient�s cell, say, a skin cell, could be reprogrammed. If the resulting embryonic stem cell could then be prompted in the culture dish to specialize into one of the various cell types of the body, such as of the heart, lung and brain, the resulting cells could provide the starting point for a host of clinical-research strategies.

Researchers could create dopamine-producing cells from Parkinson�s disease patients and study them in the culture dish to learn the earliest steps of disease development. They could also test experimental drugs on such cells in the culture dish.

Alternatively, they could generate healthy specialized cells from patients who had donated their genetic material, and transplant them into tissues -- without the risk of prompting immune rejection -- to treat failing hearts, neurological diseases such as Parkinson�s disease and amyotrophic lateral sclerosis, spinal cord injury and diabetes.

The reprogramming strategy pioneered by Yamanaka -- who in August began his transition from Kyoto University to the UCSF-affiliated Gladstone Institute of Cardiovascular Disease and UCSF -- involved over-activating four genes in mouse skin cells in the culture dish. His team showed that over-expressing these genes � oct4, sox2, klf4 and c-myc � can cause the full complement of genes in mouse cells to lose their adult functions and begin functioning as they would have as embryonic stem cells. Yamanaka named these cells �induced pluripotent (iPS) cells.�

But because only a very low percentage of cells complete reversion to the embryonic stem cell state with this technique, and because the cells are situated among millions of cells in the culture dish that do not complete the transformation, the scientists had a difficult time identifying the fully reprogrammed cells. Thus, they developed the technique of inserting the foreign �drug-resistance� gene into the mouse skin cells. This gene was designed to only �switch on� in cells that completed the reversion to the embryonic stem cell state. With addition of the drug to the culture dish, the vast majority of cells, those that had not reverted to embryonic stem cells, died. Only those that had reverted survived and could then be expanded.

With the alternative technique developed by the UCSF team, the efficiency of embryonic stem cell production remained low. However, the mouse skin cells that did start to revert to embryonic stem cells could readily be identified by their form and structure in the absence of any drug. The researchers went on to show that these cells indeed behaved like embryonic stem cells and could give rise to all cell types of the body.

Separately, the team demonstrated that reprogramming could be achieved when one of the four genes over-expressed to initiate reprogramming -- c-myc -- was replaced with a related gene, known as n-myc. These genes are involved in the formation of different tumors, so by beginning to replace genes in this method the researchers may find combinations of reprogramming genes that are safer, says Blelloch.

�Studies should address the relative efficacy of n-myc versus c-myc in reprogramming and whether n-myc reactivation, like c-myc, results in tumor formation,� he says.

An ongoing limitation of the Yamanaka method, notes Blelloch, is that it requires viral-mediated integration of four foreign genes � so-called transgenes. The goal would be to add the genes only temporarily, or to use chemical compounds that could mimic the effect of the genes in the cells. This will be a key focus of ongoing studies, he says.

The biggest hurdle, of course, says Ramalho-Santos, will be translating the methods from the mouse to human cells, a process that could take years. Researchers around the world, including Ramalho-Santos, Blelloch and Yamanaka, are working intently on this challenge.

�It�s a very exciting time in stem cell biology, as exemplified in the studies of reprogramming,� says Ramalho-Santos. �It�s fascinating enough that an embryonic stem cell can give rise to all cell types of the body. But that�s what embryonic stem cells do. They grow and in the end give rise to the whole organism.

�But taking back a differentiated cell to the embryonic stem cell state � that�s truly mesmerizing. It goes against the flow of development -- and yet we can do it. And we�re getting easier technical ways to do it.�

'Holy Grail' of hearing: True identity of pivotal hearing structure is revealed

Wed, 05 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Our ability to hear is made possible by way of a Rube Goldberg-style process in which sound vibrations entering the ear shake and jostle a successive chain of structures until, lo and behold, they are converted into electrical signals that can be interpreted by the brain. Exactly how the electrical signal is generated has been the subject of ongoing research interest.

In a study published in the September 6 issue of the journal Nature, researchers have shed new light on the hearing process by identifying two key proteins that join together at the precise location where energy of motion is turned into electrical impulses. The discovery, described by some scientists as one of the holy grails of the field, was made by researchers at the National Institute on Deafness and Other Communication Disorders (NIDCD), one of the National Institutes of Health (NIH), and the Scripps Research Institute in La Jolla, CA.

�This team has helped solve one of the lingering mysteries of the field,� says James F. Battey, Jr., M.D., Ph.D., director of the NIDCD. �The better we understand the pivotal point at which a person is able to discern sound, the closer we are to developing more precise therapies for treating people with hearing loss, a condition that affects roughly 32.5 million people in the United States alone.�

When a noise occurs, such as a car honking or a person laughing, sound vibrations entering the ear first bounce against the eardrum, causing it to vibrate. This, in turn, causes three bones in the middle ear to vibrate, amplifying the sound. Vibrations from the middle ear set fluid in the inner ear, or cochlea, into motion and a traveling wave to form along a membrane running down its length. Sensory cells (called hair cells) sitting atop the membrane �ride the wave� and in doing so, bump up against an overlying membrane. When this happens, bristly structures protruding from their tops (called stereocilia) deflect, or tilt to one side. The tilting of the stereocilia cause pore-sized channels to open up, ions to rush in, and an electrical signal to be generated that travels to the brain, a process called mechanoelectrical transduction.

Most scientists believe that the channel gates are opened and closed by microscopic bridges�called �tip links��that connect shorter stereocilia to taller ones positioned behind them. If scientists could determine what the tip links are made of, they�d be one step closer to understanding what causes the channel gates to open. This is no easy feat, however, because stereocilia are extremely small, scarce, and difficult to handle. Several proteins had been reported to occur at the tip link in earlier studies, but results have been conflicting to this point.

Low level of neuronal receptor linked to mild cognitive impairment and Alzheimer's disease

Tue, 04 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Results of a new study indicate a strong link between the loss of the neuronal receptor LR11and onset of mild cognitive impairment (MCI), often a harbinger of Alzheimer's disease.

LR11, like all receptors, selectively receives and binds specific substances. Researchers found reduced levels of LR11, also known as sorLA or SORL1, in the brain tissue of people diagnosed with MCI. In addition, the findings show that levels of LR11 in the brain tissue reflect the severity of cognitive impairment and may predict which individuals will progress to Alzheimer's disease.

Results of the study by scientists at Emory University School of Medicine, along with scientists at Rush University Medical Center in Chicago, are published online in the Annals of Neurology and will be published in a future print edition.

The research was conducted by James Lah, MD, PhD, Emory associate professor of neurology, and graduate student Kristen Sager,in the Center for Neurodegenerative Disease. The research team also included Howard Rees, PhD, research specialist, Marla Gearing, PhD, assistant professor of pathology and laboratory medicine and Allan Levey, MD, PhD, professor and chair of neurology. The team at Rush University Medical Center included Joanne Wu, biostatistician, Susan Leurgans, PhD, professor of biostatistics, and Elliot Mufson, PhD, Alla V. and Solomon Jesmer Chair in Aging and professor of neurological sciences.

Mild cognitive impairment is an abnormal condition in which memory or cognitive ability is mildly impaired, yet individuals can perform everyday activities. However, they may have difficulty remembering recent events or following a conversation. It is estimated that 10 to 15 percent of those diagnosed with MCI go on to develop Alzheimer's disease each year and over 5 million Americans have been diagnosed with Alzheimer's.

We don�t yet know what causes LR11 levels to drop, Dr. Lah says. But we do know that LR11 binds apolipoprotein E (ApoE), a protein that carries cholesterol and other fats throughout the bloodstream. LR11 also interacts with another molecule, the amyloid precursor protein, and regulates the production and deposition of the toxic amyloid-beta peptide in the brain. Both ApoE and amyloid-beta are strongly linked to degeneration of nerve cells in Alzheimer's disease. Thus, the implication is that there may be genetics, environmental, dietary or lifestyle factors that directly influence the expression of LR11.

The researchers collected data from participants in Rush University's Religious Orders study, which includes more than 1,000 religious clergy who have agreed to annual medical and psychological evaluations and brain donation after death. The clergy were diagnosed before death with either no cognitive impairment, MCI or Alzheimer's disease.

After death, we looked at protein levels in the brain cells and found the level of LR11 expression correlated directly with cognitive ability, implying a direct and highly relevant link to the human condition, Dr. Lah says.

We think this study is particularly important because of the groups we are studying, in particular those with MCI. In many cases, these individuals will go on to develop Alzheimer's disease, Dr. Lah says. So, we are getting to look at people in very early clinical stages of illness. The fact that at autopsy we see that the LR11 is lost in the group with MCI is compelling evidence that the loss occurs early in the disease and therefore may be a biomarker that can predict Alzheimer's or an important new therapeutic target. If we can restore the level of the receptor, then the implication is that we may be able to protect against the development of the disease.

Neural stem cell study reveals mechanism that may play role in cancer

Tue, 04 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) In the dynamic world of the developing brain, neural stem cells give rise to neurons deep within the brain�s fluid-filled ventricles. These newborn neurons then migrate along the stem cell fibers up to the neocortex, the seat of higher cognitive functions. Now, scientists have discovered a key mechanism of this migration � one that may also play an important role in other developmental processes and diseases, including cancer.

The finding, the cover story in a recent issue of Nature (Aug. 23, 2007), was led by Laura Elias, a neuroscience graduate student in the laboratory of senior author Arnold Kriegstein, MD, PhD, a professor of neurology and director of the UCSF Institute for Regeneration Medicine.

Elias is one of 16 UCSF CIRM Stem Cell Scholars � up and coming young scientists funded by the California Institute for Regenerative Medicine, established by California voters in 2004 to allocate $3 billion over 10 years to support stem cell research.

Scientists have known that migration of neurons depends in part on motors within the cells that drive their movement along the neural stem cell fibers. They have also known that this migration depends on receptors on the neurons� surface that sense signals in the environment that either repel or attract the cells, thus directing their path.

But little has been known about the molecules that mediate the interaction between the migrating neurons and the neural stem cell fiber itself. And relatively overlooked in this process has been the possible role of so-called �gap junctions.�

Gap junctions are pores, or channels, that form between cells. They are created when two hemi-channels, each in the membrane of a different cell, connect. The junctions are well known for their role in enabling cells to pass molecular signals to one another. In developing tissue, they are particularly active in supporting signaling that promotes cell proliferation, or cell division.

In the current study, however, the team made the unexpected finding that gap junctions also play a crucial role in neuronal migration � and that they function in a previously unrecognized way. Rather than functioning as a conduit through which molecular signals move, the two fused hemi-channels serve as a form of adhesion between the migrating neurons and the neural stem cell fibers.

Cell adhesion is a common mechanism, but its function had not been detected previously in gap junctions.

The discovery that gap junctions were involved in migration in any capacity was a surprise. Elias had been investigating whether the molecule functioned as a channel to regulate cell proliferation within embryonic neural stem cells of the developing rat brain, building on preliminary findings from the Kriegstein lab 15 years ago.

As part of one study, she had reduced the levels of gap junctions in the neural stem cells. �To our surprise,� she says, �the newborn neurons that the stem cells produced piled up on one another and failed to migrate into the cortex.�

To establish the role that gap junctions might play in neuronal migration, the team focused on the activity of the molecule�s subunits, known as connexons, in a series of studies in the developing rat brain. They honed in on two of these proteins � Cx26 and Cx43 � because they determined that they were expressed at high levels in migrating neurons and along radial fibers and that they were, in fact, highly localized in regions of the neurons that were in contact with radial fibers.

In a notable finding, says Elias, blocking the activity of either subunit significantly impaired migration to the neocortex, as seen in a �striking cellular redistribution pattern of the neurons.�

To determine the mechanism by which the gap junctions were functioning, the team selectively blocked three plausible mechanisms: the well-known channel function, a form of cellular signaling that relies on the intracellular end of the molecule, and adhesion.

�Remarkably,� says co-author Doris Wang, a student in the MD, PhD neuroscience program at UCSF and a member of the Kriegstein lab, �we found that adhesion, alone, is necessary for the role of gap junctions during neuronal migration.�

Further study revealed that the Cx43 and Cx26 molecular subunits interact with the neuron�s internal cytoskeleton to stabilize it on its path.

A series of time-lapse, live imaging studies of migrating neurons illuminated this phenomenon: The neurons start out with a branched leading process. Then one of the processes is stabilized and the neuron translocates its body into a swelling that forms in the stabilized leading process. When the levels of the gap junction protein are reduced, however, the neurons are no longer able to stabilize their leading processes and continue to send out multiple branches.

The revelation of the gap junction�s role in neural migration is provocative, says Kriegstein, because the molecule is known to be involved in several disease processes, including the spread of cancers in the brain, skin and lung. Most brain tumors are made up of glial cells that spread throughout the brain by migrating along white matter pathways -- the network of neural fibers that connect neurons.

While roles for the gap junction channel in cancer have been demonstrated, �It�s possible,� he says, �that gap junctions are also using the cell adhesion function in these disease settings to support cell migration. If so, the mechanism could become a target for therapy.�

The study also revealed another surprising phenomenon, says Kriegstein, the John G. Bowes Endowed Chair in Stem Cell and Tissue Biology. It has long been known that when neural stem cells divide they undergo a process of asymmetrical division, in which they produce one newborn neuron and one new neural stem cell. The understanding has been that the neurons then begin their migration along the radial fibers to the neocortex.

But the study revealed that newborn neurons and the newborn neural stem cell stick together for a significant period of time, up to many days, while the newborn neuron migrates to the cortex, and they are stuck together by the gap junctions. It�s possible, says Kriegstein, that the adhesion function is allowing the gap junction to also support signaling through the gap junction channel between the neural stem cell and its daughter neuron.

The discovery of the gap junction�s adhesion capacity also offers a window into its evolutionary history, says Kriegstein. �The molecule may have been functioning for some time as an adhesion molecule,� he says. �It couldn�t very well form a channel between two neighboring cells unless the two halves of the channel first stuck together.�

The team�s understanding of neuronal migration in the developing brain also appears likely to evolve. The discoveries they�ve made in this study, like the processes of the migrating neuron, are moving them forward with new hypotheses to investigate.

Novel 3-D cell culture model shows selective tumour uptake of nanoparticles

Fri, 31 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) A nanoparticle drug delivery system designed for brain tumour therapy has shown promising tumour cell selectivity in a novel cell culture model devised by scientists at The University of Nottingham. The project, conducted jointly by the Schools of Pharmacy, Biomedical Sciences and Human Development, will be featured in the September issue of the Experimental Biology and Medicine.

Therapy for brain cancers is particularly difficult for a number of reasons, including getting sufficient drug to the tumour and selectivity of drug action. Dr Martin Garnett, Associate Professor of drug delivery at the School of Pharmacy said: �We are working on a number of new therapeutic approaches using nanoparticle drug delivery systems. However, understanding and developing these systems requires suitable models for their evaluation.�

The nanoparticles used in this study were prepared from a novel biodegradable polymer poly (glycerol adipate). The polymer has been further modified to enhance incorporation of drugs and make the nanoparticles more effective.

Dr Terence Parker, Associate Professor in the School of Biomedical Sciences explained: �The interaction of tumour cells with brain cells varies between different tumours and different locations within the brain. Using 3-dimensional culture models is therefore important in ensuring that the behaviour of cells in culture is similar to that seen in real life�.

The work was mainly carried out by graduate student Weina Meng who formulated the fluorescently labelled nanoparticles and studied them in a variety of tumour and brain cell cultures. Her early studies showed faster uptake of nanoparticles into tumour cell cultures than normal brain cell cultures grown separately. This selectivity was only seen in 3-dimensional cultures and was the driving force to develop a more complex and representative model.

Tumour cell aggregates have been used as cell culture models of cancer cells for many years. Similarly thin brain slices from newborn rats can be cultured for weeks and are an important tool in brain biology. In the cell co-culture model now reported, these two techniques have been brought together for the first time. Brain tumour cell aggregates were labelled with fluorescent iron microparticles and grown on normal newborn rat-brain tissue slices. The double cell labelling technique allowed investigation of tumour cell invasion into brain tissue by either fluorescence or electron microscopy from the same samples. Using these techniques the tumour aggregates were found to invade the brain slices in a similar manner to tumours in the body. Having developed the model then the tumour selective uptake of nanoparticles was demonstrated in the co-culture.

The collaboration on this project has been nurtured by Professor David Walker of the School of Human Development who co-founded the Children�s Brain Tumour Research Group at Nottingham. Professor Walker said: �Understanding the biology of tumours is important if we are to develop effective new treatments. This work demonstrates how close co-operation between disciplines can help to push forward ideas which could lead to new clinical therapies�.

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine, agrees with Professor Walker. Dr. Goodman stated: �The convergence of cancer cell biology and nanoscience, exemplified by this study, holds great promise for the future of brain tumour therapy.�

Researchers find new taste in fruit flies: carbonated water

Wed, 29 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) That fruit fly hovering over your kitchen counter may be attracted to more than the bananas that are going brown; it may also want a sip of your carbonated water. Fruit flies detect and are attracted to the taste of carbon dioxide dissolved in water, such as water found on rotting fruits containing yeast, concludes a study appearing in the August 30 issue of the journal Nature. Scientists at the University of California, Berkeley, who conducted the study, suggest that the ability to taste carbon dioxide may help a fruit fly scout for food that is nutritious over that which is too ripe and potentially toxic. The research is partly funded by the National Institute on Deafness and Other Communication Disorders (NIDCD), one of the National Institutes of Health.

�Fruit flies contain similar versions of many human genes, which is why we study them for a variety of health issues, including taste,� says James F. Battey, Jr., M.D., Ph.D., director of the NIDCD. �This research raises the question of whether people also may have the ability to taste carbon dioxide and perhaps other chemicals in food. If this were found to be true, our sense of taste could be even more complex than we realize.� Currently, scientists recognize five tastes in humans: sweet, salty, bitter, sour, and umami, or savory. Before today�s findings, fruit flies were known to be able to taste sweet, bitter, and salty.

The researchers note that a fruit fly�s attraction for the taste of carbon dioxide is on a much smaller scale than for sugar, so it may be used more as a possible flavor enhancer as opposed to a full-fledged taste. This makes sense, they say, since carbon dioxide offers no nutrition to the fly.

In humans, taste occurs by way of taste cells, sensory cells that are clustered in the taste buds of the mouth, tongue, and throat, and that express certain proteins, called receptors. These receptors are activated by specific chemicals�called tastants�found in foods and drinks. When a receptor is activated by a tastant, an electrical signal is generated, which travels to the brain. Taste in the fruit fly, or Drosophila melanogaster, operates much the same way, except fruit flies have taste neurons instead of taste cells, and the taste neurons are found in structures called taste pegs and taste bristles instead of buds. Although taste pegs and bristles can be found all over a fruit fly�s body, most are concentrated on the labellum�the equivalent of a tongue�which is housed in the proboscis, a long tubular structure originating from the fly�s head.

To arrive at their findings, senior author Kristin Scott, Ph.D., and her research team made use of a powerful genetics technique that enables fruit fly researchers to tightly control which genes are expressed in a cell and which remain silent. The team first homed in on a class of taste neurons, called E409, found on taste pegs in the fruit fly�s labellum. These neurons had not been characterized before and were not already associated with known taste receptors for sweet and bitter. They then labeled the neurons with a fluorescent protein and found that their projections extended to separate parts of the taste area of the brain in comparison to the sweet and bitter neurons. Next, the researchers tested the E409 neurons� response to an array of compounds and found that substances high in carbon dioxide, such as beer, yeast, and carbonated water, elicited heightened neuron activity as opposed to substances low in carbon dioxide. Finally, they found that fruit flies were attracted to solutions with high carbon dioxide concentrations, while those whose E409 neurons were shut off were not.

Because fruit flies are also able to smell carbon dioxide, the team also wanted to learn if the two senses influenced one another. Under normal conditions, when fruit flies smell carbon dioxide in the air, they are repelled by it. Scott and her team showed that fruit flies that had their E409 neurons shut off avoided high carbon dioxide concentrations in the environment; likewise, flies that were missing antennae, the structures they use to smell their surroundings, were attracted to solutions with high carbon dioxide concentrations. These results indicate that the senses of taste and smell operate independently. As a result, the team concluded that fruit flies use both senses of taste and smell separately to gauge their environment for a potential food source.

�Our model is that flies like high local concentrations of carbon dioxide,� says Scott. �So if carbon dioxide is being produced by the yeast, flies taste it and they like it. But if there are increased global levels of carbon dioxide in the air�such as if a food source becomes spoiled and potentially toxic�then flies are repelled by it. So we think by having these two different carbon dioxide detectors, flies are able to compare global to local levels of carbon dioxide and then regulate their behavior accordingly.�

Emory scientists use NIH grant to develop biomarkers for ALS tracking and prevention

Thu, 16 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) The National Institutes of Health has awarded Emory University researchers a $275,000 grant aimed at developing protein biomarkers to diagnose, monitor and prevent amyotrophic lateral sclerosis (ALS).

The research team, which includes Jonathan Glass, MD, professor of neurology and pathology and Junmin Peng, PhD, professor of genetics and an internationally recognized leader in the field of proteomics, will investigate changes in proteins that correlate with the onset and progression of ALS, first in mice and then in humans.

Also known as Lou Gehrig's disease, ALS affects motor neurons, resulting in progressive muscle weakness and imminent death roughly two to five years after symptoms appear. In the United State alone, 30,000 people suffer from the disease at any one time.

The discovery of biomarkers for ALS will mark a major step forward in clinical care and development of new treatments, says Dr. Glass. ALS biomarkers could be used for early and definitive diagnosis, as well as disease progression and response to therapy. The absence of such markers represents a significant roadblock to clinical trials because the success or failures of treatment can be measured only by clinical outcome, which is always death. With the expertise of Dr. Peng we hope to identify changes in proteins that can be used as biomarkers.

Using cutting-edge techniques and building on previous protein analysis in mice, the researchers will analyze and compare thousands of proteins found in the spinal cords of mice having a specific pathogenic mutation in a gene known as superoxide dismutase (SOD1-ALS), located on chromosome 21.

We will look for proteomic biomarkers in these mice and then test for these biomarkers in people, Dr. Glass says. By doing so, we would have specific targets to test in people, starting with those who have genetically based ALS, a very small proportion of the population. At this point, people who have genetically based ALS are going to get ALS. But if we had a biomarker that heralded the onset of disease in this population, we could potentially have a clinical trial to prevent the disease from ever occurring. And later on, we could test this idea in a population without genetically based ALS.

Identifying biomarkers for ALS would also profoundly affect the efficiency of clinical trials involving possible treatments of the disease. If we had a biomarker that fluctuated with disease activity it would be possible to quickly find out if a treatment is working. Thus, we could shorten clinical trials because we would know early whether something worked or didn't work, allowing us to test more treatments on fewer people, says Dr. Glass.

Currently only one drug, riluzole, is effective in treating ALS. Riluzole is aimed at relieving symptoms, preventing complications and optimizing patients' quality of life.

Approximately 10 percent of ALS cases are genetically based, whereas the origin of the remaining 90 percent of ALS cases is still unknown.

We have no idea what causes this disease. We have dozens of theories, but no hard data, Dr. Glass says. We do know a little more about it in mice, however. We want to find a target we can go after and then see if we can make a difference.

Scientists link fragile X tremor/ataxia syndrome to binding protein in RNA

Wed, 15 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Scientists have discovered a key protein in the toxic brain pathway that leads to fragile X tremor/ataxia syndrome (FXTAS), an inherited neurodegenerative disorder. The finding, in a Drosophila (fly) model of FXTAS, could help unravel the complex mechanisms of FXTAS and lead scientists to develop therapies to target the protein. The research will be published in the Aug. 16 issue of the journal Neuron.

Fragile X tremor/ataxia syndrome was first recognized several years ago as a neurodegenerative disease caused by a premutation in carriers of the mutated FMR1 gene, the same gene that causes fragile X syndrome--the most common inherited cause of mental retardation. Individuals with the FMR1 premutation (a less exaggerated form of the mutation) do not have retardation, but instead are at risk for developing FXTAS, usually after age 50, causing progressive problems with movement (ataxia), tremor, memory loss, loss of sensation in the lower extremities (peripheral neuropathy), and mental and behavioral changes.

Fragile X syndrome occurs when a region of the FMR1 gene repeats a particular sequence of three DNA basesÑCGG--causing silencing of the FMRP protein. Called a trinucleotide repeat, this CGG sequence repeats only about 6 to 55 times in normal individuals, but between 200 and 1,000 times in those with fragile X syndrome.

In those with the premutation of the FMR1 gene, CGG repeats between 60 and 100 times.

Scientists estimate the frequency of fragile X syndrome as approximately 1 in 4,000 males and 1 in 8,000 females and the frequency of the FMR1 premutation as 1 in 800 males and 1 in 260 females. Approximately 20 percent of males with the permutation develop FXTAS. Approximately 20 percent of women with the premutation have premature ovarian failure Ð a loss of ovarian function in women younger than 40.

Lead authors of the current study are Peng Jin, PhD, assistant professor of human genetics and Stephen T. Warren, PhD, Timmie professor and chair of human genetics at Emory University School of Medicine. Dr. Warren and his colleagues led an international team that discovered the FMR1 gene in 1991, later characterized the FMRP protein, and developed diagnostic tests for fragile X syndrome.

Drs. Jin and Warren earlier discovered (Neuron, 2003) that FXTAS is caused by elongated repeats of the CGG sequence in cells' RNA Ð the molecules that translate the genetic code from DNA into proteins. In the current Neuron paper, Dr. Jin describes his discovery that the pur alpha protein, which is necessary for neuronal function and is involved in brain synapses tied to movement, is bound by the CGG trinucleotide repeats located in the RNA of the FMR1 gene.

Drs. Jin and Warren believe that because the repeated CGG sequences bind and sequester the pur alpha protein, the protein is not available for its normal function in the parts of the brain responsible for movement. The researchers also found that the pur alpha protein bound to CGG repeats becomes part of toxic brain aggregates, called inclusions, found in patients with neurodegeneration.

Now that we have discovered a protein that is depleted by RNA in the premutation gene, we will try to identify more specifically how depletion of this protein can cause neurodegeneration, and we can use our fly model to conduct drug screening and begin to develop therapeutic drugs that could overcome this problem, says Dr. Jin.

Study suggests loss of 2 types of neurons -- not just 1 -- triggers Parkinson's symptoms

Mon, 13 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) New evidence indicates that the loss of two types of brain cells--not just one as previously thought--may trigger the onset of symptoms associated with Parkinson's disease.

The evidence, based on mouse models, shows a link between the loss of both norepinephrine and dopamine neurons and the delayed onset of symptoms associated with Parkinson's disease. It was originally thought that the loss of only dopamine neurons triggered symptoms. Dopamine is a neurotransmitter critical for coordinating movement.

Results of the study by Emory scientists, along with the University of Georgia, will appear in the Proceedings of the National Academy of Sciences, Early Edition online during the week of Aug. 13-17 and in the Aug. 21 print edition.

The research was conducted by Karen Rommelfanger, graduate student in the laboratory of David Weinshenker, PhD, assistant professor of human genetics in Emory University School of Medicine and Gary Miller, PhD, associate professor in Emory's Rollins School of Public Health. The team also included Gaylen Edwards and Kimberly Freeman at the University of Georgia.

Parkinson's disease affects motor coordination and is characterized by symptoms such as tremors of hands, arms, legs, jaw and face; rigidity or stiffness of limbs and trunk; bradykinesia, or slowness of movement; and postural instability. The disease most often occurs in those over 50.

People don't start showing symptoms of Parkinson's disease until about 80 percent of their dopamine neurons are gone, which is when you cross some sort of threshold. Our study looked at what happens while the dopamine neurons are dying and people still appear fine, says Dr. Weinshenker. The lack of symptoms until the death of most of the dopamine neurons suggested the existence of a system that can temporarily compensate for the loss of the dopamine.

The dogma in the field is that Parkinson's disease involves a selective loss of dopamine neurons. The truth is, if you look at postmortem Parkinson's disease brains, you will see that both dopamine and norepinephrine neurons are gone, Dr. Weinshenker explains. We know that norepinephrine is important for regulating the activity of dopamine neurons, so we suspected that the dopamine neurons and the norepinephrine neurons function in concert. As the dopamine neurons start dying, the norepinephrine neurons compensate by signaling the surviving dopamine cells to dramatically increase their activity and the output of dopamine. Eventually, the norepineprhine neurons die, the surviving dopamine neurons lose their ability to release extra dopamine, and symptoms start to appear.

To test their hypothesis, the researchers gave healthy, one-year-old mice the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) at a dose that kills about 80 percent of the dopamine cells, but observed no motor impairments in the mice. Surprisingly, when they tested mice unable to synthesize norepinephrine and that have trouble releasing dopamine properly, they observed symptoms of Parkinson's disease including resting tremor, hunched posture and deficits in coordinated movement. These results indicate that having a normal complement of dopamine neurons is not enough for normal motor function; norepinephrine also needs to be present to ensure proper dopamine release.

Although there are no cures for Parkinson's disease, some moderately effective treatments are available, but most target the dopamine neurons only and are effective for only a limited amount of time. In light of this study, it's quite possible that simultaneously treating both the dopamine and norepinephrine loss could further ameliorate the symptoms of Parkinson's disease,Ó says Dr. Weinshenker.

UCLA scientists produce functioning neurons from human embryonic stem cells

Tue, 07 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Scientists with the Institute of Stem Cell Biology and Medicine at UCLA were able to produce from human embryonic stem cells a highly pure, large quantity of functioning neurons that will allow them to create models of and study diseases such as Alzheimers, Parkinsons, prefrontal dementia and schizophrenia.

Researchers previously had been able to produce neurons - the impulse-conducting cells in the brain and spinal cord - from human embryonic stem cells. However, the percentage of neurons in the cell culture was not high and the neurons were difficult to isolate from the other cells.

UCLAs Yi Sun, an associate professor of psychiatry and biobehavioral sciences, and Howard Hughes Medical Institute investigator Thomas Südhof at the University of Texas Southwestern Medical Center were able to produce 70 to 80 percent of neurons in cell culture. Sun and Südhof also were able to isolate the neurons and determine that they had a functional synaptic network, which the neurons use to communicate. Because they were functional, the neurons can be used to create a variety of human neurological disease models.

The study results are published today in an early online edition of the peer-reviewed journal Proceedings of the National Academy of Sciences.

Previously, the system to grow and isolate neurons was very messy and it was unknown whether those neurons were functioning, Sun said. Were excited because we have been able to purify so many more neurons out of the cell culture and they were, surprisingly, healthy enough to form synapses. These cells will be excellent for doing gene expression studies and biochemical and protein analyses.

Suns method prodded human embryonic stem cells to differentiate into neural stem cells, the cells that give rise to neurons. When the time was right, Suns team added protein growth factors into the cell culture that stopped the neural stem cells from self-renewing and prodded them into differentiating into neurons. To isolate the cells, Sun and her team added an enzyme that digests a sort of protein matrix that holds cells in culture together. The neurons could then be separated from the neural stem cells that had not yet differentiated, a sort of chemical round-up that isolated the neurons. The cells were then put into a cell strainer that allowed passage through of the isolated neurons.

The large number of pure neurons produced will allow Sun and her team to study their biological form and structure, the genes they express, the development of synapses and the electric and chemical communication activities within the synapse network.

We will be able to study the cellular properties of neurons in a very defined way that will maybe tell us what goes wrong in diseases such as Alzheimers and Parkinsons, Sun said. Were currently creating many models of human neurological diseases that may provide the answers were looking for. We dont know what causes prefrontal dementia, Huntingtons disease or schizophrenia. The key is likely in the quality of neuronal communications. By studying the chemical and electrical transmissions, we may be able to determine what goes wrong that leads to these debilitating diseases and find a way to stop or treat it.

Sun will be among the first researchers to be able to study true neuron function.

A second important discovery in Suns study showed that two embryonic stem cells lines derived in similar manners, and therefore expected to behave similarly when differentiating, did not. Using the same techniques to prod the two embryonic stem cells lines to differentiate, Sun found that one line had a bias to become neurons that are found in the forebrain. The other line differentiated into neurons found in rear portions of the brain and spinal cord. The finding was surprising, and significant, Sun said.

The realization that not all human embryonic stem cell lines are born equal is critical, Sun said. If youre studying a disease found in a certain part of the brain, you should use a human embryonic stem cell line that produces the neurons from that region of the brain to get the most accurate results from your study. Huntingtons disease, for example, is a forebrain disease, so the neurons should be differentiated from a cell line that is biased to produce neurons from the forebrain.

Sun said there are ways to prod an embryonic stem cell line biased to become neurons found in the rear brain to become neurons found in the forebrain. However, there are limits to how much prodding can be done.

Sun and her team confirmed that the two embryonic stem cell lines were different through gene expression analysis neurons that perform different functions in different parts of the brain express different genes. The cell line prone to becoming neurons found in the forebrain expressed genes typically found those neurons, while the other line expressed genes found in the rear brain and spinal cord.

Sun and her team now are studying why the two human embryonic stem cell lines have biases to become different types of neurons.

If we knew that, we might be able to tweak or alter whatever is driving the bias so that limitation in the stem cell line could be bypassed, Sun said.

Researchers link metal ions to neurodegenerative disease

Mon, 06 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) A multi-institutional team of researchers led by Emory University has defined for the first time how metal ions bind to amyloid fibrils in the brain in a way that appears toxic to neurons. Amyloid fibrils are linked to the development of neurodegenerative diseases such as Alzheimer's, Parkinson's and Creutzfeldt-Jakob. Although metal ions, most notably copper, can bind to amyloid in several specific ways, the researchers found that only one way appears toxic.

The findings will appear in the Proceedings of the National Academy of Sciences, Early Edition online during the week of Aug. 6-10 and in the Aug. 14 print edition.

Copper ions, atoms that have acquired an electric charge by gaining or losing one or more electrons, are found naturally in the brain, as are other ions such as zinc and iron. Increasing evidence now links these naturally occurring ions to amyloid assembly and to Alzheimer's disease, says David Lynn, PhD, Emory professor and chair of chemistry and principal investigator of the study.

While little is known about the exact mechanisms governing the formation of amyloid fibrils, the study's results suggest that the exact way amyloid binds to copper ions affects the fibers' architecture, rate of propagation and their effect, if any, on surrounding neurons.

Not all amyloid fibrils are toxic, says Dr. Lynn. Amyloid is made of proteins and proteins normally fold into beautiful structures. However, for whatever reason, some misfold and the resulting misfolded structures are also beautiful, but sticky. They stick to themselves and then propagate to form fibrils, but only some of the fibrils turn out to be toxic.

Those who suffer from Alzheimer's disease, for example, have an unusual amount of sticky amyloid fibrils in their brains. Over time, the fibrils accumulate instead of decomposing and increasingly interfere with the brain's structure and function. In contrast, normally folded proteins are cleared from the brain shortly after they are produced.

The scientists, collaborating throughout the United States and across Emory, focused on the smallest individual unit of amino acids that make up amyloid fibrils. By determining only an individual unit's physical and chemical properties when binding with metal, the researchers were able to determine the activity governing the assembly and toxicity of whole fibrils with respect to their effect on brain cells.

We showed that the activity of this minimal unit actually replicates the activity of the whole fibril on the neuronal cell. And it does so by binding the metal in a specific way, says Dr. Lynn.

Forty years ago, scientists began exploring a possible link between overexposure to metals and Alzheimer's disease. Because some people with the disease had aluminum deposits in their brains, it was thought that there was a direct connection between aluminum exposure and Alzheimer's. However, after many years of study, no conclusive evidence links aluminum to neurodegenerative disease, which leaves researchers to focus on zinc, iron and copper.

The researchers also found that several distinct types of structures could be assembled from individual units of amino acids. We found that we could build lots of different types of structures with an individual unit: fettuccine-shaped structures, tubes, vesicles, and so on, not just fibers. And this is remarkable, says Dr. Lynn.

Our findings now lead us to ask what other types of structures these individual units can make, what exactly happens when the units bind to one another, and whether these individual units are important to neurodegenerative diseases or whether the entire fibril must be involved, says Dr. Lynn.

Like many scientific findings, we know about amyloid because of the diseases it's associated with rather than because of its benefits, says Dr. Lynn. However, researchers are also finding situations in which amyloid is beneficial, such as in long-term memory and synapse maintenance in the marine snail.

Study identifies source of fever

Sun, 05 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) BOSTON With the finding that fever is produced by the action of a hormone on a specific site in the brain, scientists have answered a key question as to how this adaptive function helps to protect the body during bacterial infection and other types of illness.

Reported by researchers at Beth Israel Deaconess Medical Center (BIDMC), the study results appear today in Nature Neurosciences Advance Online Publication.

This study shows how the brain produces fever responses during infections, explains senior author Clifford Saper, MD, PhD, Chairman of the Department of Neurology at BIDMC and James Jackson Putnam Professor of Neurology and Neuroscience at Harvard Medical School. Our laboratory identified the key site in the brain at which a hormone called prostaglandin E2 (PGE2) acts on a target, called the EP3 receptor, on neurons to cause the fever response.

During periods of inflammation, such as when the body is fighting an infection or illness, the body produces hormones known as cytokines. The cytokines, in turn, act on blood vessels in the brain to produce PGE2.

PGE2 then enters the brains hypothalamus, causing fever, loss of appetite, fatigue and general feelings of sickness and achiness, says Saper, explaining that these common symptoms of illness function as an adaptive response to enable the body to better fight infection.

When body temperature is elevated by a few degrees, white blood cells can fight infections more effectively. Also, individuals tend to become achy and lethargic. Consequently, he adds, they tend to take it easy, thereby conserving their energy so that they can better fight the infection. That is why so many different types of illness result in more or less the same sickness behaviors.

To this point, the specific neurons on which PGE2 was acting to produce fever were unknown. Saper and his colleagues created a knockout mouse in which the gene for the EP3 receptor which registers the presence of PGE2 could be removed in one part of the brain at a time.

This was the first time that anyone has been able to remove the receptor at a single spot in the brain, says Saper. As a result, we are able to definitively say that this particular site in the brain only a little bigger than the head of a pin is where prostaglandins work to cause the fever response.

We think that the other aspects of sickness behavior, such as the achiness caused by increased sensitivity to pain, also come from specific sites in the brain, he adds. We plan to use this same approach to dissect the brains response to inflammation, and find out why people feel the way they do when they are ill.

Stem cell therapy rescues motor neurons in ALS model

Tue, 31 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) MADISON -- In a study that demonstrates the promise of cell-based therapies for diseases that have proved intractable to modern medicine, a team of scientists from the University of Wisconsin-Madison has shown it is possible to rescue the dying neurons characteristic of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disorder also known as Lou Gehrig's disease.

The new work, conducted in a rat model and reported today (July 31) in the online, open-access journal from the Public Library of Science, PLoS ONE, shows that stem cells engineered to secrete a key growth factor can protect the motor neurons that waste away as a result of ALS. An important caveat, however, is that while the motor neurons within the spinal cord are protected by the growth factor, their ability to maintain connections with the muscles they control was not observed.

At the early stages of disease, we saw almost 100 percent protection of motor neurons, explains Clive Svendsen, a neuroscientist who, with colleague Masatoshi Suzuki, led the study at UW-Madison's Waisman Center. But when we looked at the function of these animals, we saw no improvement. The muscles aren't responding.

At present, there are no effective treatments for ALS, which afflicts roughly 40,000 people in the United States and which is almost always fatal within three to five years of diagnosis. Patients gradually experience progressive muscle weakness and paralysis as the motor neurons that control muscles are destroyed by the disease. The cause of ALS is unknown.

In the new Wisconsin study, nascent brain cells known as neural progenitor cells derived from human fetal tissue were engineered to secrete a chemical known as glial cell line derived neurotrophic factor (GDNF), an agent that has been shown to protect neurons but that is very difficult to deliver to specific regions of the brain. The engineered cells were then implanted in the spinal cords of rats afflicted with a form of ALS.

GDNF has a very high affinity for motor neurons in the spinal cord, says Svendsen. When implanted, the (GDNF secreting) cells survive beautifully. In 80 percent of the animals, we saw nice maturing transplants.

The implanted cells, in fact, demonstrated an affinity for the areas of the spinal cord where motor neurons were dying. According to Svendsen, the cells migrate to the area of damage where they just sit and release GDNF.

The Wisconsin team transplanted the cells on one side of the spinal cord and used the untreated side to compare the affects of the transplanted cells and their chemical secretions.

We only put the transplant in one small area of the spinal cord and only on one side, Suzuki says. The areas where we saw the human cells were the only areas where we saw protection of motor neurons.

But while the motor neurons exposed to GDNF were protected, the Wisconsin team was unable to detect the connections between the neurons and the muscles they govern.

Even in animals that had lots of motor neurons surviving, we didn't see the (muscle) connection, which explained why we didn't see functional recovery, says Suzuki.

Although the obvious next step in the research is to try and ferret out the reasons the protected motor neurons are unable to hook up with muscles, Svendsen suggests the work further supports movement toward clinical trials in humans.

We think the cells are safe, and they do increase the survival of the motor neurons, Svendsen argues. This may be very important for patients that lose neurons every day. However, it's not a trivial intervention -- you have to drill a hole in the spinal cord to get the cells releasing GDNF in. But there are few options for these patients and we will continue to move forward with this approach.

Geisinger scientist seeks cure for Lou Gehrig's disease, creating device to find treatment

Mon, 30 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) DANVILLE- A small tropical fish, the curiosity of a Geisinger research scientist and some college students have created the perfect storm of sorts in an attempt to find a cure for one of the worlds most devastating neurological diseases.

On initial glance, there doesnt seem to be much in common between zebrafish, researcher Glenn S. Gerhard, MD and a trio of Bucknell University biomedical engineering students. Yet theyre each playing a critical role in clearing a major roadblock in the search for a cure for Lou Gehrig's disease.

Lou Gehrig's disease-or ALS or amyotrophic lateral sclerosis is a fatal neurodegenerative condition that affects nerve cells in the brain and the spinal cord. As many as 20,000 Americans suffer from ALS and about 5,000 people in the U.S. are diagnosed with the disease each year, according to the National Institutes of Health.

Its an aging-related disease that has long fascinated Gerhard, a staff scientist in Geisingers Weis Center for Research.

Gerhard believes that the cure for the diseaseor at least a more viable treatment optioncan be found in the right mix of the millions of drugs and drug compounds that have been developed in laboratories across the world.

There are so many different compounds but you dont know which ones to test, Gerhard says. We need bioengineering help to automate this process.

Thats why Gerhard turned to the zebrafish and Bucknell University professor Joe Tranquillo and students Erica Andreozzi, Meredith Kalman and Emily Thiel.

Several years ago, Gerhard started using the zebrafish, which can be easily bred and tends to exhibit diseases effects at an accelerated rate.

Yet the instruments needed to use these small and inexpensive fish for finding new drugs have not yet been brought to market.

The students have developed a working prototype screening plate that allows scientists to quickly expose zebrafish to ALS and mix chemicals together.

What once took weeks or months to screen thousands of potential cure-carrying chemical solutions may soon take days, and with far fewer research staff involved. A streamlined screening process will free up precious resources in the lab, Gerhard says.

The Bucknell students worked throughout the spring semester to improve on their design.

In their first three years, Bucknell biomedical engineering students compile an excellent set of technical and design skills through a number of open-ended experiences, Tranquillo says. But they truly become engineers in their senior year when they meet with a medical professional, identify a real problem and spend a year solving that problem. The rich and educational interactions between Dr. Gerhard, Erica, Meredith and Emily were extraordinary to witness.

Geisinger Ventures, which is the health systems corporate development arm, arranged the partnership between Gerhard and the Bucknell team.

Ventures is now seeking a corporate partner willing to license the invention for production and distribution.

Geisinger Ventures nurtures innovative ideas, licenses and brings to market intellectual property, develops business plans, and catalyzes growth of for-profit companies. Gerhards work fits perfectly into Geisinger Ventures mission, says director Bryan Allinson.

Ventures-worthy ideas generally are focused on a better way to use a device, a piece of equipment or a process, Allinson says. The work with zebrafish has the potential to identify therapeutics that could help the thousands of people who suffer from ALS.

In the diseases early stage, symptoms may be so hard to detect that the disease gets overlooked. But by the end stages of the disease, the patients are totally paralyzed.

ALS is a terrible disease, Gerhard says. Your brain is fine but your body and your muscles just waste away.

Research shows NPD1 protects a key component of vision

Mon, 30 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Two papers to be published in the Early Edition online of the Proceedings of the National Academy of Sciences (PNAS) the week of July 30-August 3, 2007 report findings that demonstrate that neuroprotectin D1 (NPD1) protects against damage to retinal pigment epithelial (RPE) cells and identifies an important trigger for its production and novel molecular mechanisms that support vision. The research was conducted at LSU Health Sciences Center New Orleans and the papers are entitled Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signaling and Photoreceptor outer segment phagocytosis attenuates oxidative stress-induced apoptosis with concomitant neuroprotectin D1 synthesis. RPE cells are responsible for the renewal of the tips of photoreceptor cells (rods and cones) crucial to vision.

Neuroprotectin D1 is a messenger (mediator) discovered by Nicolas Bazan, MD, PhD, Boyd Professor, Ernest C. and Yvette C. Villere Professor of Ophthalmology, and Director of the Neuroscience Center of Excellence at LSU Health Sciences Center New Orleans, and his colleagues that represents one of the most powerful endogenous (made by the body) neuroprotective mediators known. Its precursor is DHA (docosahexaenoic acid), an essential fatty acid (must be provided by the diet) of the omega-3 fatty acid family enriched in RPE cells in the retina and brain. DHA is a target of oxidative stress in pathological conditions and Dr. Bazans research recently showed that RPE cells create NPD1 in response to oxidative stress.

The LSUHSC scientists discovered that neurotrophins (small proteins critical in cell survival and death) trigger NPD1 synthesis. They demonstrate that the endogenous toxic component (A2E) that accumulates in the retina during aging and in retinal degenerations, including those due to gene mutations, can be counteracted by NPD1.

The LSUHSC research team conducted studies on the formation and action of NPD1 on a human transformed cell line called ARPE-19. They also used primary human RPE cells and found that they also synthesize NPD1. The researchers showed that neurotrophins regulate NPD1 by stimulating its production and also controlling its release. They found that the neurotrophin PEDF not only sparks the production of NPD1, but it acts synergistically with DHA indicating that the availability of the NPD1 initial precursor is critical for its synthesis.

To answer the question about whether or not NPD1 could prevent cell death caused by an excess of A2E known to accumulate in the RPE during aging and to be exaggerated in age-related macular degeneration, the researchers added NPD1 to an A2E-induced experimental model and found it not only stopped programmed cell death, but that the protective effects were present even six hours later. The team decided to explore whether oxidative stress triggered by another experimental condition, called serum starvation/H2O2/TNFá,, would be similarly inhibited. NPD1 also exerted protection in this experimental condition. Addition of NPD1 even eight hours after triggering oxidative stress resulted in protection. In a series of further experiments to delineate how NPD1 acts, the scientists found that NPD1 elicits a specific action rather than antioxidant activity to counteract A2E-induced cell death in RPE cells.

One of these papers reports also the discovery that the daily interaction of photoreceptors and RPE cells balance against damage is maintained by NPD1.

The regulation of these proteins involved in cell survival or death shown by this research will help us define NPD1 survival bioactivity in the RPE cell, notes Dr. Bazan. These events are clinically significant because they may allow the exploration of therapeutic interventions for retinal degenerative diseases such retinitis pigmentosa.

New protein synthesis not essential to memory formation

Thu, 26 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) New research from the University of Illinois challenges the premise that the brain must build new proteins in response to an experience for that experience to be recorded in long-term memory.

The findings, published this month in the Proceedings of the National Academy of Sciences, could alter basic assumptions about the role of protein synthesis in memory formation.

Brain researchers have long used drugs that enhance or hinder memory formation to gain insight into the mechanisms at play. Early experiments in rats found that protein synthesis inhibitors injected into brain regions involved in memory processing could disrupt long-term memory formation. This led some to hypothesize that new protein synthesis was essential to the creation of long-term memories.

A research team led by neuroscientist Paul E. Gold discovered an alternate explanation for this effect. The researchers observed that the protein synthesis inhibitor anisomycin, which is commonly used in memory studies, causes dramatic changes in brain chemistry apart from protein synthesis inhibition that interfere with memory formation. They found that exposing rat brains to anisomycin sets off wild fluctuations in neurotransmitter levels in the brain region targeted in the experiment the amygdala, one of several brain structures involved in processing memories and emotions. Large fluctuations in neurotransmitter levels in the amygdala are known to interfere with memory formation.

The researchers were surprised by the intensity of the brains response to anisomycin. Shortly after they injected the drug into the rat amygdala, they saw huge increases from 1,000 to 17,000 percent in levels of the neurotransmitters norepinephrine, dopamine and serotonin.

This is far above anything weve seen physiologically in any experiment, Gold said. Normally you think of a 200 percent increase as a really solid result and 300 percent as outrageously high. I wouldnt have thought that there was that much (neurotransmitter) to be released.

Shortly after this spike, dopamine and norepinephrine levels plummeted, dropping well below baseline for up to 48 hours after the initial exposure to anisomycin.

As expected, the rats exposed to anisomycin prior to training had impaired long-term recall of the events. To determine whether the inability to form lasting memories was caused by the anisomycin or by changes in neurotransmitter levels, the researchers repeated the experiment, adding drugs designed to counter the fluctuations in neurotransmitter levels. When the neurotransmitter imbalances were neutralized or blunted even in the presence of anisomycin memory formation was significantly restored.

If we block anisomycins effects on the neurotransmitters, then we block many of its effects on memory, Gold said. We still have the protein synthesis inhibition, but it no longer causes the (same level of) amnesia.

It is possible that some of the amnesia is due to the cessation of protein synthesis, Gold said. But, he said, the evidence suggests otherwise. I think the protein synthesis inhibition itself is causing cells to act in unusual ways, he said.

No one would deny that protein synthesis is needed to maintain normal brain functions, including memory, Gold said. But the idea that new protein synthesis is required to make long-lasting memories should be reexamined.

Discoverer of Sly Syndrome finds way of delivering medicine to fight rare genetic disorder

Wed, 25 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) ST. LOUIS -- The scientist who discovered Sly Syndrome nearly four decades ago and a team of colleagues at Saint Louis University are a step closer to finding an approach to treat the rare genetic disease. Sly Syndrome causes bone defects, mental retardation, vision and hearing problems, heart disease and premature death.

They found that a potentially life-saving enzyme can be induced to cross the blood-brain barrier, a structure which protects the brain from foreign substances, if it is given with the hormone epinephrine.

Ever since William S. Sly, M.D., chairman of the department of biochemistry and molecular biology at Saint Louis University, discovered the rare genetic disease in 1969, he and his colleagues have conducted research to learn more about how to treat it. He says their recent findings have significance beyond treating the extremely rare disease that bears his name.

There are at most 100 living cases of Sly Syndrome. Nonetheless, this disease is a model for all the diseases in this group, some of which are much more common, Sly says.

Lysosomal storage diseases affect 1 in 7,000 live births, and 90 percent of those with the diseases have brain involvement. What we find with Sly Syndrome has some importance for all those diseases as well. It is potentially a big finding and an important first step.

The discovery potentially points to a new way to get big molecules, such as certain medications, across the blood-brain barrier. It is reported in the Proceedings of the National Academy of Sciences Online Early Edition the week of July 16.

SLU researchers found that the right amount of epinephrine probably works by stimulating transport by vesicles blister-like wrappers that carry substances across the blood-brain barrier so that the enzyme missing in patients who have Sly Syndrome can get into the brain.

Those who have Sly Syndrome lack the enzyme called beta-glucuronidase. Without this enzyme, protein-sugar molecules accumulate in the brain and other organs in the body. By replacing the missing enzyme, doctors believe they can treat the genetic disease. The problem, though, was slipping the enzyme past the blood-brain barrier to where it needs to do its work.

This is a disease that is simply made for testing drug delivery vehicles. If you can get the enzyme into the brain, the vehicle that delivered it could work to deliver other chemicals, too, says William A. Banks, M.D., professor of geriatrics and pharmacological and physiological sciences at Saint Louis University, and a leading researcher on the blood-brain barrier.

Sly Syndrome, which occurs in fewer than one in 100,000 births, is a progressive disorder that ranges in severity from mild to deadly. It is among a group of genetic diseases call mucopolysaccharidoses.

Some children who have this group of diseases are doomed to an early death because they dont make a certain enzyme, Banks says.

Enzyme replacement therapy or putting the missing enzyme into the bodies of those who have Sly Syndrome holds promise in treating the physical problems of the disease.

In the case of Sly Syndrome, the missing enzyme is more than 1,000 larger than a sugar molecule and so huge it cant get across the blood-brain barrier, which prevents it from reaching the brain.

Scientists used a mouse model to figure out how to get the enzyme into the brain. They knew that injections of the missing enzyme into the brains of baby mice reached their target, but similar injections into mature mice did not. As the mice grew older, the transporter that brought the enzyme past the protective blood-brain barrier was lost.

We found that the right amount of epinephrine allowed the enzyme to pass into the brain of older mice, which means we reinduced the way to get the enzyme where it is needed, Banks says.

Epinephrine is a drug that treats cardiac arrest and is given to open the airways of asthma patients who have difficulty breathing. Discovering epinephrine as the transportation key to unlock the blood-brain barrier for the missing enzyme was a shot in the dark, Banks says.

High doses of epinephrine can destroy the blood-brain barrier and let everything into the brain, which is toxic, Banks says. We tested three things. One didnt work at all. One worked partially and epinephrine worked incredibly well.

The finding changes how scientists look at getting medications through the blood-brain barrier, he says, and could have implications for treating other diseases such as Alzheimers disease and obesity.

Instead of viewing the blood-brain barrier as an obstacle to fight, researchers should consider it something to finesse, using its special features to help in drug delivery, Banks adds.

The field has approached the problem as if you have a Volkswagen that can get across the street and you put your cargo on it so the cargo can get there too. Weve found that trying to transport the cargo changes the Volkswagen and the Volkswagen can no longer get across.

'Preconditioning' helps protect brain's blood vessels from stroke

Thu, 19 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) NEW YORK (July 17, 2007) -- Challenging brain tissue with a small noxious stimulus beforehand gives it a resilience that can lessen damage to blood vessels during a stroke, report researchers at Weill Cornell Medical College in New York City.

This preconditioning works along the theory of 'what doesn't kill me makes me stronger,' explains senior researcher Dr. Costantino Iadecola, the George C. Cotzias distinguished professor of neurology and neuroscience and Director of Neurobiology at Weill Cornell, and attending neurologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

We already knew that preconditioning helps minimize damage to heart tissue -- it's a strategy cardiologists routinely use today. And we know it can help protect brain cells -- neurons -- against stroke damage, Dr. Iadecola says. Now, besides illuminating mechanisms involved in this process, our new study in mice demonstrates that preconditioning also shields the brain's blood vessels from stroke injury, he explains.

The hope is that by studying this natural means of self-defense, we might develop potent pharmaceutical means of either preventing stroke or minimizing stroke damage, he says.

The findings appear as a special highlighted paper in the Journal of Neuroscience.

According to the National Stroke Association, stroke is the third leading killer of Americans and the number one cause of adult disability. And yet scientists have still not developed a truly effective means of treating these attacks.

We knew that preconditioning -- giving the brain a slight noxious stimulus beforehand -- can strengthen brain cells against damage from a larger insult later on. This phenomenon occurs naturally in the human brain, explains lead researcher Dr. Alexander Kunz of the University of Dresden, Germany. Dr. Kunz worked on the study while at Weill Cornell.

But exactly how does preconditioning work, and can it come to the aid of the brain's vasculature, as well

Based on their prior work, the researchers knew that the protective effect of preconditioning relies on a ubiquitous chemical in the blood called nitric oxide (NO). Injuries to tissues -- such as the ischemia that occurs in stroke -- activate certain enzymes that produce NO. This process also produces destructive, oxidative byproducts called free radicals.

According to the new study, NO combines with these free radicals to produce low levels of another molecule, called peroxynitrite.

At higher levels, peroxynitrite is a very dangerous chemical for tissues, Dr. Iadecola explains. But we discovered that at these lower concentrations, it's actually beneficial -- helping to preserve the function of blood vessels in the brain whenever a more toxic event occurs.

Normal mice given an inflammatory toxin called lipopolysaccharide (LPS) 24 hours before an induced stroke -- the preconditioning method used in this study -- had a 68 percent reduction in stroke intensity, the researchers found.

Preconditioning also boosted blood flow in areas of the brain unaffected by the stroke by 114 percent.

However, mice that were genetically engineered so that they could not produce NO gained no such advantage from preconditioning. This suggests that NO and its chemical offspring, peroxynitrite, are essential to this protective process.

Our study also demonstrates that preconditioning makes blood vessels more resilient against the damage caused by cerebral ischemia, just as it does for neurons, Dr. Iadecola notes. After preconditioning, the vessels of the brain are impervious to the effects of the stroke and continue to function at a nearly normal level. That's something no one had shown before.

He stressed that it's far too dangerous to give patients peroxynitrite, so the goal here is to figure out how low concentrations of the chemical work their protective magic.

What cell signaling mechanisms does it activate, for example If we could find that out, we might be able to create a pharmaceutical mimic that could protect stroke patients, Dr. Iadecola says.

The real novelty here is that we are looking for a stroke treatment that simply replicates strategies the brain is already using to protect itself, the researcher says. There's a large population out there at high risk for stroke, and we believe this approach could really help them. It might even help minimize brain tissue damage should any stroke occur.

Pediatric ritalin use may affect developing brain, new study suggests

Thu, 19 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) NEW YORK (July 17, 2007) -- Use of the attention deficit/hyperactivity disorder (ADHD) drug Ritalin by young children may cause long-term changes in the developing brain, suggests a new study of very young rats by a research team at Weill Cornell Medical College in New York City.

The study is among the first to probe the effects of Ritalin (methylphenidate) on the neurochemistry of the developing brain. Between 2 to18 percent of American children are thought to be affected by ADHD, and Ritalin, a stimulant similar to amphetamine and cocaine, remains one of the most prescribed drugs for the behavioral disorder.

The changes we saw in the brains of treated rats occurred in areas strongly linked to higher executive functioning, addiction and appetite, social relationships and stress. These alterations gradually disappeared over time once the rats no longer received the drug, notes the study's senior author Dr. Teresa Milner, professor of neuroscience at Weill Cornell Medical College.

The findings, specially highlighted in the Journal of Neuroscience, suggest that doctors must be very careful in their diagnosis of ADHD before prescribing Ritalin. That's because the brain changes noted in the study might be helpful in battling the disorder but harmful if given to youngsters with healthy brain chemistry, Dr. Milner says.

In the study, week-old male rat pups were given injections of Ritalin twice a day during their more physically active nighttime phase. The rats continued receiving the injections up until they were 35 days old.

Relative to human lifespan, this would correspond to very early stages of brain development, explains Jason Gray, a graduate student in the Program of Neuroscience and lead author of the study. That's earlier than the age at which most children now receive Ritalin, although there are clinical studies underway that are testing the drug in 2- and 3-year olds.

The relative doses used were at the very high end of what a human child might be prescribed, Dr. Milner notes. Also, the rats were injected with the drug, rather than fed Ritalin orally, because this method allowed the dose to be metabolized in a way that more closely mimicked its metabolism in humans.

The researchers first looked at behavioral changes in the treated rats. They discovered that -- just as happens in humans -- Ritalin use was linked to a decline in weight. That correlates with the weight loss sometimes seen in patients, Dr. Milner notes.

And in the elevated-plus maze and open field tests, rats examined in adulthood three months after discontinuing the drug displayed fewer signs of anxiety compared to untreated rodents. That was a bit of a surprise because we thought a stimulant might cause the rats to behave in a more anxious manner, Dr. Milner says.

The researchers also used high-tech methods to track changes in both the chemical neuroanatomy and structure of the treated rats' brains at postnatal day 35, which is roughly equivalent to the adolescent period.

These brain tissue findings revealed Ritalin-associated changes in four main areas, Dr. Milner says. First, we noticed alterations in brain chemicals such as catecholamines and norepinephrine in the rats' prefrontal cortex -- a part of the mammalian brain responsible for higher executive thinking and decision-making. There were also significant changes in catecholamine function in the hippocampus, a center for memory and learning.

Treatment-linked alterations were also noted in the striatum -- a brain region known to be key to motor function -- and in the hypothalamus, a center for appetite, arousal and addictive behaviors.

Dr. Milner stressed that, at this point in their research, it's just too early to say whether the changes noted in the Ritalin-exposed brain would be of either benefit or harm to humans.

One thing to remember is that these young animals had normal, healthy brains, she says. In ADHD-affected brains -- where the neurochemistry is already somewhat awry or the brain might be developing too fast -- these changes might help 'reset' that balance in a healthy way. On the other hand, in brains without ADHD, Ritalin might have a more negative effect. We just don't know yet.

One thing was clear: 3 months after the rats stopped receiving Ritalin, the animals' neurochemistry largely had resolved back to the pre-treatment state.

That's encouraging, and supports the notion that this drug therapy may be best used over a relatively short period of time, to be replaced or supplemented with behavioral therapy, Dr. Milner says. We're concerned about longer-term use. It's unclear from this study whether Ritalin might leave more lasting changes, especially if treatment were to continue for years. In that case, it is possible that chronic use of the drug would alter brain chemistry and behavior well into adulthood.

Brain region central to placebo effect identified

Wed, 18 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Researchers have pinpointed a brain region central to the machinery of the placebo effectthe often controversial phenomenon in which a persons belief in the efficacy of a treatment such as a painkilling drug influences its effect.

The researchers said their findings with human subjects offer the potential of measuring the placebo effect and even modulating it for therapeutic purposes. They also said their findings could enable measurements of brain function that would help determine dysfunctions in cerebral mechanisms that may impair recovery across a number of conditions.

Jon-Kar Zubieta and colleagues published their findings in the July 19, 2007, issue of the journal Neuron, published by Cell Press.

Their studies concentrated on a brain area known as the nucleus accumbens (NAC), a region deep in the brain, known to play a role in expectation of reward. Earlier studies had hinted at involvement of the NAC in the placebo effect, but the nature of that role was unknown, said the researchers.

In their experiments, the researchers told volunteers that they were testing the effects of a new pain-killing drug and that the subjects might receive the drug or a placebo. However, in the experiments, the researchers gave only a placebo injection of a salt solution. The experiments involved asking the subjects to rate their expectation of the pain-killing effects of the drug and also the level of pain relief with or without the drug that they felt from a moderately painful injection of salt solution into their jaw muscle.

In one set of experiments, the researchers used a molecular tracer scanning technique known as Positron Emission Spectroscopy to measure release from the NAC of the neurotransmitter dopaminea chemical trigger of the brains reward response. They found that the greater subjects anticipation of the pain-killing benefit of the placebo, the greater the dopamine release from the NAC. Also, subjects who reported greater relief from the placebo when they did experience pain showed greater NAC activity when they received the placebo before the pain.

In separate experiments, the researchers studied whether activation of subjects NAC during reward processing correlated with the magnitude of their placebo effect. They told subjects to expect monetary rewards of different amounts, as their brains were scanned using functional magnetic resonance imaging. The researchers found that the people who showed greater activation of the NAC during this reward-expectation task also showed a greater anticipation of effectiveness of a placebo.

The researchers concluded that These findings are consistent with the hypothesis that this system is involved in the encoding of the incentive value of the placebo, possibly acting as a gate or permissive system for the formation of placebo effects.

They wrote that The placebo effect then emerges as a resiliency mechanism with broad implications that, given its activation of specific circuits and mechanisms, can be both examined and modulated for therapeutic purposes.

Research study describes the role part of the brain plays in memory

Tue, 17 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) A research with experimental rats carried out by the Institute of Neuroscience of the UAB describes the brain region connected to how our declarative memory functions. According to this experiment, part of the prefrontal cortex plays a key role in the social transmission of food preference. This research has helped learn more about how this type of memory functions. In the future, this information could be useful to find new treatment for diseases that affect the memory, such as Alzheimer's disease.

Declarative memory is described as a flexible, conscience and associative type of memory (i.e., it is based on relations between different stimuli). It differs from other types of memories that allow us to recall effective or emotionally-charged data, or carry out processes such as riding a bicycle or playing an instrument. Declarative memory allows us to remember things such as specific moments of our lives, names of people, what we ate for lunch, the capitals of the world, etc. The malfunctioning of this type of memory is one of the most common symptoms found in those suffering from Alzheimer's disease.

A useful model from which to learn about how declarative memory functions is the social transmission of food preference. In other species, this task is connected to the survival of the species and plays a crucial role in their evolution. In this research, the social transmission of food preference was carried out with experimental rats.

When one rodent sniffs another rodent's snout right after the second one has eaten, the first one will later choose to eat the same exact food. Animals learn to remember what their congeners eat and, in that way, lower the risk of eating new foods that could be harmful to them. In addition, they must later use this information acquired during a brief episode of social interaction in very different circumstances. Therefore, they need the flexible expression of memory, which is one of the main traits of declarative memory.

This task depends on learning how to associate smells, a function that is commanded by a specific region of the brain, the nucleus basalis magnocellularis (NBM), which produces acetylcholine (a neurotransmitter that transfers information from one neurone to another through synapses). This chemical substance is essential in making the memory work correctly. The nucleus basalis magnocellularis equivalent in humans is the nucleus basalis Meynert. Precisely this is one of the regions of the brain that shown signs of degeneration among those who suffer from Alzheimer's (and who are often treated with drugs that help to produce acetylcholine).

The acetylcholine produced by the nucleus basalis is transferred to other regions of the brain, where it is recognised by receptor molecules. The research team examined the possibility of one part of the brain, the prelimbic prefrontal cortex, being linked to the social transmission of food preference. To do so, they applied a chemical compound to the experimental rats that neutralised the acetylcholine receptors (muscarinic cholinergic receptor) of this region. By blocking the receptor, the effect of the neurotransmitter was also neutralised and the changes in the animals' behaviour were observed.

The results demonstrated that the social transmission of food preference was clearly affected after neutralising the acetylcholine receptors. Researchers also verified that the effects were not due to other aspects that could alter the experiment, such as lack of olfactory perception, motivation or social interaction. The results therefore suggest that the prelimbic prefrontal cortex, via the use of acetylcholine, regulates cognitive operations (e.g. flexibility in behaviour, attention or strategic planning) that could be needed to correctly express social transmission of food preference, and therefore necessary for our declarative memory.

M. D. Anderson team identifies new oncogene for brain cancer

Mon, 02 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) HOUSTON -- An overexpressed gene found at the scene of a variety of tumors is implicated in the development of two types of malignant brain cancer in a paper by researchers at The University of Texas M. D. Anderson Cancer Center to be published in the Proceedings of the National Academy of Sciences. The paper will be posted online at the PNAS web site the week of July 2.

Just because a gene is associated with cancer doesnt mean that its actually causing cancer. In this paper we show for the first time that insulin-like growth factor binding protein 2 (IGFBP2) connects with two other proteins to fuel development and progression of brain tumors, says senior author Wei Zhang, Ph.D., professor in M. D. Andersons Department of Pathology.

Using a gene transfer delivery system in a mouse model, a team led by Zhang and Professor of Pathology Gregory Fuller, M.D., Ph.D., shows that IGFBP2 plays an active role in the tumorigenesis of astrocytoma and oligodendroglioma. Both cancers are forms of glioma, cancers that develop in the glial cells which normally support and nourish neurons -- that are highly resistant to treatment.

This makes IGFBP2 an important candidate for development of targeted therapy to treat gliomas, Zhang says. Gliomas kill about 13,000 people in the United States annually.

The possibilities are not limited to brain cancer, Fuller notes, because of the pervasive overexpression of IGFBP2 documented in other cancer types. The gene is expressed only at low levels in normal cells, which would potentially reduce side effects caused by a treatment that targeted the gene or its protein product.

Fuller and Zhang first associated overexpression of the gene with brain cancer in 1999. Other researchers have since found it to be overexpressed in prostate, ovarian, breast and colorectal cancers, some leukemias, and also in drug-resistant tumors.

Overabundance of IGFBP2 has since been shown to be an indicator of poor prognosis for glioma patients. The PNAS paper takes it beyond this biomarker status.

Zhang, Fuller and colleagues employed a viral gene transfer delivery agent known as RCAS, which is loaded with the gene, or genes, of interest and injected into the mouse brain. The viral particles infect only glial cells, where the genes are expressed.

This system allows the researchers to observe whether a gene identified in a correlation study plays an active role in tumorigenesis. It also permits the delivery and study of combinations of genes.

They found that a combination of IGFBP2 and another known oncogene called K-Ras leads to development of astrocytomas a glioma named for the star-like shape of its constituent cells.

A combination of K-Ras and a third gene, Akt, previously had been shown to develop astrocytomas. Activation of Akt fuels cell growth and survival. None of the three genes caused brain cancer formation when delivered alone. The researchers tried a combination of Akt and IGFBP2 and no tumor formed, suggesting that the two genes lie in the same molecular pathway and have a similar effect.

For oligodendroglioma, the researchers found that IGFBP2 combined with platelet-derived growth factor beta (PDGFB) results in a higher-grade form of the cancer than that caused by PDGFB alone. The high-grade tumors formed by the combination were indistinguishable in their shape and brain-invasive behavior from human oligodendrogliomas.

The combination also activated the Akt pathway, which PDGFB does not induce by itself. Combined with their earlier findings, this led the team to hypothesize that IGFBP2 activates the Akt pathway, which they confirmed in subsequent lab experiments.

In a final experiment, they treated IGFBP2-PDGFB infected cells in culture with a known Akt inhibitor, which killed more of the combination cells than those infected only with platelet-derived growth factor.

This connection to Akt, the researchers note, makes the presence of IGFBP2 in blood serum a potential biomarker that would indicate an active role for Akt in a patients cancer and thus a role for Akt inhibitors in their treatment.

The survival of the most advanced stage of glioma, gliobastoma, has not significantly improved for decades, note Zhang and Fuller. We hope IGFBP2 will provide an effective target for treatment of this devastating disease.

Weizmann scientists discover a new line of communication between nervous system cells

Tue, 26 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) In a host of neurological diseases, including multiple sclerosis (MS) and several neuropathies, the protective covering surrounding the nerves an insulating material called myelin is damaged. Scientists at the Weizmann Institute of Science have now discovered an important new line of communication between nervous system cells that is crucial to the development of myelinated nerves a discovery that may aid in restoring the normal function of the affected nerve fibers.

Nerve cells (neurons) have long, thin extensions called axons that can reach up to a meter and or more in length. Often, these extensions are covered by myelin, which is formed by a group of specialized cells called glia. Glial cells revolve around the axon, laying down the myelin sheath in segments, leaving small nodes of exposed nerve in between. More than just protection for the delicate axons, the myelin covering allows nerve signals to jump instantaneously between nodes, making the transfer of these signals quick and efficient. When myelin is missing or damaged, the nerve signals cant skip properly down the axons, leading to abnormal function of the affected nerve and often to its degeneration.

In research published recently in Nature Neuroscience, Weizmann Institute scientists Prof. Elior Peles, graduate student Ivo Spiegel, and their colleagues in the Molecular Cell Biology Department and in the United States, have now provided a vital insight into the mechanism by which glial cells recognize and myelinate axons.

How do the glial cells and the axon coordinate this process The Weizmann Institute team found a pair of proteins that pass messages from axons to glial cells. These proteins, called Necl1 and Necl4, belong to a larger family of cell adhesion molecules, so called because they sit on the outer membranes of cells and help them to stick together. Peles and his team discovered that even when removed from their cells, Necl1, normally found on the axon surface, and Necl4, which is found on the glial cell membrane, adhere tightly together. When these molecules are in their natural places, they not only create physical contact between axon and glial cell, but also serve to transfer signals to the cell interior, initiating changes needed to undertake myelination.

The scientists found that production of Necl4 in the glial cells rises when they come into close contact with an unmyelinated axon, and as the process of myelination begins. They observed that if Necl4 is absent in the glial cells, or if they blocked the attachment of Necl4 to Necl1, the axons that were contacted by glial cells did not myelinate. In the same time period, myelin wrapping was already well underway around most of the axons in the control group.

What weve discovered is a completely new means of communication between these nervous system cells, says Peles. The drugs now used to treat MS and other degenerative diseases in which myelin is affected can only slow the disease, but not stop or cure it. Today, we cant reverse the nerve damage caused by these disorders. But if we can understand the mechanisms that control the process of wrapping the axons by their protective sheath, we might be able to recreate that process in patients.

Does stimulant treatment for ADHD increase risk of drug abuse?

Mon, 18 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) UPTON, NY -- Parents, doctors, and others have wondered whether common treatments for attention-deficit hyperactivity disorder (ADHD) inadvertently predispose adolescents to future drug abuse. The answer may depend on the age at which treatment is started and how long it lasts, say the authors of a new brain-imaging and behavioral study conducted in animals at the U.S. Department of Energy's Brookhaven National Laboratory. The results appear in the June 5, 2007 online issue of the journal Pharmacology, Biochemistry and Behavior.

Our study shows that the brain's reward pathways are definitely influenced by methylphenidate, one of the stimulant drugs commonly used to treat ADHD, said Brookhaven researcher Panayotis (Peter) Thanos, lead author of the study. But the brain chemistry changes we observed suggest that the developmental stage at which treatment begins and the duration of treatment are important variables that need further study.

In the study, rats were given methylphenidate mixed with distilled water beginning one month after birth -- early adolescence for rats. Animals received either 1 or 2 milligrams methylphenidate per kilogram of body weight, consistent with clinical doses given to children with ADHD. A control group of rats was handled under identical conditions but given plain water.

After two months of treatment, and again after eight months, the scientists performed positron emission tomography (PET) scans to measure the levels of dopamine D2 receptors, a type of brain receptor important for experiencing reward and pleasure that has been linked to pleasure and drug abuse. After the eight-month treatment, animals were also tested for their propensity to self-administer cocaine.

Rats given the 2mg/kg dose of methylphenidate were significantly less likely to press a lever to self-administer cocaine, and received fewer self-initiated infusions of the drug following eight months of treatment than the lower-dose group or the control rats.

The changes observed in brain chemistry were specific to the age and duration of methylphenidate treatment: Specifically, after two months of treatment, brain scans revealed that both groups of treated rats had lower levels of dopamine D2 receptors in their brains than did control animals.

In contrast, after eight months of treatment, the brain scans revealed elevated levels of dopamine D2 receptors in treated rats compared with controls, with the higher-dose treatment group showing the highest level of D2 receptors. In the control group, D2 receptor levels declined with age.

Research at Brookhaven and elsewhere has suggested that low levels of dopamine D2 receptors may increase the likelihood of drug abuse, while elevated levels of dopamine D2 receptors may attenuate the propensity to abuse drugs.

This new study provides evidence that chronic methylphenidate treatment begun in adolescence affects the brain's dopamine D2 receptor levels, and thus the brain's reward circuitry, differently depending on the age and treatment duration, Thanos said. The scientists' observation of lower rates of cocaine self-administration in the animals treated for eight months with a 2kg/mg dose of methylphenidate supports this idea.

However, the observation of lower levels of D2 receptors after two months of treatment suggests that shorter lengths of treatment or the age at which treatment is evaluated could result in different effects. Lower dopamine D2 receptor levels following short-term treatment could make the animals more vulnerable to drug self-administration during early adulthood, Thanos said. Unfortunately, we cannot compare cocaine self-administration following eight months of treatment with that obtained after two months of treatment in the same animals, since animals were not tested for cocaine self-administration at this earlier time, Thanos said. We wanted to avoid any confounding effect that might have resulted from cocaine exposure during this early developmental stage, he explained.

Evaluating the effect of treatment duration is one avenue the researchers are exploring in follow-up studies to help assess optimal duration of treatment regimes to minimize adverse effects on the propensity to abuse drugs, Thanos said.

Thanos notes that the findings from this study cannot be directly extrapolated to treatment regimes used for ADHD. Also, these studies were done in healthy animals, not in rodent models of ADHD. All experiments were conducted in conformity with the National Academy of Sciences Guide for Care and Use of Laboratory Animals and Brookhaven National Laboratory Institutional Animal Care and Use Committee protocols.

Paying taxes, according to the brain, can bring satisfaction

Thu, 14 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com )

Want to light up the pleasure center in your brain? Just pay your taxes, and then give a little extra voluntarily to your local food bank. University of Oregon scientists have found that doing those deeds can give you the same sort of satisfaction you derive from feeding your own hunger pangs.

A three-member team a cognitive psychologist and two economists published its results in the June 15 issue of the journal Science. The scientists gave 19 women participants $100 and then scanned their brains with functional magnetic resonance imaging (fMRI) as they watched their money go to the food bank through mandatory taxation, and as they made choices about whether to give more money voluntarily or keep it for themselves.

The participants lay on their backs in the fMRI scanner for an hour-long session and viewed the financial transfers on a computer screen. The scanner used a super-cooled magnet, carefully tuned radio waves and powerful computers to calculate what parts of the brain were active as subjects saw their money go to the food bank and made yes or no decisions on additional giving.

Researchers found that two evolutionarily ancient regions deep in the brain the caudate nucleus and the nucleus accumbens fired when subjects saw the charity get the money. The activation was even larger when people gave the money voluntarily, instead of just paying it as taxes. These brain regions are the same ones that fire when basic needs such as food and pleasures (sweets or social contact) are satisfied.

The surprising element for us was that in a situation in which your money is simply given to others where you do not have a free choice you still get reward-center activity, said Ulrich Mayr, a professor of psychology. I dont think that most economists would have suspected that. It reinforces the idea that there is true altruism where its all about how well the common good is doing. Ive heard people claim that they dont mind paying taxes, if its for a good cause and here we showed that you can actually see this going on inside the brain, and even measure it.

The study gives economists a novel look inside the brain during taxation, said co-author William T. Harbaugh, a UO professor of economics and member of the National Bureau of Economic Research in Cambridge, Mass. To economists, the surprising thing about this paper is that we actually see people getting rewards as they give up money, he said. Neural firing in this fundamental, primitive part of the brain is larger when your money goes to a non-profit charity to help other people.On top of that, Harbaugh added, people experience more brain activation when they give voluntarily even though everything here is anonymous. Thats a very surprising result and, to me, an optimistic one.

However, this latter finding, which offers confirmation to the economic theory of warm-glow giving, doesnt necessarily mean that taxes should be lowered and charity relied on more heavily, Harbaugh said. In a voluntary environment, he added, lots of people free-ride and donations fall.

The study, Mayr said, reflects the balancing act that every society must face. What this shows to someone who designs tax policy is that taxes arent all bad, he said. Paying taxes can make citizens happy. People are, to varying degrees, pure altruists. On top of that they like that warm glow they get from charitable giving. Until now we couldnt trace that in the brain.

Neural activation from mandatory taxation, the researchers said, helps predict who will give. We could call the people whose brains light up more when money goes to charity than to themselves altruists, Mayr said. The others are egoists. Based on what we saw in the experiments, we can use this classification to predict how much people are willing to give when the choice is theirs.

There remain a lot of unanswered questions, Harbaugh said. We show that people liked paying a tax that went to a food bank. But suppose the tax had been unfair. What then Or suppose that people voted to make other people pay the tax, too That would help other people even more, so would the voter get a bigger neural reward

Harbaugh, Mayr and co-author Dan Burghart, an economics graduate student, say they are not worried about the possibility that governments could use their method to monitor tax evasion, or charities could use it to figure out whom to ask for money. To do this, we needed a $3 million scanner, some liquid helium and a few weeks of computer time, Harbaugh said.

If a participant moved her head, Burghart added, we had to start all over. It will be a while before this is built into cell phones.

Penn researchers link cell's protein recycling systems

Wed, 13 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) PHILADELPHIA - Many age-related neurological diseases are associated with defective proteins accumulating in nerve cells, suggesting that the cells normal disposal mechanisms are not operating correctly. Now, researchers at the University of Pennsylvania School of Medicine have discovered a molecular link between the cells two major pathways for breaking down proteins and have succeeded in using this link to rescue neurodegenerative diseases in a simple animal model. The study appears this week in Nature.

The cell has two internal pathways for breaking down proteins. The ubiquitin-proteasome pathway marks unwanted proteins with ubiquitin tags and shuttles them for rapid breakdown to a complicated structure called the proteasome. The second is the autophagy-lysosomal system, a more general process in which proteins are surrounded by membranes inside the cell for bulk digestion.

The dogma has been that the autophagy-lysosomal and the proteasomal systems are trains that run on different tracks, with similar purposes, but no point of intersection, explains senior author J. Paul Taylor, MD, PhD, Assistant Professor of Neurology. The new finding directly challenges this thinking by showing that one system can be induced to compensate for the other. Cells are able to shift proteins between the systems. We think that this molecular link can be used to benefit a wide variety of neurodegenerative diseases because accumulation of toxic proteins is a common underlying feature of age-related neurodegeneration.

Taylor and his group study fruit flies in which the proteasome is disabled by a genetic mutation, which results in neurodegeneration. They use the fly eye, a neuron-rich tissue, as a surrogate for the brain because it is easy to visualize. They discovered that making the lysosomal system more or less active dramatically influenced the severity of neurodegeneration.

We found that whenever we knocked the lysosome system down, neurodegeneration always got worse, says Taylor. Then when we activated the autophagy system by feeding the flies a drug called rapamycin, neurodegeneration was prevented. The accumulated misfolded proteins were cleared out by the lysosome system. Then we knew that this system can compensate for the impaired proteasome function, which in itself tells us that the two pathways intersect, says Taylor. The question was, How is this working

The Role of HDAC6Thats where the power of fruit flies comes in, Taylor explains. We can use fruit flies to rapidly screen through many genes to find the one were interested in. In the process of screening, our attention was drawn to HDAC6 because we already knew that it could bind to ubiquitin-tagged proteins and transport them within the cell. So we wondered, could HDAC6 be the link

Taylors group showed that if the HDAC6 gene is knocked out, inducing autophagy no longer rescues the fly eyes from neurodegeneration. Therefore, autophagy requires HDAC6 to work. They also showed that by simply expressing extra HDAC6, neurodegeneration was prevented in flies with proteasome impairment. Taylors group then moved on to fly models of human neurodegenerative disease and showed that they, too, are rescued by over-expression of HDAC6.

Therefore, the researchers suggest that the level of the HDAC6 in a cell regulates its sensitivity to accumulation of misfolded proteins, and that increasing the activity of HDAC6 can prevent the degeneration normally associated with accumulating old, damaged proteins. The researchers suggest further that when proteasomes are impaired or overwhelmed, which leads to accumulation of defective proteins, HDAC6 facilitates delivery to the autophagy-lysosomal system for degradation. Thats how we think HDAC6 links the two systems, says Taylor.

Dr Taylor and his team are now testing the ability of HDAC6 to prevent neurodegeneration in several mouse models, including motor neuron disease, Parkinsons disease, and Huntingtons disease. They are also attempting to identify pharmacologic approaches to augmenting HDAC6 activity.

Early results from Alzheimer's neuroimaging studies could speed research

Tue, 12 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Alzheimers disease researchers may be able to reduce the time and expense associated with clinical trials, according to early results from the Alzheimers Disease Neuroimaging Initiative (ADNI), a public-private research partnership organized by the National Institutes of Health. Preliminary results from ADNI show how it might yield improved methods and uniform standards for imaging and biomarker analysis, so these techniques can be employed in the fight against Alzheimers disease.

These first findings will be presented at the Alzheimers Association International Conference on the Prevention of Dementia being held in Washington, D.C., June 9-12.

The ADNI study observes and tracks changes in normal individuals, in people with mild cognitive impairmenta condition which often precedes Alzheimersand in people with Alzheimers. Researchers will use PET (positron emission tomography) and MRI (magnetic resonance imaging) scans to track changes in the brain, laboratory analyses of cerebrospinal fluid and blood to study biomarkers, and clinical interviews to track cognitive performance over time. ADNI is expected to improve neuroimaging and biomarker measures and consequently allow faster and more efficient evaluation of potential therapies for Alzheimers.

The $60 million, five-year study began recruiting in early 2006, and today about 800 older people at 58 sites in the United States and Canada participate in the effort. The project is supported primarily by the National Institute on Aging (NIA), a component of NIH, with private sector support from pharmaceutical companies, other organizations and the Alzheimers Association through the Foundation for NIH. In addition to NIA, other federal partners are the National Institute of Biomedical Imaging and Bioengineering, also part of NIH, and the Food and Drug Administration.

New treatment options are urgently needed for the millions of people who have Alzheimers and for those at risk as the population ages, says Richard J. Hodes, M.D., Director of the NIA. This preliminary report on aspects of ADNI is quite encouraging.

ADNI principal investigator Michael Weiner, M.D., of the Department of Veterans Affairs Medical Center, University of California, San Francisco, is scheduled to give a progress report and describe the new ADNI database during the conference. Nine other ADNI researchers will also give reports on early results and preliminary findings from various studies including:

Predicting AlzheimersA University of California, San Diego, study found that analyses of MRI and PET images could detect early changes in cerebral cortex thickness in brains of people with mild cognitive impairment over a six month period. Further study, the researchers said, would be needed to see if the changes, with other brain measures, could predict conversion from mild cognitive impairment to Alzheimers.

Validating PET scansA study reported by scientists at the Banner Alzheimers Institute, Phoenix, Ariz., and colleagues compared changes over time in PET scans of glucose metabolism in people with normal cognition, mild cognitive impairment and Alzheimers. The study found that scans correlated with symptoms of each condition and that images from different clinical sites were comparable (or consistent). This study suggests the validity of PET scans for use in future clinical trials.

MRI ReliabilityA Mayo Clinic, Rochester, Minn., study found that a standard anatomical model of a brain can be used successfully to monitor performance of MRI scanners at many different clinical sites. This will ensure accuracy of the MRI images produced from ADNI volunteers using 80 MRI scanners from scores of sites over five years.

Biomarker AnalysisUniversity of Pennsylvania, Philadelphia, scientists and colleagues compared analyses of cerebrospinal fluid samples among seven laboratories. The study evaluated differences within and among the labs performance. This study will ensure that methods for measuring biomarkers are accurate and comparable across laboratories.

An important achievement of ADNI is the creation of a publicly accessible database available to qualified researchers worldwide. The database contains thousands of MRI and PET scan brain images and clinical data and will include biomarker data obtained through blood and cerebrospinal fluid analyses. ADNI includes samples and brain scans from 200 people with Alzheimers, 400 people with mild cognitive impairment and 200 healthy people. All volunteers are between ages 55 and 90. Confidentiality of the participants is rigorously protected.

The database gives ADNI researchers easy access to a huge body of data. But its added value is its design as an international research resource, available worldwide to other researchers interested in neurodegenerative disease, says Susan Molchan, M.D., NIAs program director for ADNI.

Drug slows and may halt Parkinson's disease

Sun, 10 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) CHICAGO --- Northwestern University researchers have discovered a drug that slows and may even halt the progression of Parkinsons disease. The drug rejuvenates aging dopamine cells, whose death in the brain causes the symptoms of this devastating and widespread disease.

D. James Surmeier, the Nathan Smith Davis Professor and chair of physiology at Northwestern Universitys Feinberg School of Medicine, and his team of researchers have found that isradipine, a drug widely used for hypertension and stroke, restores stressed-out dopamine neurons to their vigorous younger selves. The study is described in a feature article in the international journal Nature, which will be published on-line June 10.

Dopamine is a critical chemical messenger in the brain that affects a persons ability to direct his movements. In Parkinsons disease, the neurons that release dopamine die, causing movement to become more and more difficult.

Ultimately, a person loses the ability to walk, talk or pick up a glass of water. The illness is the second most common neurodegenenerative disease in the country, affecting about 1 million people. The incidence of Parkinsons disease increases with age, soaring after age 60.

Our hope is that this drug will protect dopamine neurons, so that if you began taking it early enough, you wont get Parkinsons disease, even if you were at risk. said Surmeier, who heads the Morris K. Udall Center of Excellence for Parkinsons Disease Research at Northwestern. It would be like taking a baby aspirin everyday to protect your heart.

Isradipine may also significantly benefit people who already have Parkinsons disease. In animal models of the disease, Surmeiers team found the drug protected dopamine neurons from toxins that would normally kill them by restoring the neurons to a younger state in which they are less vulnerable.

The principal therapy for Parkinsons disease patients currently is L-DOPA, which is converted in the brain to dopamine. Although L-DOPA relieves many symptoms of the disease in its early stages, the drug becomes less effective over time. As the disease progresses, higher doses of L-DOPA are required to help patients, leading to unwanted side-effects that include involuntary movements. The hope is that by slowing the death of dopamine neurons, isradipine could significantly extend the time in which L-DOPA works effectively.

If we could double or triple the therapeutic window for L-DOPA, it would be a huge advance, Surmeier said.

The work by Surmeiers group is particularly exciting because nothing is known to prevent or slow the progression of Parkinsons disease.

There has not been a major advance in the pharmacological management of Parkinsons disease for 30 years, Surmeier said.

Surmeier, who has researched Parkinsons disease for 20 years, had long been frustrated because it wasnt known how or why dopamine cells die in the disease. It didnt seem like we were making much progress in spite of intense study on several fronts, he said.

Because hes a physiologist, Surmeier decided to investigate whether the electrical activity of dopamine neurons might provide a clue to their vulnerability. All neurons in the brain use electrical signals to do their job, much like digital computers.

First, Surmeier observed that dopamine neurons are non-stop workers called pacemakers. They generate regular electrical signals seven days a week, 24 hours a day, just like pacemaker cells in the heart. This was already known. But then he probed more deeply and discovered something very strange about these dopamine neurons.

Most pacemaking neurons use sodium ions (like those found in table salt) to produce electrical signals. But Surmeier found that adult dopamine neurons use calcium instead.

Sodium is a mild mannered ion that does its job without causing a whit of trouble to the cell. Calcium ions, however, are wild and rambunctious. Remember when Marlon Brando rode into town with his motorcycle gang in The Wild One Those guys were like calcium ions.

The reliance upon calcium was a red flag to us, Surmeier said. Calcium ions need to be chaperoned by the cell almost as soon as they enter to keep them from causing trouble, he noted. The cell has to sequester them or keep pumping them out. This takes a lot of energy.

Its a little like having a room full of two year olds you have to watch like a hawk so they dont get into trouble, Surmeier said. Thats really going to stress you. With three boys under age eleven, he can relate to the stressed dopamine neuron.

Surmeier theorized that the non-stop stress on the dopamine neurons explains why they are more vulnerable to toxins and die at a more rapid rate as we age.

But these findings still didnt offer him a new therapy.

Then, serendipity struck when he was working on a different problem. He discovered that young dopamine neurons and adult ones have an entirely different way of operating.

When the neurons are young, Surmeier found they actually use sodium ions to do their work. But as the neurons age, they become more and more dependent on the troublesome calcium and stop using sodium. This calcium dependence and the stress it causes the neurons --is what makes them more vulnerable to death.

What would happen, Surmeier wondered, if he simply blocked the calciums route into the adult neuron cells Would the neurons revert to their youthful behavior and start using sodium again

The cells had put away their old childhood tools in the closet. The question was if we stopped them from behaving like adults would they go into the closet and get them out again Surmeier asked. Sure enough, they did.

When he gave the mice isradipine, it blocked the calcium from entering the dopamine neuron. At first, the dopamine neurons became silent. But within a few hours, they had reverted to their childhood ways, once again using sodium to get their work done.

This lowers the cells stress level and makes them much more resistant to any other insult thats going to come along down the road. They start acting like theyre youngsters again, Surmeier said.

The next step will be launching a clinical study.

This animal study suggests that calcium channel blockers, drugs currently used to reduce blood pressure, might someday be used to slow the steady progression of Parkinson's disease, said Walter J. Koroshetz, M.D., deputy director of the NINDS.

Drug slows and may halt Parkinson's disease

Sun, 10 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) CHICAGO -- Northwestern University researchers have discovered a drug that slows and may even halt the progression of Parkinsons disease. The drug rejuvenates aging dopamine cells, whose death in the brain causes the symptoms of this devastating and widespread disease.

D. James Surmeier, the Nathan Smith Davis Professor and chair of physiology at Northwestern Universitys Feinberg School of Medicine, and his team of researchers have found that isradipine, a drug widely used for hypertension and stroke, restores stressed-out dopamine neurons to their vigorous younger selves. The study is described in a feature article in the international journal Nature, which will be published on-line June 10.

Dopamine is a critical chemical messenger in the brain that affects a persons ability to direct his movements. In Parkinsons disease, the neurons that release dopamine die, causing movement to become more and more difficult.

Ultimately, a person loses the ability to walk, talk or pick up a glass of water. The illness is the second most common neurodegenenerative disease in the country, affecting about 1 million people. The incidence of Parkinsons disease increases with age, soaring after age 60.

Our hope is that this drug will protect dopamine neurons, so that if you began taking it early enough, you wont get Parkinsons disease, even if you were at risk. said Surmeier, who heads the Morris K. Udall Center of Excellence for Parkinsons Disease Research at Northwestern. It would be like taking a baby aspirin everyday to protect your heart.

Isradipine may also significantly benefit people who already have Parkinsons disease. In animal models of the disease, Surmeiers team found the drug protected dopamine neurons from toxins that would normally kill them by restoring the neurons to a younger state in which they are less vulnerable.

The principal therapy for Parkinsons disease patients currently is L-DOPA, which is converted in the brain to dopamine. Although L-DOPA relieves many symptoms of the disease in its early stages, the drug becomes less effective over time. As the disease progresses, higher doses of L-DOPA are required to help patients, leading to unwanted side-effects that include involuntary movements. The hope is that by slowing the death of dopamine neurons, isradipine could significantly extend the time in which L-DOPA works effectively.

If we could double or triple the therapeutic window for L-DOPA, it would be a huge advance, Surmeier said.

The work by Surmeiers group is particularly exciting because nothing is known to prevent or slow the progression of Parkinsons disease.

There has not been a major advance in the pharmacological management of Parkinsons disease for 30 years, Surmeier said.

Surmeier, who has researched Parkinsons disease for 20 years, had long been frustrated because it wasnt known how or why dopamine cells die in the disease. It didnt seem like we were making much progress in spite of intense study on several fronts, he said.

Because hes a physiologist, Surmeier decided to investigate whether the electrical activity of dopamine neurons might provide a clue to their vulnerability. All neurons in the brain use electrical signals to do their job, much like digital computers.

First, Surmeier observed that dopamine neurons are non-stop workers called pacemakers. They generate regular electrical signals seven days a week, 24 hours a day, just like pacemaker cells in the heart. This was already known. But then he probed more deeply and discovered something very strange about these dopamine neurons.

Most pacemaking neurons use sodium ions (like those found in table salt) to produce electrical signals. But Surmeier found that adult dopamine neurons use calcium instead.

Sodium is a mild mannered ion that does its job without causing a whit of trouble to the cell. Calcium ions, however, are wild and rambunctious. Remember when Marlon Brando rode into town with his motorcycle gang in The Wild One Those guys were like calcium ions.

The reliance upon calcium was a red flag to us, Surmeier said. Calcium ions need to be chaperoned by the cell almost as soon as they enter to keep them from causing trouble, he noted. The cell has to sequester them or keep pumping them out. This takes a lot of energy.

Its a little like having a room full of two year olds you have to watch like a hawk so they dont get into trouble, Surmeier said. Thats really going to stress you. With three boys under age eleven, he can relate to the stressed dopamine neuron.

Surmeier theorized that the non-stop stress on the dopamine neurons explains why they are more vulnerable to toxins and die at a more rapid rate as we age.

But these findings still didnt offer him a new therapy.

Then, serendipity struck when he was working on a different problem. He discovered that young dopamine neurons and adult ones have an entirely different way of operating.

When the neurons are young, Surmeier found they actually use sodium ions to do their work. But as the neurons age, they become more and more dependent on the troublesome calcium and stop using sodium. This calcium dependence and the stress it causes the neurons --is what makes them more vulnerable to death.

What would happen, Surmeier wondered, if he simply blocked the calciums route into the adult neuron cells Would the neurons revert to their youthful behavior and start using sodium again

The cells had put away their old childhood tools in the closet. The question was if we stopped them from behaving like adults would they go into the closet and get them out again Surmeier asked. Sure enough, they did.

When he gave the mice isradipine, it blocked the calcium from entering the dopamine neuron. At first, the dopamine neurons became silent. But within a few hours, they had reverted to their childhood ways, once again using sodium to get their work done.

This lowers the cells stress level and makes them much more resistant to any other insult thats going to come along down the road. They start acting like theyre youngsters again, Surmeier said.

The next step will be launching a clinical study.

This animal study suggests that calcium channel blockers, drugs currently used to reduce blood pressure, might someday be used to slow the steady progression of Parkinson's disease, said Walter J. Koroshetz, M.D., deputy director of the NINDS.

AMPAKINE compounds a new potential treatment for respiratory depression

Mon, 04 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Drug-induced respiratory depression is a life-threatening condition caused by analgesic, hypnotic, and anesthesia medications. Although it is a leading cause of death from the overdose of some classes of abused drugs, respiratory depression also arises during normal, physician-supervised procedures such as surgical anesthesia, post-operative analgesia, and as a result of normal out-patient management of pain from cancer, accidents, or illnesses.

The majority of adverse events occurring with these drugs take place during the dose adjustment period, when two or more central nervous depressants are taken together, or when patients take prescribed drugs in ways not intended by their physician.

Although only 0.5%-1.2% of total adverse drug events caused by prescription medications are respiratory in nature, these serious side effects account for 25%-30% of drug-induced deaths. Opiates and barbiturates are the primary drugs classes responsible for these effects. Opiates include the standard pain-killing drugs morphine, fentanyl, and codeine, as well as related products vicodin, hydrocodone, and oxycontin. Barbituates comprise the sedative drugs amobarbital, aprobarbital, butabarbital, pentobarbital, and others. Sleeping disorders are another common predisposing factor for respiratory depression, in this case known as sleep apnea.

Currently, the only way to counter opiate-induced respiratory depression is to administer opiate receptor antagonists, drugs that block the effectiveness of opiate analgesia. While this approach may prevent a serious side effect or even death, it dramatically reduces the effectiveness of drugs administered for management of severe pain.

Researchers at the University of Alberta (Edmonton, AB) and Cortex Pharmaceuticals (Irvine, CA) believe that AMPAKINE drugs may provide protection from drug-induced respiratory depression, while simultaneously allowing the sedative or analgesic to continue working as it was intended.

The drug tested in this study belongs to a novel class of molecules known as AMPAKINE compounds being developed by Cortex Pharmaceuticals, Inc. located in Irvine, California. AMPAKINE compounds act on the most common excitatory receptor in the brain, the AMPA Glutamate type receptor, which has been shown in rodent models to boost the brain's own protein for improving age-related deficits in memory mechanisms. In primate models AMPAKINE compounds have replicated the studies in rodents and in adults patients suffering from Attention Deficit Hyperactivity Disorder, significant clinical and statistical improvement in increase attention and decrease hyperactivity have been observed. The U. Alberta research provide evidence that another important AMPAKINE indication is to stimulate primitive areas of the brain called the pre-Botzinger Complex responsible for breathing, without causing side effects. The pre-Botzinger Complex generated respiratory-related oscillations similar to those generated by the whole brainstem in vitro, and neurons with voltage-dependent pacemaker-like properties that have been identified in this brain region.

In a study published in 2006, Dr. John J. Greer of U. Alberta demonstrated that certain AMPAKINE compounds enhance the respiratory drive and breathing rhythm at the brain-stem level containing the pre-Botzinger Complex in laboratory rats whose respiration rates were purposely suppressed by administration of central nervous system depressants.

Dr. Greer found that respiratory depression induced by these agents can be reversed or prevented in test animals with an experimental AMPAKINE drug, without a reduction of pain relief or sedation.

Greer and coworkers treated rats with the opioids analgesic fentanyl or the barbiturate sedative Phenobarbital, both commonly prescribed in the United States. Greer used a technique known as plethysmography, which measures blood flow throughout the body, to determine the level of respiratory distressed caused by the drugs. When drugged rats were treated with the AMPAKINE , the respiratory distress quickly resolved. The drug worked in both newborn and adult rats. Interestingly, the drug on its own did not affect blood flow in animals not treated with the sedative drugs, nor did administration of the drug cause noticeable arousal in the animals.

Greer concluded, in a study published in the September 20, 2006 issue of the American Journal of Respiratory Critical Care Medicine, that CX546, effectively reverses opioid- and barbiturate-induced respiratory depression without reversing the analgesic response.

These results open up the real possibility of combining an ampakine compound with commonly prescribed barbiturates or opiates to reduce the likelihood that life-threatening respiratory depression will occur, noted explained Roger G. Stoll, Ph.D., Chairman, President, and CEO of Cortex.

Cortex Pharmaceuticals has entered into a Patent Licensing Agreement with the University of Alberta for this new respiratory application for the use of AMPAKINE compounds. Under terms of the license Cortex will evaluate a number of novel low and high impact AMPAKINE compounds for a range of new respiratory applications, such as, respiratory depression induced by opiates and barbiturates to start and others to be named at a future time. In return, Cortex will provide the University with an undisclosed upfront payment, milestone compensation, and royalties from the commercialization of specific AMPAKINE drugs approved for any therapeutic and/or prophylactic indication associated with respiratory depression . Dr. Greer, who has successfully filed a patent for the use of AMPAKINE drugs for these respiratory indications, will receive multiple years of research support funding from Cortex.

Cortex focuses on novel drug therapies for neurological and psychiatric disorders. Its lead compounds belong to two classes of ampakines, which act on the brain's AMPA receptor. Approximately 85% of neurons that handle brain electrical activity do so through this receptor, which controls traffic of the neurotransmitter glutamate. Ampakine molecules bind to the AMPA receptor, causing its glutamate channel to remain open for a longer time period, thereby allowing more glutamate to enter the cell. As a result, ampakines cause amplification of signals at connections between brain cells.

The loss of these connections may be, in part, responsible for memory and behavior problems in Alzheimer's disease, neurological disorders, and even aging. Research data suggests that ampakine molecules may improve neurotransmitter deficiencies implicated in schizophrenia, Huntingtonâs disease, fragile X syndrome, and Rhett's syndrome.

Cortex is developing two classes of AMPAKINE drugs: Low and High impact compounds. , CX717 is an example of a Low impact AMPAKINE drugs, which is currently in human clinical trials, and high-impact molecules which are currently in lead optimization and are currently being tested in transgenic animal models for a variety of neurodegenerative diseases . The two classes of AMPAKINE drugs operate at different binding sites on the AMPA_type glutamate receptor.

Cortex has partnered with several leading pharmaceutical companies for specific therapeutic applications of ampakines. The company has an alliance with Organon Biosciences (soon to be part of Schering-Plough) for AMPAKINE -based treatment of schizophrenia and depression, and with Les Laboratoires Servier.

The study of AMPAKINE drugs in respiratory depression opens a new chapter in the development of this class of therapeutics, and a potentially significant breakthrough in how medication for pain, analgesia, and sedation are used. Ampakines may allow for improved safety and a more effective use of opiate analgesics and barbiturate sedatives, Dr. Stoll of Cortex observes, two important classes of central nervous system drugs.

Every moment counts: Predicting treatment responses earlier for brain tumor patients

Sun, 03 Jun 2007 04:00:00 PST

( from http://www.rxpgnews.com ) WASHINGTON, D.C.Using metabolic or molecular imaging to measure brain tumor patients' response to treatment is a powerful predictor of survival, notes a first-of-its-kind study presented at the 54th Annual Meeting of SNM, the world's largest society for molecular imaging and nuclear medicine professionals.

Our study opens the door to the possibility that brain tumor patients may live longer and respond better to drug treatments, said Wei Chen, assistant professor in the Department of Molecular and Medical Pharmacology at the David Geffen School of Medicine, University of California, Los Angeles. Malignant brain tumors are very difficult to treat. Typically, patients live for three months without treatment and up to a year with treatment, she said.

Using positron emission tomography (PET) imagingwith the radiotracer FLT (fluorothymidine)UCLA researchers were able to determine within one or two weeks after starting the treatment whether patients were responding well to the drugs bevacizumab and irinotecan. This quick response determination is unheard of with the traditionally used magnetic resonance imaging, a procedure that looks at the anatomy rather than metabolic activities of tumor cells, she explained. With MRI, it is often difficult to tell tumor growth from changes caused by treatment (such as radiation). In addition, it could take months before it's known whether a patient is responding to treatment, said Chen.

A brain tumor is an abnormal mass of tissue that grows and multiplies uncontrollablytaking up space within the skull and interfering with the brain's vital functions. Malignant brain tumors are rapidly fatal, said Chen. This year, nearly 21,000 people in this country will be diagnosed with brain and other related nervous system tumors in this country and nearly 13,000 individuals will die from them. Neurooncologists are desperately in need of an imaging modality that could evaluate reliably and rapidly the response to a treatment, she added.

We studied the predictive value of PET with FLT, a marker of cell proliferation, in patients with recurrent malignant brain tumors, said Chen. We used molecular imaging to measure the changes of metabolism in tumor cells, and FLT-PET provided much higher response rates than MRI, she explained. Additionally, the research shows the FLT-PET imaging is predictive of patients' outcomesindicating that in those cases where patients responded to drug treatment, they lived three times as long as those who did not, she added. FLT-PETas an imaging biomarkeris strongly predictive of overall survival for these patients with brain cancer, she noted. No matter one's age, number of times cancer recurred or number of prior drug treatmentsFLT-PET was the most powerful independent predictor of survival, she said.

The drug bevacizumab is an antiangiogenic agent, which inhibits the development of blood vessels that supply blood and oxygen that contribute to a tumor's growth, said Chen. Until this study, there were no reliable predictors of therapeutic response for patients with primary brain tumors undergoing treatment with these types of drugs, said Chen. Our research paves the way for developing drugs that could improve the lives of those with malignant brain tumors, said Chen, adding that research will continue factoring in metabolic response into drug treatment.

PET is a safe, highly specialized, noninvasive imaging technique that uses short-lived radioactive substances to produce three-dimensional images of those substances functioning within the body. A special type of camera works with computers to provide precise pictures of the areas of the body being imaged and molecular images of the body's biological functions.

Detecting cold, feeling pain: Study reveals why menthol feels fresh

Wed, 30 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Scientists have identified the receptor in cells of the peripheral nervous system that is most responsible for the body's ability to sense cold.

The finding, reported on-line in the journal Nature (May 30, 2007), reveals one of the key mechanisms by which the body detects temperature sensation. But in so doing it also illuminates a mechanism that mediates how the body experiences intense stimuli temperature, in this case that can cause pain.

As such, the receptor known as menthol receptor TRPM8 -- provides a target for studying acute and chronic pain, as can result from inflammatory or nerve injury, the researchers say, and a potential new target for treating pain.

By understanding how sensory receptors work, how thresholds for temperature are determined, we gain insight into how these thresholds change in the setting of injury, such as inflammatory and nerve injury, and how these changes may contribute to chronic pain, says senior author David Julius, PhD, chairman and professor of physiology at UCSF.

The methanol receptor, and other temperature receptors discovered in recent years by the Julius lab, offer potential targets for developing analgesic drugs that act in the peripheral, nervous system, rather than centrally, where opiate receptors act, he says.

The finding is a milestone in an investigation the team began several years ago. In 2002, the researchers discovered that the receptor was activated by chemical cooling agents such as menthol, a natural product of mint, and cool air. They reported their discovery, or cloning, of the receptor in Nature (March 7, 2002), hypothesizing that the receptor would play a key role in sensing cold. However, some subsequent papers questioned this theory.

In the current study, the team confirmed their hypothesis by knocking out the gene that synthesizes the receptor, both in sensory neurons in cell culture and in mice. The cells in culture were unresponsive to cooling agents, including menthol. The genetically engineered mice did not discriminate between warm and cold surfaces until the temperature dropped to extremes.

It's been known for years that menthol and related cooling agents evoke the psychophysical sensation of cold somehow by interacting with the aspect of the sensory nervous system that's related to cold detection, says Julius.

The current study, he says -- led by Diana M. Bautista, PhD, and Jan Siemens, PhD, of the Julius lab and Joshua M. Glazer, PhD, of the lab of co-senior author Cheryl Stucky, PhD, of the Medical College of Wisconsin puts that question to rest.

As the mice lacking the gene were not completely insensitive to cold -- they avoided contact with surfaces below 10 degrees C, though with reduced efficiency -- the next step, says Julius, will be to illuminate this residual aspect of cold sensation.

The finding is the latest of a series of discoveries led by the Julius lab on the molecular mechanisms of temperature sensation and pain. In 1997, the lab cloned the gene for the capsaicin receptor, the main pungent ingredient in some chili peppers (Nature, Oct. 23, 1997), and in 2000 reported that, in mice, the receptor triggers the nerves to fire pain signals when they are exposed to high ambient heat or the fiery properties of peppery food. (Science, April 14, 2000). The study demonstrated that capsaicin and noxious heat elicit the sensation of burning pain through activation of the same receptor on sensory neurons.

Most recently, they identified the receptor of isothiocyanate compounds, which constitute the pungent ingredients in such plants as wasabi and yellow mustard. In response to high temperatures, the receptor produces pain and irritation.

All of these studies use natural products to understand pain mechanisms in the periphery of the body, where they are first sensed, says Julius.

Ultimately, pain signals are transmitted from the peripheral nervous system into the body's central nervous system moving through nerves in the spinal cord and brain stem up to the brain, which prompts a response, or feeling. Co-author of the current study Allan Basbaum, PhD, also of UCSF, is a pioneer of research into the mechanism of chronic pain within the central nervous system.

The Julius team's complementary work is focused at the level of the sensory nerve fiber, where the signals are first initiated. We want to know, Julius says, how do you detect these stimuli to begin with How do your sensory nerve endings do this to begin with And what are the biochemical and biophysical mechanisms that account for this

All three receptors the Julius lab has discovered are members of the TRP family of ion channels expressed on sensory neurons. The latest finding adds to the evidence, says Julius, that TRP channels are the principal transducers of thermal stimuli in the mammalian periphery nervous system.

Limiting stroke damage is focus of study

Wed, 30 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Brain damage that occurs even days after a stroke, increasing stroke size and devastation, is the focus of researchers trying to identify new treatments.

This would be a death wave coming through; neurons are dying here, says Medical College of Georgia Neuroscientist Sergei Kirov as he watches moving images of compounding events that kill brain tissue in the stroke's core.

Within seconds of a clot or hemorrhage cutting off blood, oxygen and glucose, the neuron's powerhouses, or mitochondria, shut down and the key energy source ATP goes away. Energy loss shuts down the sodium-potassium pump and the membrane that keeps the right substances inside and outside the cell becomes dysfunctional. Neurons swell and the proper electrical balance essential for neuronal activity is lost.

This is what is happening in the ischemic core; dendrites get beaded, spines are lost and synapses are probably lost at the same time, says Dr. Kirov describing rapidly deteriorating communication points for neurons. This is not recoverable; everything dies here, he says of the destruction, termed anoxic depolarization.

Damage doesn't stop there. In the minutes, hours and even days following stroke, waves of peri-infarct depolarization pound surrounding brain tissue, where blood flow is reduced by about 60 percent.

It's enough oxygen and energy for neurons to survive for some time, but not enough to function properly, says Dr. Kirov, who received a $1.4 million, five-year grant from the National Institute of Neurological Disorders and Stroke, to study this compromised tissue around the stroke core called the penumbra. His grant was ranked among the top 1 percent of those reviewed by the study section.

If the recurring waves continue, finally they will kill cells, says Dr. Kirov who wants to better understand this depolarizing event with the goal of stopping it. We are trying to block this event to save the penumbra. Part of the recovery is if you can restore the normal electrical activity of neurons. We need some energy to do that.

He's using real-time microscopical imaging to monitor changes in neurons and their dendrites and spines following a stroke, and pharmaceuticals including an antibiotic and an anesthetic to try to stop it. Disintegration of a neuron's dendrites and spines, which receive messages from other neurons via synapses, is an early indicator of trouble. Studies are being done in an animal model for stroke and dissected but still-viable brain tissue.

The penumbra exists for several days, so this is basically a window of opportunity to save this region, but we don't yet have good drugs to do this. We need to target this area for drug treatment, Dr. Kirov says.

So Dr. Kirov studies dendrite and spine damage that occurs in anoxic depolarization and peri-infarct depolarization and watches their recovery after a short simulated stroke.

He believes by finding a way to inhibit anoxic depolarization in a slice of living brain, he can protect neurons by stopping structural and functional damage and promoting recovery.

His previous work has shown that cold also inhibits the sodium-potassium pump, resulting in dendrite beading and spine loss, and that warming of brain tissue and pump revival quickly heals old spines and induces new ones.

Now he wants to know if the new spines function and last and if this adaptive recovery also occurs when stroke is the culprit.

Check and balance for neuron activity provides insight into schizophrenia, seizures

Wed, 23 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Two genes important for human development and implicated in cancer and schizophrenia also help keep a healthy balance between excitation and inhibition of brain cells, researchers say.

Neuregulin-1 and its receptor, ErbB4, promote inhibition at the site of inhibitory synapses in the brain by increasing release of GABA, a major inhibitory neurotransmitter, Medical College of Georgia researchers led by Dr. Lin Mei report in the May 24 issue of Neuron.

In 2000, a research team led by Dr. Mei showed that neuregulin-1 and ErbB4 also are at excitatory synapses, communication points between neurons where the neurotransmitter glutamate excites cells to action. Here, neuregulin-1 and ErbB4 suppress excitation.

Right beside the place where the excitatory synapse can be activated, there is also something that can suppress it, says Dr. Mei, chief of developmental neurobiology at MCG. Now we have identified another novel target of neuregulin-1 which is the inhibitory synapse.

Together the findings reveal a check and balance for brain cell activity managed by neuregulin-1 in the brain's prefrontal cortex, where complex reasoning and decisions about appropriate social behavior occur, he says.

They also provide new treatment targets for psychiatric diseases such as schizophrenia and neurological disorders such as epilepsy, researchers say.

The genes are both associated with schizophrenia, a disease that affects about 1 percent of the population, but the exact role of malfunctioning neuregulin-1 signaling was unclear.

(Dr. Mei's) findings help explain how a gene that is potentially causative in disorders like schizophrenia and bipolar disorder relate to a neurotransmitter that is critical for explaining the cognitive deficits associated with the illness, says Dr. Daniel R. Weinberger, director of the Genes, Cognition and Psychosis Program at the National Institute of Mental Health in Bethesda, Md.

What we have found is neuregulin-1 can regulate GABA release from these neurons and if the GABA is released here that may play a role in controlling the output of this neuron, Dr. Mei says, pointing to an illustration of pyramid-shaped neurons that looks like a high-tech switchboard with information coming in from all angles.

Pyramidal neurons get information from nearby interneurons, integrate it, then decide what message to move forward. This pyramidal neuron receives inhibitory input and excitatory input, and neuregulin-1 can regulate both, says Dr. Mei.

They nicely balance input in most people, enabling folks to balance their checking accounts and suppress the urge to run naked down the street.

In 2006, University of Pennsylvania researchers reported in Nature Medicine an altered signaling pathway for neuregulin-1 and ErbB4 genes in the brains of schizophrenics. Dr. Mei's findings show that these factors associated with a schizophrenic brain have at least two places to act.

There is a ton of evidence that when inhibitory synapses, such as GABA, go wrong, the symptoms of mice and rats look similar to those of schizophrenia in people, he says.

Mounting evidence suggests that problems with the excitatory and inhibitory synapses regulated by neuregulin-1 result in other problems as well: Excess excitation results in mind-rattling seizures and excess inhibition in depression, as examples.

If this neuron is too excited, people may get manic or have seizures, says Dr. Mei. Patients with schizophrenia, for example, show symptoms that implicate alterations in inhibitory neurotransmission in addition to excitatory neurotransmission.

Dr. Mei co-authored a companion paper in Neuron with scientists at Cold Spring Harbor in New York that provides yet another link between neuregulin-1, its receptor ErbB4 and schizophrenia. It shows ErbB4 plays a key role in the maturation and plasticity of excitatory synapses and that normal synapse development is impaired by genetic defects in neuregulin-1 and ErbB4 signaling. The result is impaired function of the excitatory neurotransmitter, glutamate.

Now he wants to study disease processes in a neuregulin-1/ErbB4 knockout mouse and learn more about how neuregulin-1 mediates GABA release. Another key unknown is what regulates neuregulin-1.

Brain research poised to dramatically advance global society

Mon, 21 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) FAIRFAX, Va., May 21, 2007 -- World-renowned scientists will convene at George Mason University on May 21 and 22 to call for a 10-year intellectual revolution the decade of the mind. The proceedings that will be published after this historic gathering will make the case for a $4 billion public research initiative dedicated to reaching the next level of understanding the human brain--the yet-to-be-discovered inner workings of the mind. The symposium also will outline the dramatic implications the decade will have on the global economy and health care.

We are at the 'tipping point' of making enormous advances in public health, particularly in managing diseases that affect the mind, such as Alzheimer's disease, Parkinson's disease, autism and schizophrenia, said Jim Olds, director of Mason's Krasnow Institute for Advanced Study. We at Mason are honored to be hosting this gathering of the world's leading researchers in brain study who together will outline the vision for the 'Decade of the Mind' that we will present to federal policymakers.

The two-day symposium will include nine sessions, each featuring one aspect of brain research, and will be moderated by scientists from the Krasnow Institute for Advanced Study. The symposium will be anchored by a plenary session including the nine panelists. Moderated by New York Times science writer George Johnson, the session will provide an open forum for the scientists to discuss their groundbreaking research in areas such as neuroscience, neurobiology, computer science, psychology, robotics and economics. The panel will also explain the urgent need to continue the study of the human mind and the benefits this research could bring to society.

It is our intention to cover a lot of ground in two days because we need to capture the magnitude of the impact of what we are proposing to Congress, said Olds. A 10-year focus to bring the enormous promise of brain research will launch an intellectual revolution here and throughout the world, with lasting impacts on society.

In the United States today, more than five million people are living with Alzheimer's disease according to the Alzheimer's Association. The number of people affected by this ultimately fatal disease will only increase over the next decade as early onset Alzheimer's begins to affect the baby boomer generation.

Today, one in 17 Americans suffer from a serious mental illness, the leading cause of disability in the U.S. for people 15 to 44 years old, according to the National Institute on Mental Health. New brain research during the initiative, coupled with advances in MRI technology and other non-invasive research tools, will allow scientists to better understand what causes these illnesses and how to manage or cure them.

This initiative also could help thousands of soldiers, sailors and airmen who have served in Afghanistan and Iraq more quickly and easily recover from brain injuries caused during combat, especially by improvised explosive devices.

Further research could allow advances in robotics and artificial intelligence that would make most future military vehicles and aircraft operate unmanned and autonomously, thereby saving thousands of lives during combat operations.

The economic impact of the Decade of the Mind will be felt in all levels of society, said Olds. By translating our knowledge of the human mind to building more intelligent machines and computer applications, we can improve the welfare of millions of people worldwide.

The groundwork for this initiative was laid during the Decade of the Brain, declared by President George H.W. Bush in 1990. It produced immense advances in brain research, including the development of MRI scanners and progress in the understanding of Alzheimer's disease and mental illness. Using these advances as a basis for further exploration into the human mind, this new decade would provide the nations scientific community the opportunity to understand more about the mind than ever before and tackle some of society's most pressing challenges.

MIT reports key pathway in synaptic plasticity

Mon, 21 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Cambridge, Mass. -- Scientists are keenly studying how neurons form synapses--the physical and chemical connections between neurons--and the pruning of neural circuits during development, not least because synaptic abnormalities may partially underlie many developmental and neurodegenerative diseases.

Several key molecules are involved in normal synaptic formation, but their interactions are not well understood. Now MIT neuroscientists have taken an important step toward solving this challenging jigsaw puzzle. They have pieced together a direct linear pathway connecting three molecules involved in synaptic formation, to be reported in the May 21 advance online publication of Nature Neuroscience.

We haven't solved the whole puzzle yet, cautions Martha Constantine-Paton, a developmental neuroscientist in the McGovern Institute for Brain Research at MIT, professor in the Department of Biology and senior author of the paper. But we do now have a broader view of what happens in synaptic plasticity (adaptability). More importantly, we have an exciting model of this new pathway's role in development and learning. We hope this study might advance the study of normal, healthy brain development in people so that we may be able to prevent or treat many devastating developmental neurological disorders.

Constantine-Paton and her co-author, Akira Yoshii, a pediatric neurologist and research scientist in her lab, use the rodent visual pathway as an accessible model for studying how the signaling properties of synapses change during development and how those changes relate to structural changes in the brain and developmental milestones in behavior.

Specifically, they focus on a major developmental event-eye opening, which in rodents happens after birth and is followed by rapid increases in synapse strength and visual circuit refinement that follow the onset of visual stimulation. Previously, the authors had discovered a possible mechanism for that increase in synaptic strength. Namely, a protein called PSD-95 rushes to the synapses within hours of eye opening. PSD-95 is a scaffold that anchors, among other things, two classes of receptors for the neurotransmitter glutamate, which triggers the cell's electrical activity during development and learning. Curiously, PSD-95 also held the receptor for BDNF (TrkB), an important factor that is necessary for synaptic strengthening during development and learning.

In the current work, the researchers set out to explore the relationship between BDNF and PSD-95. In so doing, they defined an entirely new pathway that may explain an intriguing phenomenon in development.

In short, stimulating visual neurons initiates a positive feedback loop, starting with one class of glutamate receptors known as NMDA receptors, which activate BDNF. BDNF triggers a signaling pathway involving another well-studied duo, PI3 kinase/AKT. That pathway causes more PSD-95, and with it more receptors for BDNF, to accumulate at the synapse within one hour of stimulation. As a result, the synapse becomes more responsive to BDNF, which sends more PSD-95 to the synapse.

Surprisingly, stimulating just a few synapses with BDNF sends more PSD-95 to excitatory synapses throughout the entire neuron within the hour. This newly described pan-neuron effect of local synaptic stimulation is similar to synaptic tagging, which is a mechanism originally proposed to explain how a few very active synapses can prime larger regions of a neuron for long-term synaptic strengthening in response to subsequent stimulation.

A mechanism like the BDNF/PSD-95 pathway could account for numerous observations at the cellular level in animal models, or during behavioral development in young children, explains Yoshii. Namely, the development of particular neurological connections or skills does not occur gradually over time. Instead such changes tend to occur suddenly, appearing in short intervals after robust stimulation. It is as if there is a single important trigger and then a functional circuit rapidly comes online.

Nanomedicine opens the way for nerve cell regeneration

Sun, 20 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) The ability to regenerate nerve cells in the body could reduce the effects of trauma and disease in a dramatic way. In two presentations at the NSTI Nanotech 2007 Conference, researchers describe the use of nanotechnology to enhance the regeneration of nerve cells. In the first method, developed at the University of Miami, researchers show how magnetic nanoparticles (MNPs) may be used to create mechanical tension that stimulates the growth and elongation of axons of the central nervous system neurons. The second method from the University of California, Berkeley uses aligned nanofibers containing one or more growth factors to provide a bioactive matrix where nerve cells can regrow.

It is known that injured neurons in the central nervous system (CNS) do not regenerate, but it is not clear why. Adult CNS neurons may lack an intrinsic capacity for rapid regeneration, and CNS glia create an inhibitory environment for growth after injury. Can these challenges be overcome even before we fully understand them at a molecular level why axons in central nervous system do not regenerate Dr. Mauris N. De Silva describes the novel nanotechnology based approach designed that includes the use of magnetic nanoparticles and magnetic fields for addressing the challenges associated with regeneration of central nervous system after injury. By providing mechanical tension to the regrowing axon, we may be able to enhance the regenerative axon growth in vivo. This mechanically induced neurite outgrowth may provide a possible method for bypassing the inhibitory interface and the tissue beyond a CNS related injury. Using optic nerve and spinal cord tissues as in vivo models and dissociated retinal ganglion neurons as an in vitro model, De Silva and his colleagues are currently investigating how these magnetic nanoparticles can be incorporated into neurons and axons at the site of injury. Although, this study is at a very preliminary stage to explore the possibility of using magnetic nanoparticles for enhancing in vivo axon regeneration, this work may have significant implications for the treatment of spinal cord injuries, and is a vital next step in bringing this new technology to clinical use.

The second presentation focuses on peripheral nerve injury, which affects 2.8% of all trauma patients and quite often results in lifelong disability. Since peripheral nerves relay signals between the brain and the rest of the body, injury to these nerves results in loss of sensory and motor function. Upper extremity paralysis alone affects more than 300,000 individuals annually in the US. The most serious form of peripheral nerve injury is complete severance of the nerve. The severed nerve can regenerate; the nerve fibers from the nerve end closest to the spinal cord have to grow across the injury gap, enter the other nerve segment and then work their way through to their end targets (skin, muscle, etc). Usually, when the gap between the severed nerve endings is larger than a few millimeters, the nerve does not regenerate on its own. If left untreated, the end result is permanent sensory and motor paralysis. A few hundred thousand people suffer from this debilitating condition annually in the US.

Currently, the most successful form of treatment is to take a section of healthy nerve (autograft) from another part of the patient's body to bridge the damaged one. This autograft then serves as a guide for nerve fibers to cross the injury gap. Although successful, this autograft procedure has major drawbacks including loss of function at the donor site, multiple surgeries and, quite often, it's just not possible to find a suitable nerve to use as a graft. Various synthetic nerve grafts are currently available but none work better than the autograft and can't bridge gaps larger than 4 centimeters.

Researchers at the University of California, Berkeley have developed a technology that has the potential to serve as a better alternative than currently available synthetic nerve grafts. The graft material is composed entirely of aligned nanoscale polymer fibers. These polymer fibers act as physical guides for regenerating nerve fibers. They have also developed a way to make these aligned nanofibers bioactive by attaching various biochemicals directly onto the surfaces of the nanofibers. Thus, the bioactive aligned nanofiber technology mimics the nerve autograft by providing both physical and biochemical cues to enhance and direct nerve growth.

This technology has been tested by culturing rat nerve tissue ex vivo on our bioactive aligned nanofiber scaffolds. When the nerve tissue was cultured on unaligned nanofibers there was no nerve fiber growth onto the scaffolds. However, on aligned nanofiber scaffolds, they not only observed nerve fibers growing from the tissue but the nerve fibers were aligned in the same orientation as the nanofibers. Furthermore, when there were biochemicals present on the nanofibers, the nerve fiber growth was enhanced 5 fold. In a matter of just 5 days, nerve fibers had extended 4 millimeters from the nerve tissue in a bipolar fashion on the bioactive aligned nanofiber scaffolds. Thus, this technology can induce, enhance and direct nerve fiber regeneration in a straight and organized manner.

In order to make the technology clinically viable, they have also developed a novel graft fabrication technology in their laboratory. The most common method for fabricating polymer nanofibers is to use an electrical field to spin very thin fibers. This technique is called electrospinning and can be used to make nanofiber scaffolds in various shapes such as sheets and tubes. They have made a key innovation to this technology that enables us to fabricate tubular nerve grafts composed entirely of polymer nanofibers aligned along the length of tubes. This technology also allows customization of the length, diameter and thickness of the aligned tubular nanofiber grafts. The group will evaluate the performance of these aligned nanofiber nerve grafts in small animal pre-clinical studies starting in mid-May.

The technology presented herein is being patented by the University of California, Berkeley and has been licensed to NanoNerve, Inc.

According to Principal Investigator, Shyam Patel, Speed is the key to successful nerve regeneration. Our aligned nanofiber technology takes full advantage of the fact that the shortest distance between damaged nerve endings is a straight line. It directs straightforward nerve growth and never lets them stray from the fast lane.

Inexpensive 'nanoglue' can bond nearly anything together

Wed, 16 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Troy, N.Y. -- Researchers at Rensselaer Polytechnic Institute have developed a new method to bond materials that dont normally stick together. The teams adhesive, which is based on self-assembling nanoscale chains, could impact everything from next-generation computer chip manufacturing to energy production.

Less than a nanometer or one billionth of a meter thick, the nanoglue is inexpensive to make and can withstand temperatures far higher than what was previously envisioned. In fact, the adhesives molecular bonds strengthen when exposed to heat.

The glue material is already commercially available, but the research teams method of treating the glue to dramatically enhance its stickiness and heat resistance is completely new. The project, led by Rensselaer materials science and engineering professor Ganapathiraman Ramanath, is featured in the May 17 issue of the journal Nature.

Like many key scientific discoveries, Ramanath and his team happened upon the novel, heat-hardened nanoglue by accident.

For years Ramanath has investigated ways of assembling layers of molecular chains between two different materials to enhance the structural integrity, efficiency, and reliability of semiconductor devices in computer chips. His team has shown that molecular chains with a carbon backbone ending with appropriate elements such as silicon, oxygen, or sulfur can improve adhesion and prevent heat-triggered mixing of atoms of the adjoining substances. Recently, Ramanaths group and other researchers have found these nanolayers to be useful for creating adhesives, lubricants, and protective surface coatings.

The nanolayers, however, are extremely susceptible to heat and begin to degrade or simply detach from a surface when exposed to temperatures above 400 degrees Celsius. This severe limitation has precluded more widespread use of the nanolayers.

Ramanaths team decided to sandwich a nanolayer between a thin film of copper and silica, thinking the extra support would help strengthen the nanolayers bonds and boost its adhesive properties. It proved to be an insightful venture, and the research team found more than it bargained for.

When exposed to heat, the middle layer of the nanosandwich did not break down or fall off as it had nowhere to go. But that was not the only good news. The nanolayers bonds grew stronger and more adhesive when exposed to temperatures above 400 degrees Celsius. Constrained between the copper and silica, the nanolayers molecules hooked onto an adjoining surface with unexpectedly strong chemical bonds.

The higher you heat it, the stronger the bonds are, Ramanath said. When we first started out, I had not imagined the molecules behaving this way.

To make sure it wasnt a fluke, his team recreated the test more than 50 times over the past two years. The results have been consistent, and show heating up the sandwiched nanolayer increases its interface toughness or stickiness by five to seven times. Similar toughness has been demonstrated using micrometer-thick layers, but never before with a nanometer-thick layer. A nanometer is 1,000 times smaller than a micrometer.

Because of their small size, these enhanced nanolayers will likely be useful as adhesives in a wide assortment of micro- and nanoelectronic devices where thicker adhesive layers just wont fit.

Another unprecedented aspect of Ramanaths discovery is that the sandwiched nanolayers continue to strengthen up to temperatures as high as 700 degrees Celsius. The ability of these adhesive nanolayers to withstand and grow stronger with heat could have novel industrial uses, such as holding paint on hot surfaces like the inside of a jet engine or a huge power plant turbine.

Along with nanoscale and high heat situations, Ramanath is confident the new nanoglue will have other unforeseen uses.

This could be a versatile and inexpensive solution to connect any two materials that dont bond well with each other, Ramanath said. Although the concept is not intuitive at first, it is simple, and could be implemented for a wide variety of potential commercial applications.

The molecular glue is inexpensive 100 grams cost about $35 and already commercially available, which makes our method well-suited to todays marketplace. Our method can definitely be scaled up to meet the low-cost demands of a large manufacturer, he said.

Ramanath and his team have filed a disclosure on their findings and are moving forward toward a patent, which will complement the robust portfolio of other intellectual property they hold in this field. The team is also exploring what happens when certain variables of the nanoglue are tweaked, such as making taller nanolayers or sandwiching the layers between substances other than copper and silica.

Along with Ramanath, Rensselaer materials science and engineering graduate students Darshan Gandhi and Amit Singh contributed to the paper. Other co-authors include Rensselaer physics professor Saroj Nayak and graduate student Yu Zhou, IBM researcher Michael Lane at the T.J. Watson Research Center in Yorktown Heights, N.Y., and Ulrike Tisch and Moshe Eizenberg of the Technion-Israel Institute of Technology.

Ramanaths ongoing research is supported by the National Science Foundation, the U.S.-Israel Binational Science Foundation, the Alexander von Humboldt Foundation, and New York state through the Interconnect Focus Center.

LaVerne Hess, the NSF program official most familiar with Ramanaths work, applauded the interdisciplinary nature and strong technical relevance of the nanoglue project.

Its a good example of basic materials science research motivated by an understanding of engineering needs in the electronics field, and involving fundamental chemistry concepts to create new materials capabilities to enable progress in a field important to U.S. competitiveness, Hess said.

UCSF-led team receives $15 million to study genetics of epilepsy

Thu, 03 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) A team led by UCSF scientists has received a grant of $15 million, provided over five years, to study the complex genetic factors that underlie some of the most common forms of epilepsy.

The study, known as the Epilepsy Phenome/Genome Project (EPGP), is funded by the National Institute of Neurological Disorders and Stroke, and brings together more than 50 researchers and clinicians from 15 medical centers around the country.

The project is led by Daniel Lowenstein, MD, professor and vice chairman of the Department of Neurology at the University of California, San Francisco (UCSF), and director of the UCSF Epilepsy Center. Lowenstein and Ruben Kuzniecky, professor and director of research in the Department of Neurology at the New York University Comprehensive Epilepsy Center, are co-principle investigators of the project.

Epilepsy is among the most common neurological disorders in the world, affecting one in every 100-200 people. It is characterized by seizures caused by abnormal electrical activity between nerve cells in the brain.

Although it has been known since antiquity that the disorder is influenced by inherited genes, progress to date has been limited to the discovery of single gene mutations that cause the disease in a relatively few number of families, says Lowenstein. For the more common types of epilepsy, heredity plays a more subtle role, and it is thought that a combination of variations in multiple genes likely determine an individuals susceptibility to the disorder, as well as the responsiveness to anti-epileptic medications.

In their study, the scientists will work to identify the constellation of genes that contribute to the more common types of epilepsy. The long term goal of the project, says Lowenstein, will be to identify potential molecular targets that could be the basis of much more specific and effective treatments for patients who have epilepsy, and the prevention of epilepsy in those at risk.

Because the approach to teasing apart the more complicated genetic factors in epilepsy requires a very large number of patients whose epilepsy has been extremely well-characterized, the investigators will enroll 3,750 patients and 3,000 people who do not have the disorder so-called controls used for comparison -- over the course of the study.

Details about each patients disorder type of seizures, results of electroencephalograms and imaging studies, and effects of treatment -- will be collected and archived in a central data repository at UCSF, and all participants will be asked to submit a sample of blood or saliva as a source of their DNA. (All the clinical information and the DNA samples will be de-identified so that it cannot be traced back to a specific individual.)

Once this first phase of the study is completed, Neil Risch, PhD, and colleagues in the UCSF Institute for Human Genetics, along with researchers at Emory University, will carry out whole genome scans and look for potential connections between patterns of DNA sequences and specific characteristics of epilepsy in the study population.

This is an extremely exciting step in the effort to illuminate the underlying causes of the common forms of epilepsy, says Risch, UCSF Lamond Distinguished Professor in Human Genetics. The endeavor illustrates the type of research now taking place in human genetics thanks to advances in technology and our understanding of the human genome.

Researcher receives $1.8M AIDS-related grant

Wed, 02 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Edward M. Johnson, Ph.D., professor and chairman of microbiology and molecular cell biology at Eastern Virginia Medical School (EVMS), received a grant totaling more than $1.8 million over five years to study the molecular mechanics of a brain disease that kills four percent of AIDS patients worldwide.

Funded by the National Institute of Neurological Disorders and Stroke, Johnson's research focuses on the JC virus, discovered in 1971 and named for the initials of a patient who died of progressive multifocal leukoencephalopathy, or PML. A disease that afflicts patients with a weakened immune system, PML kills by, essentially, causing the brain's neurons to short-circuit. Aggressive and incurable, PML can kill a patient just a few months after the onset of symptoms. The brain-wasting disease can occur even in patients whose AIDS is kept in check by aggressive antiretroviral drugs.

The JC virus, the focus of Johnson's study, causes the brain to lose myelin, the sheath that insulates the passage of nerve signals. Such demyelination is also found in diseases such as multiple sclerosis.

Although researchers have known for years that the JC virus caused the brain-wasting PML, nobody has figured out exactly how. In fact, researchers don't understand how the JC virus, or even the AIDS virus, gets into the brain through a kind of microscopic cheesecloth that filters from the blood anything that can harm the brain. Johnson speculates that the viruses may infect cells that are able to squeeze through the protective blood-brain barrier. This remains an important problem to solve, Johnson said.

Johnson's newest five-year grant will help him unravel the mystery of exactly how the JC virus does its damage. While many have theorized that damaged immune systems of AIDS patients leave them vulnerable to otherwise benign viruses, Johnson, going a step further, believes that proteins produced by the AIDS virus, HIV, may actually supercharge the JC virus. To do this the HIV proteins interact with proteins produced by cells in the brain.

This prompts a molecular cascade that kills brain cells called oligodendrocytes. These cells have long, sticky tendrils that wrap around and insulate wire-like nerve fibers that connect the brain's neurons. Without this insulation, myelin, the brain's neurons misfire and then atrophy, leaving dead tissue scattered through the brain.

Because brain tissues don't divide, Johnson must conduct his study using oligodendrocytes removed from patients suffering from malignant brain cancer. Ironically, the cancerous cells are taken from patients whose cancer kills by causing massive overproduction of the cells that are destroyed in patients with PML.

If Johnson can decipher the molecular mechanics, the research could help doctors find a way to disrupt the sequences of infection in both PML and AIDS and help stop these diseases.

The interaction of HIV with other viruses is definitely a target for therapeutic agents, he said.

Higher calcium and vitamin D intakes positively associated with brain lesions in older men and women

Tue, 01 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Elderly men and women who consumed higher levels of calcium and vitamin D are significantly more likely to have greater volumes of brain lesions, regions of damage that can increase risk of cognitive impairment, dementia, depression and stroke.

Duke University scientist Dr. Martha Payne reported this finding at Experimental Biology 2007, in Washington, DC. Her presentation, on May 1, is part of the scientific program of the American Society for Nutrition.

Dr. Payne and her co-investigators from Duke and the University of North Carolina examined magnetic resonance imaging (MRI) scans from 232 men and women (79 men, 153 women) between the ages of 60 and 86 (average age 71). All the subjects had at least some brain lesions of varying sizes, including the extremely miniscule ones often seen in even healthy older persons, but those who reported consuming more calcium and vitamin D were markedly more likely to have higher total volume of brain lesions as measured across numerous MRI scans.

Age, hypertension, and other medical conditions - all factors related to the presence of brain lesions - were taken into account during statistical analysis (were controlled for) and were found not to account for the strong relationship between total lesion volume and high intake of calcium and vitamin D. Since the calcium/vitamin D research was part of a longitudinal study of late-life depression, almost half the subjects had been diagnosed with depression. However, the presence or absence of depression also did not appear to influence of relationship between calcium, vitamin D, and brain lesions.

In earlier studies, Dr. Paynes team had found that individuals who consumed more high-fat dairy products had more brain lesions than those who did not follow such a diet but that fat intake in general was not a significant factor. If not the fat, the researchers asked, what was it about a high fat dairy diet that accounts for the positive correlation with brain lesions? This new study points the finger to a prominent component of dairy - namely calcium - and the Vitamin D that is found in many dairy products and vitamin D-fortified foods.

In addition to its well-known function in bone health, calcium is important to the functioning of nerve and muscle cells. But when too much calcium is taken up into blood vessel walls, the calcium becomes incorporated into bone-like deposits that can lead to loss of elasticity and narrowing of the blood vessels. Vitamin D helps regulate calcium retention and activity, which may further enhance this arterial calcification. If blood vessels in the brain are affected, damage could lead to brain lesions.

At this point, says Dr. Payne, we do not know if high calcium and vitamin D intake are involved with the causation of brain lesions, but the study provides support to the growing number of researchers who are concerned about the effects of too much calcium, particularly among older adults, given the current emphasis on promoting high intakes of calcium and vitamin D.

Dr. Payne and her colleagues are continuing to investigate the effect and significance of high calcium and vitamin D intakes on brain lesions, including possible causality, in older patients with and without late-life depression. This research was funded by grants from the National Institute of Mental Health. MRI brain scans of a person with lesions are available to reporters, courtesy of Duke Universitys Neuropsychiatric Imaging Research Laboratory.

Estrogen fluctuation affects epileptic seizures

Mon, 30 Apr 2007 04:00:00 PST

( from http://www.rxpgnews.com ) In more than a third of women with epilepsy, seizures fluctuate across the menstrual cycle, due in part to continually fluctuating effects of estrogen on the neural circuitry in the hippocampus, a region of the brain involved in learning and memory - and in epileptic seizures.

Northwestern University scientist Dr. Catherine S. Woolley, a pioneer in understanding the effects of hormones on the structure and function of neural circuitry, says understanding how estrogen contributes to seizure activity could lead to novel and needed therapeutic targets for anti-epileptic drugs.

On April 30, Dr. Woolley told fellow scientists meeting at Experimental Biology 2007 in Washington, DC, that new and unexpected findings in her laboratory suggest where such therapies might intervene. Dr. Woolley had been selected to present this years C. J. Herrick Award Lecture, a distinguished award presented as part of the scientific program of the American Association of Anatomists.

A decade ago, Dr. Woolley discovered that estrogen increases the number of excitatory synapses on neurons in the hippocampus. Excitatory synapses activate neurons, sending and receiving neurotransmitters, explaining how estrogen could enhance learning and memory consolidation. Beyond the fact that estrogen played this role, her findings surprised the scientific community for two more reasons. First, based on natural hormone cycles, the synaptic turnover was very rapid, demonstrating remarkable plasticity of the brain. Second, the estrogen-influenced changes were taking place in the hippocampus, outside what were then considered the traditional hormone-sensitive regions of the brain.

Dr. Woolleys research since has focused on these estrogen fluctuations and how they drive synaptic changes. She now has shown that, in addition to their effect on excitatory synapses that turn on neurons, fluctuating levels of estrogen also have an equally dramatic effect on the inhibitory synapses that silence neurons. Using a combination of electrophysiology to measure synaptic function and nanoscale measurements of synaptic structure, her team has shown that estrogen suppresses the release of inhibitory neurotransmitters, and that this occurs by regulating vesicles at inhibitory synapses (vesicles being the membranes that contain neurotransmitters).

And once again, there was an additional, surprising finding, says Dr. Woolley. Estrogen receptors are typically found in the cell nucleus where they regulate the expression of genes, a relatively slow mechanism to change brain function. Her group found that these receptors also are located on vesicles at inhibitory synapses and that estrogen mobilizes these vesicles toward synapses. The synaptic location of estrogen receptors shows that the effects of this hormone in the brain can be targeted to individual synapses, fine-tuning how neurons communicate, and on a much more rapid time scale then previously appreciated. The estrogen regulation of neurotransmitter vesicles points to novel targets for anti-epilepsy therapies.