RxPG News : Taste

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."

Insects evolved radically different strategy to smell

Sun, 13 Apr 2008 04:00:00 PST

( from http://www.rxpgnews.com ) Darwin's tree of life represents the path and estimates the time evolution took to get to the current diversity of life. Now, new findings suggest that this tree, an icon of evolution, may need to be redrawn. In research to be published in the April 13 advance online issue of Nature, researchers at Rockefeller University and the University of Tokyo have joined forces to reveal that insects have adopted a strategy to detect odors that is radically different from those of other organisms -- an unexpected and controversial finding that may dissolve a dominant ideology in the field.

Since 1991, researchers assumed that all vertebrates and invertebrates smell odors by using a complicated biological apparatus much like a Rube Goldberg device. For instance, someone pushing a doorbell would set off a series of elaborate, somewhat wacky, steps that culminate in the rather simple task of opening the door.

In the case of an insect's ability to smell, researchers believed that when molecules wafting in the air travel up the insect's nose, they latch onto a large protein (called a G-protein coupled odorant receptor) on the surface of the cell and set off a chain of similarly elaborate steps to open a molecular gate nearby, signaling the brain that an odor is present.

It's that way in the nematode, it's that way in mammals, it's that way in every known vertebrate, says study co-author Leslie Vosshall, head of the Laboratory of Neurogenetics and Behavior at Rockefeller University. So it's actually unreasonable to think that insects use a different strategy to detect odors. But here, we show that insects have gotten rid of all this stuff in the middle and activate the 'gate' directly.

The gate, a doughnut-shaped protein called an ion channel, provides a safe pathway for ions to flow into a cell. When molecules bind to the odor-sensitive ion channel, the protein changes its shape much like a gate or door changes its conformation as it is opened and closed. Opened, it allows millions of ions to surge into the cell. Closed, it prohibits the activity of the ions from sending a signal to the brain that an odor is present.

At the University of Tokyo, Vosshall's colleague Kazushige Touhara and his lab members puffed molecules onto cells engineered to make insect olfactory receptors. They then measured how long it took for the ion channel to open and recorded their electrical movement as they surged inside the cell via the channel. The rush of electrical activity occurred too fast for a series of steps to be involved, says Vosshall. In addition, poisoning several proteins involved in the G-protein pathway didn't affect the ions or the ion channel, suggesting that G-protein signaling isn't primarily involved in insect smell.

Experiment after experiment, the most consistent interpretation is that these are ion channels directly gated by odors, says Vosshall. But the dominant thinking in the field may have reflected an experimental bias that aimed at proving a more elaborate scheme.

The ion channels don't resemble any known ion channel on Earth, says Vosshall. They are composed of two proteins that work in tandem with one another: an olfactory receptor and its coreceptor, Or83b. While the coreceptor is common to every ion channel, the olfactory receptor is unique. Together, they form the olfactory receptor complex. Vosshall and Touhara specifically show that this complex forms nonselective cation channels, meaning that they allow any ion to pass through the gate as long as it has a positive charge.

Touhara and Vosshall developed their ion channel hypothesis in parallel with Vosshall's work on DEET, a widely used chemical in bug spray that jams the receptor complex. This research, which was published in Science last month, also showed that DEET jams other proteins that have nothing to do with smell, including several different types of ion channels that play important roles in the human nervous system. What these radically different proteins have in common, though, is that they all specifically inhibit the influx of positively charged ions into the cell. Now the curious result in the DEET paper showing that this insect repellent blocks insect olfactory receptors and unrelated ion channels makes sense, says Vosshall. I am optimistic that we can come up with blockers specific for this very strange family of insect olfactory ion channels.

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.

Smell experience during critical period alters brain

Wed, 05 Dec 2007 05:00:00 PST

( from http://www.rxpgnews.com ) Unlike the circuitry of the visual system, that of the olfactory system was thought to be hardwired: Once the neurons had formed, no amount of sensory input could change their arrangement. Now researchers at Rockefeller University and their collaborators have upturned this scientific dogma by showing that there is a sensitive period during which the external environment can alter a circuit in the fly brain that detects carbon dioxide, a gas that alerts flies to food and mates. This research, to be published in the December 6 issue of Neuron, may suggest that this brain plasticity isn't limited to the carbon dioxide detection circuit. Rather, it may be a general feature of the olfactory system itself.

The circuit has a genetic plan, but that genetic plan can adjust to real world conditions, says Leslie Vosshall, head of the Laboratory of Neurogenetics and Behavior. This paper is the first compelling case that the olfactory system is plastic.

Using several imaging techniques, Vosshall and her colleagues traced the carbon dioxide circuit, a well-described pathway that consists of three different types of neurons, the axons and dendrites of which form an entangled ball called a glomerulus. The researchers exposed flies to elevated levels of carbon dioxide to see whether it would alter the shape of this circuit or how it functioned. The glomerulus's volume was already increased after two days of exposure (from birth) and kept on increasing for five days, at which point it stopped. The increase in this specific glomerulus could only be induced by elevated levels of carbon dioxide and was also reversible.

After those initial few days, however, the researchers saw a different story unfold. If they didn't expose the flies to carbon dioxide within the first five days, genetics locked in the glomerulus's size such that no matter how long the flies were exposed to the gas, the glomerulus's volume didn't increase. These findings suggest that the fly's external environment can rewire the carbon dioxide detection circuit only during a five-day window of development.

During this critical period, the olfactory system is flexible enough to calibrate its genetic map to its local environment, says first author Silke Sachse, a former postdoc in the Vosshall lab who is now a group leader in optical imaging at the Max Planck Institute for Chemical Ecology in Jena, Germany. But once that window closes, the circuit is no longer plastic.

To figure out the mechanism by which the glomerulus increases its volume, the Vosshall group imaged the three types of neurons that make up the glomerulus -- olfactory sensory neurons, projection neurons and interneurons -- to see whether their structure or function had changed. The olfactory sensory neurons, which report sensory information to glomeruli, did not show any sign of structural or functional changes. However, the projection neurons, which send information from the glomeruli to the brain, and the interneurons, which communicate with the two types of neurons as well as the glomeruli, showed significant functional changes. Usually the sensory neurons collect information and send it to the brain and it is the job of the brain to interpret what the information means, says Vosshall. For plasticity to be useful, it probably makes sense to delegate that job to the brain rather than to the external sensory neurons.

Pheromones identified that trigger aggression between male mice

Wed, 05 Dec 2007 05:00:00 PST

( from http://www.rxpgnews.com ) A family of proteins commonly found in mouse urine is able to trigger fighting between male mice, a study in the Dec. 6, 2007, issue of Nature has found. The study, which is the first to identify protein pheromones responsible for the aggression response in mice, was funded in part by the National Institute on Deafness and Other Communication Disorders (NIDCD), one of the National Institutes of Health. Pheromones are chemical cues that are released into the air, secreted from glands, or excreted in urine and picked up by animals of the same species, initiating various social and reproductive behaviors.

Although the pheromones identified in this research are not produced by humans, the regions of the brain that are tied to behavior are the same for mice and people. Consequently, this research may one day contribute to our understanding of the neural pathways that play a role in human behavior, says James F. Battey, Jr., M.D., Ph.D., director of the NIDCD. Much is known about how pheromones work in the insect world, but we know very little about how these chemicals can influence behavior in mammals and other vertebrates.

Researchers at Scripps Research Institute, La Jolla, Calif., and Harvard University chose to study aggression for this study because it is a strongly exhibited social behavior in male mice. Because mouse urine had already been linked to aggressive behavior in males, the team narrowed the field of pheromone candidates by separating out progressively smaller compounds in the urine and studying their effects on both mouse behavior and their ability to activate sensory receptor neurons in the vomeronasal organ. The vomeronasal organ is one of two locations in the mouse's nasal cavity that houses sensory receptor cells that detect pheromones. The other location is the main olfactory epithelium, the part of the nasal cavity that also detects smells. Earlier research conducted by the group had determined that receptor neurons from the vomeronasal organ are required for the aggression response to occur.

To study behavior, the researchers swabbed the backs of neutered male mice with the various pheromone candidates and placed them in a cage with a normal male mouse. Neutered males are useful for the study of aggression because they can neither emit nor detect the aggression pheromones. Whereas normal males will begin fighting as soon as they are placed together in a cage, neutered males remain docile around normal males, and vice versa. If a neutered male whose back has been swabbed with a pheromone candidate elicits hostility in a normal male, the researchers know that the pheromone candidate is responsible for the behavior.

Using a technique called calcium imaging, the team also studied whether pheromone candidates were able to directly activate sensory receptor neurons. Receptor neurons were removed from a mouse vomeronasal organ, spread out on a Petri dish, and labeled with a substance that changed color when the neuron was activated.

The researchers discovered that the protein family that comprises the major urinary protein (MUP) complex in mouse urine is one of two pheromones that can elicit the aggression response in male mice. They also found that the MUP protein is recognized exclusively in the vomeronasal organ, not in the main olfactory epithelium, and activates a specific type of sensory receptor neuron. A second pheromone was also found to elicit an aggression response in male mice, however further study needs to be done regarding its make-up and activity.

There are about 20 members of the MUP family, and each mouse expresses four to six of the members randomly, explains senior investigator Lisa Stowers, Ph.D. This creates a bar code of individuality for each mouse. And we don't know whether the proteins are actually coding for aggression per se, or whether they're serving as a general cue of individuality for a male.

Sweet smell

Tue, 18 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) What makes one smell pleasant and another odious? Is there something in the chemistry of a substance that can serve to predict how we will perceive its smell? Scientists at the Weizmann Institute of Science and the University of California at Berkeley have now discovered that there is, indeed, such a link, and knowing the molecular structure of a substance can help predict whether we will find its smell heavenly or malodorous.

In sight and hearing, for instance, our perceptions are determined by the physical properties of waves � the length of light waves in sight, and the frequency of sound waves in hearing. But until now, there was no known physical factor that could explain how our brains sense odors. The new study, conducted by Prof. Noam Sobel of the Institute�s Neurobiology Department and his colleagues, represents a first step in understanding the physical laws that underlie our perception of smell. Their results appeared last week in the Journal of Neuroscience.

To identify the general principles by which our sense of smell is organized, the researchers began with a database of 160 different odors that had been ranked by 150 perfume and smell experts according to a set of 146 characteristics (sweetish, smoky, musty, etc.). These data were then analyzed with a statistical program that analyzed the variance in perception among the smell experts. The scientists found that the data fell along an axis that describes the 'pleasantness rating' of the odors � running from 'sweet' and 'flowery' at one end to 'rancid' and 'sickening' at the other. The same distribution along this axis, they discovered to their surprise, closely describes the variation in chemical and physical properties from one substance to another. From this, the researchers found they could build a model to predict, from the molecular structure of a substance, how pleasing its smell would be perceived.

To double check their model, Sobel and his team tested how experimental subjects assessed 50 odors they had never smelled before for pleasantness. They found that the ratings of their test subjects fit closely with the ranking shown by their model. In other words, they were able to predict the level of pleasantness quite well, even for unfamiliar smells. They noted that, although preferences for smells are commonly supposed to be culturally learned, their study showed that the responses of American subjects, Jewish Israelis and Muslim-Arab Israelis all fit the model�s predictions to the same extent. Sobel: 'Our findings show that the way we perceive smells is at least partially hard-wired in the brain. Although there is a certain amount of flexibility, and our life experience certainly influences our perception of smell, a large part of our sense of whether an odor is pleasant or unpleasant is due to a real order in the physical world. Thus, we can now use chemistry to predict the perception of the smells of new substances.'

Genetic variant linked to odor perception

Sun, 16 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) DURHAM, N.C. � Why the same sweaty man smells pleasant to one person and repellant to another comes down to the smeller�s genes.

Duke University Medical Center researchers demonstrated that genetic variants of odor receptors within the nose determine how a particular odor is perceived. The researchers, led by Duke�s Hiroaki Matsunami, Ph.D., assistant professor of molecular genetics and microbiology, published the results of their experiments early online Sept. 16 in the journal Nature.

The researchers focused on two chemicals � androstenone and androstadienone � that are created naturally by the body during the breakdown of the male sex hormone testosterone and are excreted in sweat and urine.

�We found that genetic variations of a specific odor receptor determine, to a significant degree, why the same chemicals smell pleasant or unpleasant to different people,� Matsunami said. �These results demonstrate the first link between the functioning of a human odor receptor gene and how that odor is perceived.�

Humans have about 400 odor receptors within the nose that detect various odors or chemicals. Smells typically bind to their corresponding receptors, and the information is then relayed to the brain for processing.

The researchers wanted to uncover the reasons why people react differently when they smell these two sex steroid-derived chemicals. Hanyi Zhuang, a student in the Matsunami laboratory, tested all the known smell receptors in the laboratory and found one that reacted strongly with the two chemicals.

In conjunction with their collaborators at Rockefeller University, the researchers asked 391 volunteers to inhale the two chemicals and describe what they smelled. The results ranged from no smell at all, to descriptions such as �vanilla and sweet� and �sickening and urine.� DNA extracted from blood samples from each volunteer were sent to Matsunami�s laboratory.

�After performing genetic analysis on each of the samples and correlating the results with the smell descriptions, we were able to link specific genetic variants with specific perceptions,� Matsunami said. �While many theories of the different perceptions of smell focus on culture, experience or memory, our results show that an important portion of this variability is due to an individual�s genes.�

Matsunami added that these results will likely add to the debate over the existence of pheromones in humans. Pheromones are chemical signals between animals that express alarm, mating and navigation cues. In other species, they've been found to trigger behavioral changes in the smeller.

�The sex-steroid odors that we tested in humans act as pheromones in pigs, and there has been debate whether these same chemicals act similarly in humans,� Matsunami said. �There is evidence that smelling these odors can affect the mood and physiological state of both men and women.�

Matsunami and his colleagues plan further studies to understand how smelling these chemicals might affect human social and sexual behavior.

He added that there are likely other receptors and receptor variants that may also play roles in how these two chemicals are perceived. Since it is known that there are about 400 specific smell receptors and humans can detect more than 10,000 different odors, it follows that different combinations of receptor genes and variants must be involved in perceiving each odor, he said.

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.�

Flies prefer fizzy drinks

Wed, 29 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) While you may not catch a fly sipping Perrier, the insect has specialized taste cells for carbonated water that probably encourage it to binge on food with growing microorganisms. Yeast and bacteria both produce carbon dioxide (CO2) when they feast, and CO2 dissolves readily in water to produce seltzer or soda water.

This is one of the first, if not the only taste sensation discovered in animals beyond the five that humans taste - sweet, sour, bitter, salty and umami, or savory.

This was unexpected, because fruit flies also smell CO2 and they avoid it, said neurobiologist Kristin Scott, assistant professor of molecular and cell biology at UC Berkeley. One way that we like to think of it is that flies seek the right amount of rottenness - if fruit is only half rotten, producing a little CO2, it's good; if too rotten, it gives off a lot of CO2 and is bad tasting. They seek a balance.

Scott and her UC Berkeley colleagues, graduate students Walter Fischler, technician Priscilla Kong and postdoctoral fellow Sunanda Marella - all in the Department of Molecular and Cell Biology and the Helen Wills Neuroscience Institute - report their discovery in the Aug. 30 issue of Nature.

Mammals have five known types of taste receptors, though there may be more to discover, Scott said. Flies may have five distinct receptors also, but not the same ones mammals have. While Scott has shown that fruit flies can detect sweet and bitter compounds, and now carbonation, she has discounted their ability to taste umami and said that their ability to taste sour compounds is questionable. She and her lab continue to investigate other unknown taste modalities in fruit flies, which could be any of a number of tastes, such as salt or alcohol.

The discovery came when Fischler, frustrated that he could not find a chemical that stimulated an unknown type of fruit fly taste cell he had isolated, tested the cells' reaction to a drop of Samuel Adams beer. Surprised by a positive response, he tried to narrow down the taste preference to one of the many chemicals in beer. Flat beer and dry yeast, for example, did not work. That's when he discovered the leftover bottle of Calistoga mineral water.

As he was searching for beer components to test, he said, I opened the refrigerator and looked in, when a light bulb went on. Calistoga would be a great way of testing CO2.

The rest is history. Dry ice - frozen CO2 - produced a strong response, while high levels of gaseous CO2 produced a weak response in the taste cells. Sodium bicarbonate in a basic solution that does not contain CO2 bubbles did not work; bicarbonate in a solution with CO2 bubbles did. The liquid in which yeast grow, though not the yeast themselves, also elicited a response from the taste cell. These and a few other genetic tests narrowed the taste trigger down to dissolved carbon dioxide.

The preference for carbonation is weak compared with that for sweetness, Scott noted, implying that seltzer enhances taste or makes other tastes more acceptable. This makes sense because CO2 has no nutritional value, but is a byproduct of organisms - yeast and bacteria - that do provide nutrients, she said.

The newly discovered taste sensors for carbonation reside on their own structures, called taste pegs, on the tongue of the fly. While a fruit fly's four other taste cells are perched on the tip of bristles that cover the entire body, the carbonated water taste cells are clustered around the margins of the sponge-like tip of the proboscis, at the base of taste bristles.

Scott investigates taste cells, which are a type of nerve cell, and is characterizing the cells and genes associated with different tastes. So far, she and her laboratory colleagues have identified the sweet and bitter cells and some of the gustatory receptor genes that detect sweet and bitter compounds in fruit flies.

Fischler now is trying to isolate the actual receptor in the CO2-sensing nerve cell that grabs the CO2 molecule and sends a signal to the fly brain that there is carbonation in the food. It will then be possible to see if others, including humans, also have carbonation receptors on taste cells.

There may be many more taste modalities in humans than the five known today, said Scott. Even if CO2 is a taste unique to fruit flies, it's discovery suggests that other animals may have taste receptors tuned to important chemicals in their environment, she said, either to avoid them, as is the case with bitter chemicals, or seek them out, as is the case with sugars and CO2.

Thus, taste modalities may differ according to nutritional needs, she and her colleagues wrote. Alternatively, CO2 may be an unappreciated taste modality in many organisms.

Mice use specialized neurons to detect carbon dioxide in the air

Thu, 16 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) For mice, carbon dioxide often means danger - too many animals breathing in too small a space or a hungry predator exhaling nearby. Mice have a way of detecting carbon dioxide, and new research from Rockefeller University shows that a special set of olfactory neurons is involved, a finding that may have implications for how predicted increases in atmospheric carbon dioxide may affect animal behavior. The finding is reported in the August 17 issue of the journalScience.

Most olfactory sensory neurons express odorant receptor molecules and reside within the lining of the nasal cavity that detect odors. But a small subset express an enzyme called guanylyl cyclase-D (GC-D). Peter Mombaerts, professor and head of the Laboratory of Developmental Biology and Neurogenetics at Rockefeller, and Andreas Walz, a research associate in Mombaerts' lab, created a strain of mice in which GC-D expressing neurons glow with a green fluorescent protein. These GC-D expressing neurons also project their nerve endings to an unusual structure in the back of the olfactory bulb called necklace glomeruli, which resemble a string of beads.

The Rockefeller team's collaborators in China, led by Minmin Luo at the National Institute of Biological Sciences in Beijing, found that all the GC-D expressing neurons in the olfactory epithelium were activated by exposure to carbon dioxide. Conversely, all the cells in the lining of the nasal cavity that were activated by carbon dioxide are the GC-expressing neurons.

These findings show that a specialized subsystem has evolved in the mouse to detect carbon dioxide, says Mombaerts.

Carbon dioxide makes up about four-hundredths of one percent of the atmosphere. To determine the threshold for carbon dioxide detection in the mouse, the Beijing team trained mice to lick water when they received a whiff of air with higher levels of carbon dioxide. As the amount of carbon dioxide in the whiffs of air was decreased, the accuracy of the animals' response became random. Statistical analysis fixed the threshold for detection at about six-hundredths of a percent, just above the average atmospheric level.

Mombaerts cautions that scientists still do not know if the GC-D enzyme is responsible for detecting carbon dioxide. GC-D is a marker for the neurons that have specific carbon dioxide sensitivity, Mombaerts says. At this time, we have not shown that the marker is mechanistically involved in sensory perception of carbon dioxide. The research does, however, suggest that scientists need to be on the lookout for behavioral changes in animals as carbon dioxide levels increase in the atmosphere, since, at some point increased levels may be detectable by animals, Mombaerts says.

Animals may adapt to this gradual and persistent increase. Alternatively, the change may induce behavioral changes, such as an increase in irritability and aggression or a decrease in fertility, he says.

Sour taste make you pucker? It may be in your genes

Wed, 11 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Philadelphia (June 11, 2007) -- Scientists at the Monell Chemical Senses Center report that genes play a large role in determining individual differences in sour taste perception. The findings may help researchers identify the still-elusive taste receptor that detects sourness in foods and beverages, just as recent gene studies helped uncover receptors for sweet and bitter taste.

Scientists have long known that sour taste is stimulated by acids in foods and beverages. In fact, the word acid is derived from the Latin acidus, meaning sour. However, we still do not completely understand how the taste system is able to detect and translate acidic molecules on the tongue into a neural signal that the brain perceives as sour.

Demonstrating a genetic component to individual differences in sour taste is the first step in pinpointing the genes that determine sensitivity. The products of those genes, in turn, are likely to be involved in sour taste perception, says study lead author Paul M. Wise, PhD, a Monell sensory psychologist.

In the study, published online in advance of print in the journal Chemical Senses, researchers tested 74 pairs of monozygotic (MZ, identical) twins and 35 pairs of dizygotic (DZ, fraternal) twins to determine the lowest concentration needed for each twin to correctly identify a citric acid solution as sour.

Because MZ twins have nearly identical genes while DZ twins share only about 50% of their genes, more similar responses in MZ than DZ pairs suggests that genes help determine sensitivity to the taste in question.

Responses were compared within the twin pairs, and then entered into a computer model to determine the relative contributions of genetic and environmental influences on sour taste sensitivity.

The models estimated that genes played a more important role than environment in determining individual differences in sour taste sensitivity, accounting for 53 percent of the variation.

The finding that genes influence sour taste perception suggest that genetic analyses could potentially help identify sour receptors. Future studies will evaluate possible receptors by determining whether individual differences in genes for these structures such as the recently-discovered PKD ion channel are correlated with individual differences in sensitivity to sourness. For any given candidate receptor, a strong association of genetic with perceptual variation would support the likelihood that the receptor detects sour taste.

The findings, in conjunction with previous work on sweet, bitter, and umami (savory) taste, suggest that people differ in how they perceive the taste of foods, and that these differences are determined in part by their taste genes. So someone who inherited a high sensitivity to sour taste may find foods containing lemons or vinegar off-putting, whereas the same foods may be better accepted by a person whose genes make them less sensitive.

Wise comments, These taste perceptions presumably evolved because they have a significant impact on food choice and therefore nutrition. If we can understand how and why people differ in their taste perception, we might eventually be able to manipulate the taste of individual diets to help encourage healthy eating.

Difficulty identifying odors may predict cognitive decline

Mon, 02 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Older adults who have difficulty identifying common odors may have a greater risk of developing problems with thinking, learning and memory, according to a report in the July issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

Mild cognitive impairmentor a decline in thinking, learning and memory abilitiesis increasingly recognized as a precursor to Alzheimers disease, according to background information in the article. Impairments in the ability to recognize odors have been associated with more rapid cognitive decline and also with the development transition from mild cognitive impairment to Alzheimers disease. However, little is known about factors that predict the development of mild cognitive impairment.

Robert S. Wilson, Ph.D., of Rush University Medical Center, Chicago, and colleagues studied 589 older adults (average age 79.9) who did not have cognitive impairment in 1997. At that time, the participants took a smell identification test, during which time 12 familiar odors were placed under their nose. They were asked to match each odor to one of four possible alternatives, and were scored from one to 12 based on the number of correct responses. At the beginning of the study and again every year for up to five years, the participants underwent a clinical evaluation that included a medical history, neurological examination and testing of their cognitive function.

During the study, 177 individuals (30.1 percent) developed mild cognitive impairment. Risk of developing mild cognitive impairment increased as odor identification decreased, so that those who scored below average (eight) on the odor identification test were 50 percent more likely to develop the condition than those who scored above average (11). This association did not change when stroke, smoking habits or other factors that might influence smell or cognitive ability were considered. Impaired odor identification was also associated with lower cognitive scores at the beginning of the study and with a more rapid decline in episodic memory (memory of past experiences), semantic memory (memory of words and symbols) and perceptual speed.

The neurobiological bases of age-associated olfactory dysfunction are uncertain, the authors write. Evidence suggests that even before the symptoms of Alzheimers disease develop, hallmark tangles develop in certain areas of the brain that may be associated with the processing of smells. Because difficulty identifying odors is associated with other neurological diseases, including Parkinsons disease, other mechanisms are likely involved. Further clinicopathological and clinicoradiological research on age-related olfactory dysfunction is needed, they continue.

Among older persons without manifest cognitive impairment, difficulty in identifying odors predicts subsequent development of mild cognitive impairment, the authors conclude. The findings suggest that olfactory dysfunction can be an early manifestation of Alzheimers disease and that olfactory assessment may be useful for early disease identification.

Smelling for first time results from knowing abnormalities in congenital loss of smell

Mon, 30 Apr 2007 04:00:00 PST

( from http://www.rxpgnews.com ) New discoveries about the biochemical basis of the majority of cases of the congenital inability to smell any odor, no matter how strong, have enabled their discoverer, Dr. Robert I. Henkin, director of The Taste and Smell Clinic in Washington, DC, to treat such patients, enabling them to smell something for the first time in their lives.

These patients respond with amazement, Dr. Henkin told fellow scientists gathered at Experimental Biology 2007 meeting in Washington. Until the treatment began to take effect, they had never experienced the olfactory world that surrounds us all, and it is with excitement that they quickly begin to learn what different things smell like and to relate those odors to objects they have known all their lives, says Dr. Henkin.

Dr. Henkins Experimental Biology presentation, on April 30, is part of the scientific program of The American Physiological Society. His study is the first to characterize the biochemical abnormalities in these patients and the first to successfully treat patients using this new understanding.

In the United States alone, there are about 400,000 people who have never smelled anything in their lives. (This does not include those who lose their once normal smell function because of illness or accident.) A relatively small percentage - 12 percent - of individuals with congenital smell loss have multiple anatomical abnormalities of the brain and other organs. The vast majority - 88 percent - of individuals with congenital smell loss, however, do not have any such obvious organ abnormalities and their olfactory nerves and the brain regions that process olfactory information are intact.

Why, then, have they never been able to smell?

In order to answer that question, Dr. Henkin examined these seemingly normal patients nasal mucus, the fluid that bathes the olfactory nerve receptors. From earlier studies in his laboratory, Dr. Henkin knew that the nasal mucus contains growth factors responsible for olfactory stem cell maturation and function. Without these growth factors, olfactory receptor cells can not maintain normal cell function. As he suspected, the nasal mucus from these patients was deficient in these important growth factors.

The studies also found a double whammy in these patients nasal mucus. Normal mucus contains not only growth factors to allow new olfactory receptor cells to function, it also contains death factors that kill the aging receptor cells (a normal process of programmed cell death, or apoptosis), making way for the new. The congenital smell loss patients had five to 10 times the concentration of these death factors as do people who can smell. That guaranteed that the high concentration of death factor would destroy any receptor cell growth that was able to take place.

After determining the family of enzymes to which the growth and death factors belong and defining the biochemical pathway responsible for these factors, Dr. Henkin was able to treat these patients with PDE inhibitors that increase the concentration of growth factors and inhibit the secretion o death factors in nasal mucus. The treatment has been successful in restoring smell function in some of these patients, with the higher the dose and longer the use having the greatest effect.

NIDCD director to be named first recipient of Distinguished Service Award

Tue, 24 Apr 2007 04:00:00 PST

( from http://www.rxpgnews.com ) James F. Battey Jr., M.D., Ph.D., director of the National Institute on Deafness and Other Communication Disorders (NIDCD), one of the National Institutes of Health, will be the first recipient of the Distinguished Service Award from the Association for Chemoreception Sciences (AChemS), an international body of scientists that advances understanding of the senses of taste and smell. Researchers are working to learn more about taste and smell because these senses can have a major impact on a person's quality of life, food preferences, diet, and overall health. The newly created award, to be conferred on special occasions, recognizes individuals with a record of outstanding service to the chemical senses research community.

As director of the NIDCD, Dr. Battey has moved far beyond the role of administrator by his genuine interest in the chemical senses, said Dr. Diego Restrepo, president-elect of AChemS, citing Dr.Battey's participation at international meetings, his leadership in trans-NIH scientific efforts such as NIH's Knockout Mouse Project, the stem cell research program, and his support of promising young investigators. Dr. Battey is the perfect example of the outstanding scientific administrator -- an astute scientist/administrator intimately engaged in the affairs of science, Dr. Restrepo said.

One of the most distinguished honors that a scientist can receive is the recognition of his or her peers, said Elias A. Zerhouni, director of the NIH. James Battey's ability to make significant contributions to the study of the chemical senses while effectively serving as director of the NIDCD demonstrates a rare combination of leadership and scientific expertise that have served the NIH well. In addition, during the time that he was chair of the NIH Stem Cell Task Force, Dr. Battey demonstrated extraordinary insight in advancing our knowledge about this exciting and challenging area of research.

Dr. Battey received his B.S. degree in physics from the California Institute of Technology, and his M.D. and Ph.D. in biophysics from Stanford University School of Medicine. After receiving training in pediatrics, he pursued a postdoctoral fellowship in genetics at Harvard Medical School. Dr. Battey is widely recognized for his work on G-protein coupled receptors (GPCRs), a large family of proteins important in cell-to-cell communication, and integral to an array of physiological processes, including taste and smell. His laboratory is collaborating on a large-scale project to identify molecules that are important for taste. He has held a vareity of positions at the NIH, including serving in the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, and NIDCD, before being named director of the NIDCD in 1998.

Dr. Battey will receive the award during the opening ceremony at the AChemS annual meeting in Sarasota, Fla., on Wednesday, April 25 at 8:00 p.m. Scientists from around the world will be in attendance and will be presenting their latest research findings throughout the meeting.

How learning influences smell

Wed, 20 Dec 2006 05:00:00 PST

( from http://www.rxpgnews.com ) The smell of an odor is not merely a result of chemical detection but is also influenced by what the smeller learns about the odor. Now, researchers have discovered how such perceptual learning about an odor influences processing of information from the purely olfactory chemical detection system. Wen Li, Jay Gottfried, and colleagues at Northwestern University reported their findings with human subjects in the December 21, 2006, issue of the journal Neuron, published by Cell Press.

Verbal context strongly influences the perception of odor qualitya rose by any other name would not smell as sweet, explained the researchers. For example, the same odorant smells entirely different depending on whether it is labeled as fresh cucumber or mildew.

Learning also changes odor quality. A cherry odor becomes smokier in quality after being experienced together with a smoky odor. Thus, a given set of olfactory receptors activated by an odorant may not map directly onto a given odor percept. Rather, odor perception may rely on more synthetic, or integrative, mechanisms subserved by higher-order brain regions, they wrote.

In a previous study, also published in Neuron, Gottfried and colleagues had identified regions of the cortex involved in coding odors. In the new study, they sought to explore whether perceptual learning about an odor lead to changes in subjects ability to differentiate the odors.

In their experiments, the researchers first exposed volunteers to a set of odors and tested their ability to differentiate the odors. They next habituated the subjects to one of the odorants by exposing them to the odor for several minutes. Finally, they retested the subjects ability to distinguish the odors. The odors the subjects were asked to distinguish included those that had the same odor quality, for example floral, as well as those that shared characteristic molecular groups, for example being an alcohol.

As the subjects were undergoing the odor differentiation trials, their brains were scanned using functional magnetic resonance imaging (fMRI). This widely used technique for measuring brain activity involves using harmless radio waves and magnetic fields to measure blood flow in brain regions, which reflects brain activity.

Gottfried and his colleagues found the subjects better able to differentiate odors after the period of habituation to a similar odor. Whats more, the fMRI scans revealed increases in response in the odor-processing areas of their brains that reflected learning.

The researchers concluded that prolonged exposure to one odorant resulted in improved differentiation among related odorants (and even among novel related odorants). Thus, with exposure to a floral-smelling alcohol (i.e., phenethyl alcohol), subjects effectively became floral experts and simultaneously became experts for the underlying molecular group, they wrote. The subjects appeared to be developing more refined, or differentiated, subcategories of these olfactory features, wrote the researchers.

The current findings, along with recent data from our laboratory, provide further evidence that odor quality coding in olfactory cortex is not a straightforward outcome of odorant structure, they concluded. In all likelihood, neural representations of odor quality are a dynamic product of lower-level coding from olfactory bulb and higher-level cortical inputs, under the regulation of learning and experience, attention, sensory context, and language.

We speculate that the process of odor feature differentiation, via sensory exposure, may underlie much of the way that humans naturally learn to identify odors in the environment, with progressive and ever more refined differentiation, to the point where we are able to recognize thousands, if not hundreds of thousands, of different smells, they wrote.

This mechanism may underlie the acquisition of fine-grained percepts that distinguish, for example, the smell of Rosa damascena (Bulgarian Rose) from that of Rosa centifolia (Rose Maroc), to the point where we would be able to appreciate the immense richness of aromas in everyday life, they wrote.

Sniffers show that humans can track scents, and that two nostrils are better than one

Mon, 18 Dec 2006 05:00:00 PST

( from http://www.rxpgnews.com ) Berkeley -- University of California, Berkeley, graduate student Allen Liu last Friday donned coveralls, a blindfold, earplugs and gloves, then got down on all fours and sniffed out a 33-foot chocolate trail through the grass.

This was no fraternity initiation, but part of an experiment to find out whether mammals compare information coming from their two nostrils in order to aid scent-tracking performance, much like they compare information from their ears in order to locate a sound.

In a paper appearing this week in the advance online edition of Nature Neuroscience, UC Berkeley researchers report conclusive evidence from these experiments that humans do indeed gain a performance advantage from cross-nostril comparisons. They also found that humans can scent-track, and that, with training, they can improve their accuracy significantly while nearly doubling their speed along the scent trail.

In one experiment, the authors found that while volunteers with one nostril blocked could still track a scent - in this experiment, essence of chocolate - volunteers with two open nostrils tracked a scent quicker and with fewer deviations from the trail. We were asking the question, 'Are two nostrils better than one' said lead author Jess Porter, a graduate student in biophysics at UC Berkeley. The answer is yes.

Apparently, according to Porter and her colleagues, the mammalian brain compares smells between nostrils to tell where an odor is coming from in the same way that the brain compares the sounds entering a person's two ears to locate a source. Until now, many researchers thought this was unlikely because a mammal's nostrils, in a mouse, for example, are too close together to receive distinctly different smells.

The human brain compares information from two 'noses' to turn smell information into spatial information, said Noam Sobel, associate professor of neuroscience and psychology and member of the program in biophysics at UC Berkeley.

Sobel hopes to use information from these experiments to design scent-tracking robots equipped with his eNose, an electronic nose that one day could detect odors such as that from an explosive mine.

To test Sobel and Porter's smell hypothesis, the UC Berkeley researchers soaked a 33-foot (10-meter) string in chocolate essence and laid it in the grass outside Barker Hall, located at the northwest corner of the UC Berkeley campus. They then garbed volunteers to block their senses of sight, hearing and touch, eliminating all clues other than smell to guide them along the trail. Sniffing like bloodhounds, two-thirds of 32 subjects were able to follow the chocolate scent to the end of the trail within three attempts. All volunteers zigzagged along the trail in the same way that tracking dogs follow a scent.

The researchers then trained four of these volunteers to see if they could improve. All were able to double their speed along the track within just a few days and deviated much less from the scent trail than on their first attempts. The researchers measured subjects' sniffs and noticed that the faster the subjects moved along the trail, the more rapid their sniffing - just as with dogs, though not as fast as the six sniffs per second rate exhibited by dogs.

The big question, however, was whether two nostrils allow scent localization in the same way that a human's two ears and eyes help locate sounds and sights.

To further test this, the researchers devised an ingenious nasal prism that mixed scents from the outside world and then presented this to both nostrils, so that there was no difference between what the nostrils smelled. The four subjects were half as accurate at tracking smells under these conditions.

Independent measurements showed that a human's two nostrils sample odors from distinct areas separated by approximately 1.5 inches (3.5 centimeters), more than enough distance to distinguish the edge of a scent plume.

All of these experiments put the lie to a common assumption that humans are lousy smellers compared to all other mammals. While it's true that humans are predominantly visual creatures, Sobel said, their olfactory sense can be compared to that of dogs and other mammals.

Our sense of smell is less keen partly because we put less demand on it, Porter said. But if people practice sniffing smells, they can get really good at it.

Carnegie Mellon study reveals that odor discrimination is linked to the timing at which neurons fire

Tue, 07 Nov 2006 05:00:00 PST

( from http://www.rxpgnews.com ) PITTSBURGH -- Timing is everything. For a mouse trying to discriminate between the scent of a tasty treat and the scent of the neighborhood cat, timing could mean life or death. In a striking discovery, Carnegie Mellon University scientists have linked the timing of inhibitory neuron activity to the generation of odor-specific patterns in the brain's olfactory bulb, the area of the brain responsible for distinguishing odors.

Their work, appearing in the Nov. 8 issue of the Journal of Neuroscience, describes for the first time a cellular mechanism linking a specific stimulus to the timing at which inhibitory neurons fire. This breakthrough lays a cellular foundation for the temporal coding hypothesis, which proposes that odor identity is encoded by the timing of neuronal firing and not the rate at which neurons fire.

Past research has shown that specific odors trigger unique patterns of electrical activity in the brain. Generating these patterns requires reliably timed inhibition, but relatively little was known about the timing of the activity of inhibitory neurons -- until now.

There is a clear link between which odor is being presented and the time at which inhibitory neurons fire. This timing controls which excitatory neurons are active and at which time. This modulation contributes to the generation of reliable temporal patterns of neuronal activity, said Nathan Urban, an assistant professor of biological sciences at the Mellon College of Science at Carnegie Mellon.

Populations of mitral cells, a type of excitatory neuron in the olfactory bulb, receive input from neurons in the nose that respond to a single odorant. After receiving this input, the mitral cells convey messages about odor identity to other parts of the brain. But they don't simply relay information. Their activity, and therefore which message they send, is modulated by the inhibitory activity of granule cells. In a first, Urban has shown that the timing of granule cell firing encodes odor information.

Urban's work is especially provocative given that the traditional view holds that the rate of neuronal firing is what really matters, not the time that it takes for a stimulated neuron to fire. Recognition of a stimulus like an odor relies on the orchestrated firing of neurons, both ones that excite other neurons to relay a message as well as ones that inhibit or alter how a message is relayed.

Our results indicate that the latency period before a single granule cell fires is associated with a specific odor, thus linking the timing of inhibitory modulation of mitral cell activity to odor identity. In other words, the timing of granule cell firing conveys different messages. In this case, the messages relay which odor is present, explained Urban.

Urban monitored the subtle-yet-coordinated activity of populations of granule cells in living brain slices using calcium imaging, an optical imaging technique that has never been applied to studies of the olfactory system. Urban loaded the neurons with a fluorescent dye that emits a yellow glow. This glow decreases when the dye binds to calcium. Because the flow of calcium ions into and out of cells corresponds to their firing, Urban was able to actually watch which neurons were firing and when.

Urban stimulated mitral cells, which in turn stimulated granule cells. He found that granule cells respond by firing over a range of times, from a fraction of a millisecond to hundreds of milliseconds. But, according to Urban, the most striking observation was that specific granule cells reliably fired with the same latency when they receive input from certain populations of mitral cells. Input from one group of mitral cells (hence, one set of odor receptors) caused certain granule cells to fire with a 500-millisecond delay, for example. Input from another set of mitral cells (a different set of odor receptors) caused the same granule cells to fire with a 50-millisecond delay. Thus, he found that the timing of granule cell firing is directly related to the input the mitral cells receive -- the original odorant.

This is the first time we have seen reliable timing of firing. It turns out that cells are better at clocking their firing than previously thought, Urban said.

This finding is a springboard to addressing other important questions, Urban added. For example, what are the molecular mechanisms by which granule cells time their firing? We are now exploring this question, as well as how we can observe this odor-specific timing in living animals.

Bitter taste identifies poisons in foods

Mon, 18 Sep 2006 04:00:00 PST

( from http://www.rxpgnews.com ) Scientists at the Monell Chemical Senses Center report that bitter taste perception of vegetables is influenced by an interaction between variants of taste genes and the presence of naturally-occurring toxins in a given vegetable. The study appears in the September 19 issue of Current Biology.

Scientists have long assumed that bitter taste evolved as a defense mechanism to detect potentially harmful toxins in plants. The Current Biology paper provides the first direct evidence in support of this hypothesis by establishing that variants of the bitter taste receptor TAS2R38 can detect glucosinolates, a class of compounds with potentially harmful physiological actions, in natural foods.

The findings show that our taste receptors are capable of detecting toxins in the natural setting of the fruit and vegetable plant matrix, said senior author Paul Breslin, a Monell sensory scientist.

Glucosinolates act as anti-thyroid compounds. The thyroid converts iodine into thyroid hormones, which are essential for protein synthesis and regulation of the body's metabolism. Glucosinolates inhibit iodine uptake by the thyroid, increasing risk for goiter and altering levels of thyroid hormones. The ability to detect and avoid naturally-occurring glucosinolates would confer a selective advantage to the over 1 billion people who presently have low iodine status and are at risk for thyroid insufficiency.

In the study, 35 healthy adults were genotyped for the hTAS2R38 bitter taste receptor gene; the three genotypes were PAV/PAV (sensitive to the bitter-tasting chemical PTC,) AVI/AVI (insensitive), and PAV/AVI (intermediate).

Subjects then rated bitterness of various vegetables; some contained glucosinolates while others did not. Examples of the 17 glucosinolate-containing vegetables include watercress, broccoli, bok choy, kale, kohlrabi, and turnip; the 11 non-glucosinolate foods included radicchio, endive, eggplant and spinach. Subjects with the sensitive PAV/PAV form of the receptor rated the glucosinolate-containing vegetables as 60% more bitter than did subjects with the insensitive (AVI/AVI) form. The other vegetables were rated equally bitter by the two groups, demonstrating that variations in the hTAS2R38 gene affect bitter perception specifically of foods containing glucosinolate toxins.

Together, the findings provide a complete picture describing individual differences in responses to actual foods at multiple levels: evolutionary, genetic, receptor, and perceptual. The sense of taste enables us to detect bitter toxins within foods, and genetically-based differences in our bitter taste receptors affect how we each perceive foods containing a particular set of toxins, summarizes Breslin.

Breslin notes, The contents of the veggies are a double-edged sword, depending upon the physiological context of the individual eating them. Most people in industrialized cultures can and should enjoy these foods. In addition to providing essential nutrients and vitamins, many are reported to have anti-cancer properties.

Lead author Mari Sandell comments on additional nutritional and practical implications of the study, Taste has a great impact on food acceptability and choice. A comprehensive understanding how food components contribute to taste is necessary to develop modern tools for both nutritional counseling and food development.

Researchers identify the cells and receptor for sensing sour taste

Wed, 23 Aug 2006 04:00:00 PST

( from http://www.rxpgnews.com ) In the last seven years, Howard Hughes Medical Institute researcher Charles S. Zuker and Nicholas J.P. Ryba at the National Institutes of Health have worked together to identify the cells, receptors and signaling mechanisms for three of the five tastes humans can sense -- sweet, bitter, and umami (the taste of monosodium glutamate). Now, Zuker, Ryba, and their team of researchers have identified the cells and the receptor responsible for sour taste, the primary gateway in all mammals for the detection of spoiled and unripe food sources.

The receptor is found in a subpopulation of taste receptor cells of the tongue that do not function in sweet, bitter, or umami taste, the researchers report in the August 24, 2006, issue of the journal Nature.

This finding is very satisfying, said Zuker, because it seals the case that we had built before with sweet, bitter, and umami, showing that each taste is mediated by fully dedicated sensors. A contrasting view held that individual tongue cells detect more than one taste modality, with the quality of the taste being encoded in a complicated pattern of nerve signals sent to the brain.

The hunt for the sour receptor began with a search of DNA and protein sequence databases. Angela Huang, a graduate student in Zuker's lab at the University of California, San Diego, and the lead author of the paper, screened the mouse genome for all of the genes encoding proteins that have transmembrane domains -- sections of the protein that allow the protein to be located in cell membranes.

That screen narrowed the list significantly, from 30,000 to about 10,000, Huang said. She then used what Zuker calls a stroke of ingenuity to reduce the list further. Proteins that could detect sour compounds are likely to be found only in small numbers of tissues, including taste cells in the tongue. Huang therefore eliminated from the list all those proteins that are expressed in many different tissues. That got it down to about 900 candidates, she said.

Huang then used a technique called reverse transcriptase polymerase chain reaction (RT-PCR) to find which of the candidates were expressed specifically in taste receptor cells. Of the approximately 30 proteins identified through RT-PCR, Huang searched for genes that were expressed in a small population of taste receptor cells -- the pattern that Zuker's and Ryba's team had previously discovered with taste receptors for sweet, bitter, and umami.

The researchers' attention was drawn immediately to a receptor molecule known as PKD2L1, which is related to a large family of proteins that shuttle ions into and out of cells. As predicted for a candidate sour receptor, PKD2L1 was not found in the cells that express the receptors for sweet, bitter, and umami, but instead was found in a novel population of taste cells. Our fundamental premise was that salt and sour were going to be mediated by dedicated cells, said Zuker, and those candidate receptors should not be present in sweet-, bitter-, or umami-sensing cells.

To link the receptors with the taste of sour, Zuker and his colleagues turned to another clever experimental strategy. Using a special mouse strain, they created genetically engineered mice that produced a diphtheria toxin in cells that expressed PKD2L1, thus killing the cells. They then recorded the nerve signals and tongue function coming from taste cells in the genetically-engineered mice. Remarkably, no matter what sour compounds they fed the mice, nerve signals from the taste cells remained absent; the animals were completely insensitive to all kinds of acids. But these sourless mice continued to be able to taste sweet, bitter, umami, and salt. Killing these cells and showing that the mice now are totally unable to detect sour proved that these cells are the sensors for sour taste, and that indeed no other taste cells detect sour, said Zuker.

In an interesting extension of this work on taste, the investigators then examined whether cells expressing the sour receptor might be found anywhere else in the body, perhaps where sensing acidity might be important. They looked for the receptor in a large number of other tissues and discovered that it is expressed in a particular set of neurons surrounding the central canal of the spinal cord. Suspecting that these cells might be responsible for monitoring the level of acidity in the cerebrospinal fluid (CSF), the researchers recorded nerve signals from the cells in a slice of spinal cord tissue. When the surrounding solution turned acid, the cells became activated selectively, and immediately began firing nerve signals much more rapidly than when the solution was neutral or basic.

Discovery of the sour (acid) receptor in the central nervous system could help explain how the body monitors the quality of critical body fluids, Zuker said. For example, the body controls respiration in part by monitoring the acidity of the blood, since an increase in carbon dioxide dissolved in the blood increases acidity. Defects in these blood-, CSF-, and brain-fluid-sensing systems may underlie a wide range of disorders, said Zuker.

Several intriguing questions can be pursued now that the sour-taste cells and candidate receptor have been found. One is how the PKD2L1 receptor is activated by acid stimuli. Another concerns the role of the neurons that innervate the central canal. And as Zuker pointed out, This work also proved that salt-sensing cells, just like those mediating sweet, bitter, umami and sour, must function as independent sensors because the sourless mice have perfectly normal salt perception, he said. So this opens an exciting experimental platform to molecularly dissect the last of the five basic taste qualities: salt taste.

Location, location, location!

Wed, 16 Aug 2006 04:00:00 PST

( from http://www.rxpgnews.com ) It's a classic upper middle class dilemma: Should we buy a perfect second home in a place that takes hours to get to, or should we settle for something closer but not as nice? In the rodent world, an equivalent decision-making situation might be, Was the food I liked better down this alley or over there?

By discovering that particular rat brain neurons combine or integrate dissimilar pieces of information (e.g. location versus reward), researchers have begun to learn how the brain controls decision-making and goal-oriented behaviors. Examples of these include foraging and navigation in animals and--in humans--whether to buy a particular second home or, in general, whether to favor a long-term benefit over immediate gratification.

Led by Dr. Zach Mainen of Cold Spring Harbor Laboratory on Long Island, the study represents the first time that brain neurons have been shown to integrate spatial and reward information. Its results contrast with a previous pure economic view that neurons in the orbitofrontal cortex (or OFC) are involved solely in assessing value.

Moreover, the study--published this week in Neuron--has implications for understanding pathological conditions in humans that affect decision-making, motivation, and emotions such as addiction, depression, obsessive-compulsive disorder, autism, and other disorders of thought or mood.

Ultimately, we're trying to understand how groups of neurons participate in the creation of perception, awareness, and goal-oriented behavior, says Mainen. With this study, we're getting some of the first concrete clues about how the brain represents an animal's goals.

The research was spearheaded by graduate student Claudia Feierstein, who recorded the activity of OFC neurons while rats performed an odor discrimination task that they had previously learned to accomplish.

In the task, the animal receives a test odor (A or B) by poking its nose into a centrally located odor port. Next, the animal chooses odor A or odor B as being the same as the test odor by poking its nose into a choice port located to its right (odor A) or left (odor B). If the animal chooses correctly, it receives a reward (a drop of water).

As expected, many of the neurons actively signaled I'm getting a reward when the animal moved right or left, i.e. toward odor A or odor B.

Surprisingly, however, several of the OFC neurons signaled I'm getting the reward to my right whereas several others signaled I'm getting the reward to my left.

Mainen says that one of his next steps will be to examine what happens in the brain while the animals are learning to recognize new odors. This may or may not figure into those experiments, but we've already found that about one quarter of the rats we use are significantly below average in learning. Their motivation levels also vary quite a bit, which might be interesting to explore as well.

Quick -- whats that smell?

Wed, 02 Aug 2006 04:00:00 PST

( from http://www.rxpgnews.com ) Researchers at the Monell Chemical Senses Center have found that taking as little as a hundred milliseconds longer to smell an odor results in more accurate identification of that odor. This seemingly simple observation has important implications regarding how olfactory information is processed by the brain. The findings appear in the August issue of Neuron.

By demonstrating a clear relationship between odor sampling time and accurate odor identification, the Monell researchers solved a controversy centering on whether the brain processes olfactory information in a similar manner to how it processes visual and auditory stimuli.

Previous published work suggested that olfaction was different from vision and audition in lacking this fundamental property, notes senior author Alan Gelperin, PhD, a computational neuroscientist. We now can use accumulated information about these other sensory systems to help us understand olfaction.

Exactly how the many thousands of different odorants are detected and identified remains a mystery. The human nose probably contains several hundred different types of olfactory receptors, while animals with a highly developed sense of smell - such as dog, rat, or cat - may have over a thousand different receptor types. It is thought that perception of any one odorant probably involves simultaneous stimulation of several different receptors and that an olfactory code enables identification of specific odorants by the brain. Previous experience and motivational state also interact with odorant information to influence processing and identification. It still is not known how the brain deals with all this information to let us perceive odors.

Using an approach that has provided insight into information processing by the visual and auditory systems, the Monell researchers developed a new behavioral paradigm using trained mice to ask whether longer exposure to an odor would result in more accurate identification of that odor. The results indicated that the mice needed extra time to accurately identify more complex odors.

The well-trained mouse needs almost half a second to solve a difficult olfactory discrimination task, says lead author Dmitry Rinberg, PhD. This time window is very important as we seek to design experiments and develop models that explain what the brain is doing in the extra time it takes to identify complex odors.

Rinberg, a physicist and computational neuroscientist, comments, The development of color television was based on extensive studies of visual sensory processing. Modern MP3 players are built based on a deep knowledge about properties of our hearing capabilities. Similarly, increased knowledge of olfactory processing has the obvious potential to open many doors, perhaps including development of electronic olfactory systems that would have capabilities such as identification of odors for medical diagnosis or detection of land mines.

Researchers show how brain decodes complex smells

Fri, 16 Jun 2006 04:00:00 PST

( from http://www.rxpgnews.com ) In studies in mice, the researchers found that nerve cells in the brain's olfactory bulb -- the first stop for information from the nose -- do not perceive complex scent mixtures as single objects, such as the fragrance of a blooming rose. Instead, these nerve cells, or neurons, detect the host of chemical compounds that comprise a rose's perfume. Smarter sections of the brain's olfactory system then categorize and combine these compounds into a recognizable scent. According to the researchers, it's as if the brain has to listen to each musician's melody to hear a symphony.

Humans may rely on the same smell decoding system, because mice and men have similar brain structures for scent, including an olfactory bulb, the researchers said.

We wanted to understand how the brain puts together scent signals to make an odor picture. We discovered the whole is the sum of its parts, said Da Yu Lin, Ph.D., who conducted the research as a graduate student studying with neurobiologist Lawrence Katz, Ph.D., a Howard Hughes Medical Institute investigator at Duke. Katz died in November 2005.

The research appears June 16, 2006, in the journal Neuron. The study was supported by the National Institutes of Health, the Howard Hughes Medical Institute and the Ruth K. Broad Biomedical Research Foundation.

Scientists have long debated how the brain makes order out of the hundreds of volatile chemical compounds that assault the nose. Is the brain's odor code redundant, with single cells responding to multiple components in the smell of a freshly baked cookie? Or does the brain process each scent component like a jigsaw puzzle piece, assembling the signals until it recognizes the picture is a cookie?

To find answers, the Duke researchers exposed mice to different odors and measured response of neurons across the olfactory bulb with intrinsic signal imaging. The imaging technique maps brain activity by detecting changes in reflected light from the brain with a sensitive camera.

To start, the researchers separated and identified the volatile compounds in each odor with gas chromatography. A complex mixture like urine has at least a hundred separate compounds in it, Lin said. They analyzed scents as diverse as peanut butter, coffee and fresh bobcat urine shipped to the laboratory on dry ice.

The researchers then exposed the mice to the original odor and its individual compounds. We found that glomeruli, the functional units of the olfactory bulb, act as detectors for individual compounds, Lin said. There are no single detectors for complete smells.

Thus, to distinguish different scents, the brain must integrate the signals of multiple chemical components into an odor picture. The researchers suspect that this integration doesn't happen in the olfactory bulb. Instead, the bulb likely passes the data to more advanced brain structures where it is assembled and recognized as a specific scent.

Understanding how the olfactory system works in mice may also provide broader insights into human perception, said Stephen Shea, Ph.D., a Duke University Medical Center research associate who participated in the study. Perception relies on combining multiple components, whether the input is smell, sight or sound. Shea suggested that probing the olfactory system could help scientists better understand, for example, how the various biological and neurological components underlying perception formed and evolved.

Dr. McCluskey receives top honor for young taste researchers

Wed, 26 Apr 2006 04:00:00 PST

( from http://www.rxpgnews.com ) Dr. McCluskey received the Ajinomoto Award for Young Investigators in Gustation during the 28th annual meeting of the Association for Chemoreception Sciences April 26-30 in Sarasota.

She was nominated by former mentor Dr. David Hill, neurobiologist at the University of Virginia in Charlottesville, who received the 1996 gustation award. Dr. McCluskey studied with Dr. Hill while earning her PH.D. in Virginia.

She got her first taste of gustation research in the late 1980s as an undergraduate at Florida State University. There another mentor, Dr. James C. Smith, a now-retired senior investigator, was the first to interest her in the complex system connecting thousands of taste buds on the tongue and palate with the brain.

Receptor cells on your tongue are part epithelial cells: they turn over and they renew, and they are partly like neural cells, so they can fire action potentials and tell your brain about what is on your tongue, she says.

One of the most interesting and fortunate things about the system is that when communication with the brain is severed, nerves regenerate. You can section a nerve and the taste buds go away but the whole thing regenerates and becomes functional again. I was really fascinated by the functional changes that you can see in this system even in an adult.

She hopes her studies of a system that successfully regenerates in the face of constant onslaught from the likes of food, teeth, bacteria and viruses will one day help nerves that are less successful at repair, such as those severed in a spinal cord injury.

It's the flip side to the approach of looking at a spinal cord injury in an animal and seeing if you can reverse that. We chose to look at it a different way and say, 'Let's take a system that does regenerate pretty well and see what happens.'

Her focus has become the role the immune system plays in recovery as she and others are learning more about how that system affects neurons and vice versa and how, as with any relationship, there are good and bad interactions.

Macrophages, one of the first immune cells to move in after an injury, seem to be a major player. The cells, known for their scavenging ability, also secrete nerve growth factors. It turns out, if you don't have macrophages, you get deficiencies in neural function, says Dr. McCluskey, noting the finding is pretty amazing to many neuroscientists who have largely viewed the immune system as bad for neurons.

We are trying to narrow down what molecules macrophages are secreting that are affecting taste receptors cells. Our goal is to show a definitive role for those cells and to also determine what other immune cells play a role, says Dr. McCluskey, who adds that for macrophages at least, that role may change over time following an injury.

She and her colleagues are starting with the adhesion molecules that summon macrophages circulating in the bloodstream to an injury site. We are backtracking to the signals then that tell macrophages when to come into this area of injury and whether they just die, whether they exit, whether they proliferate, just what happens to these cells once they get the cue from dying cells.

Melissa Cavallin, an MCG graduate student Dr. McCluskey now mentors, recently received a National Institutes of Health predoctoral award to help elucidate these earliest interactions between injured taste buds and macrophages.

More recently, Dr. McCluskey's lab also began using the taste system as a model for poor nerve regeneration.

She has found that old healthy rats are not quite as good at functional taste bud regeneration as their younger counterparts.

Although most older people seem to have plenty of taste buds, they aren't quite so lucky with recovery from peripheral nerve injuries, such as a significant hand injury, which creates the opportunity for another model.

It looks like in the older rats, the nerve cells don't functionally grow back, Dr. McCluskey says. She knows this is true out to 100 days, 60 days after a younger rat would have functional recovery. Apparently macrophage signaling is faulty or at least delayed in the older animals, a problem that may be replicated in the peripheral nervous system of older people. If you sever a nerve in some place that should regenerate, it may be in aged people that it does not. So we want to set up a model where we can boost immune function, to see whether there are things we can do with growth factors to make these nerves regenerate in older rats as well. It looks promising, she says.

Sweet 'water taste' paradoxically predicts sweet taste inhibitors

Sun, 23 Apr 2006 04:00:00 PST

( from http://www.rxpgnews.com ) Reporting in an advance online publication in Nature, scientists from the Monell Chemical Senses Center describe how certain artificial sweeteners, including sodium saccharin and acesulfame-K, paradoxically inhibit sweet taste at high concentrations. The researchers further report that taste perception switches back to sweetness when these high concentrations are rinsed from the mouth with water, resulting in the aftertaste experience known as sweet 'water taste.'

The Nature article describes the phenomenon of sweet 'water taste' and then goes on to explain it at the level of the sweet taste receptor.

These findings will open doors for tweaking the sweet taste receptor and finding new sweeteners and inhibitors that can be used both by food industry and in medicine, states senior author Paul A.S. Breslin, PhD, a Monell geneticist.

Lead author Veronica Galindo-Cuspinera, PhD, noted while working on a separate study that saccharin commonly used at low concentrations as an artificial sweetener loses its initially sweet taste when tasted at high concentrations. Galindo-Cuspinera subsequently observed that strong sweetness returned when the high concentrations of saccharin were rinsed from the mouth with water.

Working with Breslin, she next discovered that high concentrations of saccharin inhibit the sweetness of any other sweetener tasted at the same time.

Testing a variety of compounds, the researchers found that any sweetener that elicits sweet 'water taste' also acts as a sweet taste inhibitor.

To understand how sweet 'water taste' compounds could act both as a sweetener and as a sweet inhibitor, collaborators Marcel Winnig, Bernd Bufe, and Wolfgang Meyerhof of the German Institute of Human Nutrition conducted a series of molecular studies using cultured cells expressing the human sweet taste receptor.

Findings revealed that the cellular responses directly parallel the human perceptual responses.

At lower concentrations, sweeteners activate the sweet taste receptor by attaching to a high affinity binding site, leading to perception of sweetness. However, high concentrations of saccharin and acesulfame-K inhibit the cellular responses to other sweeteners by binding to a second, low-affinity inhibitory site that causes the receptor to shift from an activated to an inhibitory state. When a water rinse removes sweet taste inhibitors from the inhibitory site, the sweet receptor is re-activated and the perception of sweetness returns.

The phenomenon of sweet water taste is the direct result of releasing the receptor from inhibition, explains Galindo-Cuspinera. It is rare to find so complete a molecular explanation for a complex perceptual phenomenon. We can now use sweet water taste as a predictor for potential sweet inhibitors.

Sweet inhibitors are used by the food industry to counteract the undesirable high sweetness that results from replacing fats with sweet carbohydrates in reduced-fat products such as snack foods and salad dressings.

The extremely close parallels between the behavior of the human sweet taste receptor and the perceptual phenomenon are remarkable, comments Breslin. This two-site model should enable a more complete understanding of human sweet taste perception, leading directly to studies of how to stimulate, manipulate, enhance, inhibit, and create synergy of sweet taste.

The results will be presented at the 28th annual Meeting of the Association for Chemoreception Sciences, to be held April 26-30 in Sarasota, Florida.

Creating Sugar Substitutes by Understanding How People Percieve Taste

Wed, 29 Mar 2006 06:22:00 PST

( from http://www.rxpgnews.com ) The most important factor in what kind of sweetener people prefer has little to do with how sweet it tastes. Rather, it has more to do with other tastes in the sweetener, such as bitterness or sourness, new research suggests.

Food scientists at Ohio State University asked 30 college students to rate 13 different sweeteners and sweet substances, including sugar, based on how much bitter, sour and metallic tastes they perceived with each substance. Many of these compounds are found in items such as diet soda, gum, candy and Jell-O, and some can be used for baking.

Not surprisingly, sugar was rated highest. Participants found sucralose (brand name Splenda), a sweetener derived from sugar, the most acceptable alternative to sugar. The researchers attribute this to a lack of noticeable sour and bitter tastes in this sweetener.

So many sugar substitutes also have unpleasant tastes, said Jeannine Delwiche, a study co-author and an assistant professor of food science and technology at Ohio State University. Understanding how people perceive these tastes may help create a sugar substitute that is more palatable. That ultimately means making tastier products with fewer calories.

Sugar is the gold standard for companies that make artificial sweeteners, said Delwiche, who also directs Ohio State's Sensory Science Group. But it's packed with calories. Most of these other substances have few to no calories.

Delwiche and study co-author Amanda Warnock, a former graduate student in food science at Ohio State, presented their findings March 28 in Atlanta at the annual meeting of the American Chemical Society.

The researchers asked the 30 panelists to rate the sweet, bitter, sour and metallic tastes that accompanied the 13 sweeteners and sweet substances. Each participant rinsed his or her mouth out thoroughly with water between tasting small samples of each compound. Most of the substances sampled in this study are already used by the food industry.

A few of the sweet substances listed aren't typically used by the food industry as sweeteners. However, the researchers wanted to know how the panelists reacted to a variety of sweet substances; in the future this information may lead to better-tasting sweeteners. (See the side bar for a complete list of the sweeteners and sweet substances used in this study.)

In the first of three sessions, participants rated their overall liking and acceptance of the sweet compounds. In the second and third sessions, each panelist rated the sweet, sour, bitter and metallic intensities of each sample.

The results showed that the sweeteners that the participants liked best had no, or next to no, sour, bitter or metallic tastes.

Next to sugar and sucralose, the panelists liked xylitol best. Xylitol is used primarily in chewing gum. Aspartame (sold under the brand names Equal and Nutra Sweet) and fructose were also highly rated. The panelists liked stevia, saccharin, D-tryptophan and glycine the least.

Most of these last four substances have pronounced bitter, sour or metallic tastes, Delwiche said.

The rest of the substances thaumatin, cyclamate, acesulfame potassium and glucose were ranked in between the most-preferred and the least-liked compounds.

Delwiche plans to continue this work and include larger groups of participants to figure out what drives individual differences in taste perception.

There is a need for much more research to fully understand how people perceive sweet tastes, she said.

Neuroscientists discover new cell type that may help brain maintain memories of smells

Wed, 15 Mar 2006 05:00:00 PST

( from http://www.rxpgnews.com ) It was surprising to the researchers that no one had studied these cells before given the references to them in important scientific papers going back for over a hundred years.

This is a well-studied part of the brain, said Ben W. Strowbridge, Ph.D., associate professor of neuroscience at Case and the senior author. These are large cells that weren't really hiding.

The perception of a smell begins when odor molecules in the air interact with one of the millions of specialized olfactory sensory neurons in the nose. These sensory neurons then send signals to a brain region called the olfactory bulb, where the work of recognizing the odor begins. One of the puzzling aspects of olfaction is how our perception of an odor can evolve over multiple sniffs. Because of their unique ability to maintain their activity between sniffs, Blanes cells may provide the missing link needed to answer this critical question. While there are relatively few Blanes cells in the brain, they appear to play a critical role in shaping the output of the olfactory system.

The Case researchers found that the influence of Blanes cells on the output signals leaving the olfactory bulb is magnified hundreds of times by the specific pattern of connections they make with other cell types. One of the surprising results from their study was the discovery that Blanes cells selectively choose to talk with another cell type in the olfactory bulb, the granule cell. It is this specific pattern of connections that explains how Blanes cells can have such a disproportionately large impact in the olfactory system.

Discovering how one brain cell talks with another brain cell remains one of the most important but technically challenging questions in neuroscience. The Case researchers faced two significant hurdles in trying to answer this question in the olfactory system. The first was the shear numbers of potential partner neurons each Blanes cell might have. The other hurdle relates to difficulty in visualizing the incredibly thin connection between the Blanes cell and its target neurons.

Todd Pressler, a doctoral candidate student in Strowbridge's lab and the lead author on the study, took advantage of a new type of imaging method called multiphoton microscopy to overcome these hurdles and to discover that Blanes cells talk to granule cells.

The multiphoton microscope allowed me to identify the axon and then follow it for long distances without damaging the Blanes cell. Once I could follow the axon as it coursed through the brain, it was relatively easy to see where it ended and where I should look for potential target cells. Because I knew where to look, this part of the project was shortened from potentially years to just a matter of weeks, said Pressler.

The multiphoton microscope used in this study was built by Strowbridge specifically for these types of experiments and was funded by grants from the Mt. Sinai Health Care Foundation and the National Institutes of Health.

Strowbridge and Pressler highlighted two distinct set of experiments they hope to pursue in the near future. The first relates to the possible connection between the sense of smell and Alzheimer's disease. The Case investigators found that the same biological machinery that helps the olfactory brain to remember smells is identical to the machinery that enables other types of memories in the cortical brain region most susceptible to damage in this debilitating disease.

By understanding the biological process that allow us to store memories in the olfactory brain, we might find a novel window into pathological changes that affect memory in people with Alzheimer's disease, said Strowbridge.

In addition to leveraging the olfactory system to better understand Alzheimer's disease, Pressler is excited about the prospect of unraveling the patterns of synaptic connections made by the other five named but as yet unstudied brain cells in the olfactory bulb.

Living taste cells produced outside the body

Sat, 25 Feb 2006 10:04:00 PST

( from http://www.rxpgnews.com ) Researchers from the Monell Chemical Senses Center have succeeded in growing mature taste receptor cells outside the body and for the first time have been able to successfully keep the cells alive for a prolonged period of time. The establishment of a viable long-term model opens a range of new opportunities to increase scientists' understanding of the sense of taste and how it functions in nutrition, health and disease.

"We have an important new tool to help discover molecules that can enhance or block different kinds of tastes," explains principle investigator Nancy Rawson, PhD, a cellular biologist. "In addition, the success of this technique may provide hope for people who have lost their sense of taste due to radiation therapy or tissue damage, who typically lose weight and become malnourished. This system gives us a way to test for drugs that can promote recovery."

The findings are reported in an online issue of Chemical Senses.

Taste receptor cells are located in taste buds on the tongue and in the throat. These cells contain the receptors that detect taste stimuli: sweet, sour, salty, bitter, and umami (savory). Each taste receptor cell lives for only about 10-14 days, after which it is replaced. The new taste cells develop from a population of undifferentiated precursors known as basal cells.

Understanding of the process of taste cell differentiation, growth and turnover has been hampered by the inability of researchers to keep taste cells alive outside the body in controlled laboratory conditions.

To address this long-standing problem, the Monell researchers utilized a novel approach. Instead of starting with mature taste cells, they obtained basal cells from rat taste buds and placed these cells in a tissue culture system containing nutrients and growth factors. In this environment, the basal cells divided and differentiated into functional taste cells.

The new cells, which were kept alive for up to two months, were similar to mature taste cells in several key respects. A variety of methods were used to show that the cultured cells contain unique marker proteins characteristic of mature functioning taste receptor cells. In addition, functional assays revealed that the cultured cells responded to either bitter or sweet taste stimuli with increases of intracellular calcium, another property characteristic of mature taste cells.

Lead author Hakan Ozdener, MD, PhD, observes, "Although scientists have tried for many years to maintain taste cells in a long-term culture system, it was commonly believed that these cells could not be kept alive for longer than about 10 days. Now, we have demonstrated that taste cells can be generated in vitro and maintained for a prolonged period of time."

The taste cell culture system provides new insight into how basal cells turn into functional taste cells. Although previous dogma had held that induction was somehow dependent on interactions with the nervous system, the current findings suggest otherwise. Ozdener explains, "By producing new taste cells in an in vitro system, our results demonstrate that direct stimulation from nerves is not necessary to generate taste cells from precursors."

By using the cultured taste cells, researchers now have more precise control over the cell's surrounding environment, as well as better access to subcellular mechanisms, allowing them to ask certain questions that could not previously be addressed.

For instance, cultured cells can be used to study how taste stimuli interact to enhance good tastes or suppress unpleasant tastes. Similarly, new molecules, including potential artificial sweeteners or bitter blockers, can be evaluated to see if they interact with taste receptors to activate the cell.

Another important avenue for research aims to help people who have lost their sense of taste from radiation or diseases. Identification of factors that promote taste cell regeneration and growth may provide new avenues of treatment for these patients.

Researchers also hope to gain insight into how taste cell function changes across the lifespan, from infancy and childhood through old age.

Although the current experiments utilized rat taste cells, Ozdener, Rawson, and colleagues intend to use taste cell biopsies from humans to try to grow human taste cells.

Living taste cells produced outside the body

Thu, 23 Feb 2006 05:00:00 PST

( from http://www.rxpgnews.com ) We have an important new tool to help discover molecules that can enhance or block different kinds of tastes, explains principle investigator Nancy Rawson, PhD, a cellular biologist. In addition, the success of this technique may provide hope for people who have lost their sense of taste due to radiation therapy or tissue damage, who typically lose weight and become malnourished. This system gives us a way to test for drugs that can promote recovery.

The findings are reported in an online issue of Chemical Senses.

Taste receptor cells are located in taste buds on the tongue and in the throat. These cells contain the receptors that detect taste stimuli: sweet, sour, salty, bitter, and umami (savory). Each taste receptor cell lives for only about 10-14 days, after which it is replaced. The new taste cells develop from a population of undifferentiated precursors known as basal cells.

Understanding of the process of taste cell differentiation, growth and turnover has been hampered by the inability of researchers to keep taste cells alive outside the body in controlled laboratory conditions.

To address this long-standing problem, the Monell researchers utilized a novel approach. Instead of starting with mature taste cells, they obtained basal cells from rat taste buds and placed these cells in a tissue culture system containing nutrients and growth factors. In this environment, the basal cells divided and differentiated into functional taste cells.

The new cells, which were kept alive for up to two months, were similar to mature taste cells in several key respects. A variety of methods were used to show that the cultured cells contain unique marker proteins characteristic of mature functioning taste receptor cells. In addition, functional assays revealed that the cultured cells responded to either bitter or sweet taste stimuli with increases of intracellular calcium, another property characteristic of mature taste cells.

Lead author Hakan Ozdener, MD, PhD, observes, Although scientists have tried for many years to maintain taste cells in a long-term culture system, it was commonly believed that these cells could not be kept alive for longer than about 10 days. Now, we have demonstrated that taste cells can be generated in vitro and maintained for a prolonged period of time.

The taste cell culture system provides new insight into how basal cells turn into functional taste cells. Although previous dogma had held that induction was somehow dependent on interactions with the nervous system, the current findings suggest otherwise. Ozdener explains, By producing new taste cells in an in vitro system, our results demonstrate that direct stimulation from nerves is not necessary to generate taste cells from precursors.

By using the cultured taste cells, researchers now have more precise control over the cell's surrounding environment, as well as better access to subcellular mechanisms, allowing them to ask certain questions that could not previously be addressed.

For instance, cultured cells can be used to study how taste stimuli interact to enhance good tastes or suppress unpleasant tastes. Similarly, new molecules, including potential artificial sweeteners or bitter blockers, can be evaluated to see if they interact with taste receptors to activate the cell.

Another important avenue for research aims to help people who have lost their sense of taste from radiation or diseases. Identification of factors that promote taste cell regeneration and growth may provide new avenues of treatment for these patients.

Researchers also hope to gain insight into how taste cell function changes across the lifespan, from infancy and childhood through old age.

Although the current experiments utilized rat taste cells, Ozdener, Rawson, and colleagues intend to use taste cell biopsies from humans to try to grow human taste cells.

Brain anticipates taste, shifts gears - Study

Wed, 22 Feb 2006 16:22:00 PST

( from http://www.rxpgnews.com ) As the prism of our senses, the human brain has ways of refracting sensory input in defiance of reality.

This is seen, for example, in the placebo effect, when simple sugar pills or inert salves taken by unwitting subjects are seen to ease pain or have some other beneficial physiological effect. How the brain processes this faked input and prompts the body to respond is largely a mystery of neuroscience.

Now, however, scientists have begun to peel back some of the neurological secrets of this remarkable phenomenon and show how the brain can be rewired in anticipation of sensory input to respond in prescribed ways. Writing in the current issue (March 1, 2006) of the journal Brain, Behavior, and Immunity, a team of University of Wisconsin-Madison scientists reports the results of experiments that portray the brain in action as it is duped.

The new work, conducted by a team led by UW-Madison assistant professor of psychology and psychiatry Jack B. Nitschke, tested the ability of the human brain to mitigate foul taste through a ruse of anticipation. The work, conducted at the UW-Madison Waisman Center using state-of-the-art brain imaging techniques and distasteful concoctions of quinine on a cohort of college students, reveals in detail how the brain responds to a manipulation intended to mitigate an unpleasant experience.

"There is a potent impact to expectancy," says Nitschke, who, with his colleagues, exposed 43 undergraduate subjects to potions of quinine, sugar water or distilled water while undergoing magnetic resonance imaging (MRI).

The subjects, Nitschke explains, were asked beforehand to associate a prescribed set of cues with a taste. A "minus sign" flashed through fiber optic goggles to subjects undergoing MRI, for instance, was to be an anticipatory signal that a liquid subsequently dripped into the mouth would have a very bitter taste. A "zero "cue corresponded with a neutral taste, and a "plus sign" with a pleasant, sugary taste.

The cues, according to Nitschke, were flashed to subjects just prior to the administration of a few drops of liquid. But in the study, the cues would not always match the taste they were said to presage.

His group observed that when subjects were given a cue that suggested the taste they were about to experience would be less bitter, the taste was perceived as such, and the regions of the brain that code tastes were activated less.

"When the subject sees the warning signal, portions of the brain activated by the misleading cue predict the decreased brain response to the awful taste," Nitschke says. What's more, "the (brain's) response to the misleading cue will predict the subject's perception of what the taste is going to be. The subject anticipates that the taste won't be that bad, and indeed that's what they report."

In short, the new study shows how expectancy affects how humans perceive sensory input, and how events in the brain are directly related to those perceptions.

Importantly, by mapping how the brain anticipates an event and kicks in a placebo effect, Nitschke argues, scientists can begin to think about ways that knowledge could be used in clinical settings.

For Nitschke, who also practices as a clinical psychologist specializing in the treatment of depression and anxiety disorders, the new detailed insights into the power of anticipation could lead to better treatments for such conditions.

"The placebo operates through expectancy. In this study, we've taken the pill out of the picture. We're just manipulating expectancies," he says. "The results beg the question of what can we do to target anticipatory processes in our patients that might lead to better outcomes."

Bitter taste receptor gene and risk of alcoholism

Tue, 10 Jan 2006 15:07:00 PST

( from http://www.rxpgnews.com ) A team of researchers, led by investigators at Washington University School of Medicine in St. Louis, has found that a gene variant for a bitter-taste receptor on the tongue is associated with an increased risk for alcohol dependence. The research team studied DNA samples from 262 families, all of which have at least three alcoholic individuals. The families are participating in a national study called the Collaborative Study of the Genetics of Alcoholism (COGA). COGA investigators report in the January issue of the American Journal of Human Genetics on the variation in a taste receptor gene on chromosome 7 called TAS2R16.
"In earlier work, we had identified chromosome 7 as a region where there was likely to be a gene influencing alcoholism risk," says principal investigator Alison M. Goate, D. Phil., the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry at Washington University. "There's a cluster of bitter-taste receptor genes on that chromosome, and there have been several papers suggesting drinking behaviors might be influenced by variations within taste receptors. So we decided to look closely at these taste receptor genes."

Because taste receptors tend to vary a lot in the general population, Goate and colleagues had the opportunity to look at a large number of differences in genetic sequences and determine whether certain sequences might influence risk. In this study, they concentrated on TAS2R16, which helps regulate the response to bitter tastes.

They found a single base variation in the TAS2R16 receptor gene that seemed to put people at an increased risk for alcoholism. In cell culture experiments, Goate found that the variant receptor produced by this gene was less responsive to bitter compounds.

"The more common variant is more sensitive to bitter tastes, and people with that variant had a lower risk of being alcohol dependent," Goate says.

Goate hopes to replicate these findings in human taste tests, to verify that individuals with this variant also tend to be less sensitive to bitter tastes as suggested by the cell culture experiments.

As part of this investigation, Goate's team took advantage of available genome sequence databases to speed work in identifying and studying genes on chromosome 7. She says data from the Human Genome Project allowed the investigators to more quickly recognize individual variations in genes, called polymorphisms, that can influence how a gene product or protein functions.

As part of this study, Goate's team sequenced the TAS2R16 receptor gene in a number of individuals, but they didn't identify genetic variants they hadn't found already in the public databases.

The variant that increases risk of alcohol dependence was common in African Americans -- where about 45 percent of those studied carried this variation in the TAS2R16 receptor gene -- but rare in Caucasians -- where only 0.6 percent had this variation. Although the increased incidence of the variant means a larger percentage of African Americans are at risk because of this genetic factor, the variant in the TAS2R16 receptor also significantly increased risk in those Caucasians who carried the genetic variation.

The fact that this particular genetic variation is more common in African Americans does not necessarily mean African Americans will have a higher incidence of alcoholism. The difference in the TAS2R16 gene is only one of several genetic and environmental factors involved in risk for alcoholism, according to Goate.

"I don't think our result has any implications for the levels of alcoholism within different populations," Goate says. "We know that this polymorphism is more common in African Americans than in Caucasians, but the frequency of alcoholism still can be similar between the two groups because many genes and environmental factors influence risk."

Where your brain wires itself to like

Wed, 04 Jan 2006 05:00:00 PST

( from http://www.rxpgnews.com ) Now, John O'Doherty and his colleagues have traced where in the reward-processing regions of the brain such associations are developed. They described their findings in an article in the January 5, 2006, issue of Neuron. More broadly than offering insights into food preference, they said, their findings aid understanding of the fundamental neural machinery by which the brain establishes all preference behavior.

In their experiments with human volunteers, they first determined the subjects' rank-order preference of four juices--blackcurrant, melon, grapefruit, and carrot--and a tasteless, odorless control solution.

They then scanned the subjects' brains using functional magnetic resonance imaging (fMRI) as they established a Pavlovian conditioning association in the subjects. Such conditioning is the same type that Pavlov used to condition dogs to associate an otherwise irrelevant stimulus such as a bell with food. However, in this case, the researchers conditioned the subjects to associate each juice with an arbitrary visual stimulus--a geometric shape flashed on a screen.

In these experiments, the subjects were not told that the appearance of a specific shape would be associated with a subsequent squirt of the corresponding juice into their mouths. Rather, their instruction was to indicate with a button-press on which side of the screen the shape appeared.

As the subjects performed the task--becoming unconsciously conditioned to associate the shapes with the juices--the researchers used fMRI to search for tell-tale activity in brain regions known to be associated with reward and reward-related learning. The widely used fMRI technique uses harmless magnetic fields and radio waves to detect enhanced blood flow in brain regions, which reflects greater neural activity.

The researchers measured how effectively the subjects became conditioned to anticipate the juice squirts by measuring the dilation of their pupils after the stimuli and before the juice.

In analyzing the brain scans, the researchers detected significant responses reflecting learning of behavioral preferences in a region called the ventral midbrain, as well as an area of the ventral striatum. In the former region, the researchers found that the response increased with increasing preference for the juice. And in the latter area, the researchers found a bivalent response, with the highest responses for the most and least preferred juices.

It has long been known that associating brand items with other rewarding or appetitive stimuli, through the process of classical conditioning, makes it possible to modulate subjects' preferences, wrote the researchers. This process may account in large part for the efficacy and power of advertising.

The principal implication of the present study is that it provides an account of how predictive representations, learned through classical conditioning, come to elicit activity in the human brain that relate directly to subsequent behavioral preference. We suggest that such representations play an important role in the guidance of action based upon future reward, a form of elementary behavioral decision making.

A spoonful of sugar makes some kids feel good

Thu, 15 Dec 2005 05:00:00 PST

( from http://www.rxpgnews.com ) Now researchers at the Monell Chemical Senses Center report in the current issue of the journal Pain that the analgesic efficacy of sweet taste is influenced both by how much a child likes sweet taste and by the child's weight status.

Some children like sweets not just because they taste good, but also because sweets make them feel good, explains senior author Julie Mennella, Ph.D. This study further reveals that for children, sweetness' effectiveness as an analgesic is related to liking for sweet taste and also to weight status.

In the study, sucrose preferences were determined for 198 children, ranging in age from 5 to 10 years, and their mothers. Children as a group preferred higher levels of sweetness than the adults, selecting a favorite sweetness concentration equivalent to adding 11 teaspoons of sugar to an 8-ounce glass of water. For comparison, an 8-ounce serving of soda contains approximately 6 teaspoons of sugar.

There were individual differences across both age groups, with approximately half of the children and one quarter of mothers preferring sucrose concentrations of 24 percent (14 teaspoons per 8-ounce water) or greater.

To evaluate response to pain, the researchers used a classical model known as the cold pressor test, measuring how long subjects were able to keep their hands in a cold water bath maintained at 50 degrees F (10 C). The cold pressor test was repeated twice, once with the subject holding a 24 percent sucrose solution in the mouth and again with water in the mouth.

In normal weight children, palliative properties of the sweet sucrose taste were related to the children's sweet preferences: sucrose reduced the experience of pain in children with higher sweet taste preferences, but not in children who preferred lower concentrations of sweetness.

However, when the child's weight status was taken into account, sucrose's effectiveness as an analgesic was blunted in overweight and at-risk-for-overweight children who preferred higher levels of sweetness.

Mennella comments, This intriguing finding may reflect differences in brain chemistry systems. Additional studies clearly are needed to evaluate how dietary habits and individual differences contribute to preference for sweet taste in children and its physiological consequences.

Unlike for children, sweet taste was not an effective analgesic for mothers, regardless of their preferred sweetness level.

Even women who preferred high levels of sweetness similar to that selected by the majority of children did not evidence an analgesic response to sucrose. Thus, the lack of an analgesic response to sucrose during adulthood apparently is not due to the lowered sucrose preference observed in adults overall, states lead author Yanina Pepino, Ph.D.

Children and adults differ with regard to a wide variety of physiological and endocrine differences, and future studies should identify variables that promote or impede the ability of sweet taste to act as an analgesic in both children and adults.

Salty taste preference linked to birth weight

Wed, 07 Dec 2005 05:00:00 PST

( from http://www.rxpgnews.com ) In a paper published in the European Journal of Clinical Nutrition, the Monell researchers report that individual differences in salty taste acceptance by two-month old infants are inversely related to birth weight: lighter birth weight infants show greater acceptance of salt-water solutions than do babies who were heavier at birth.

According to lead author Leslie Stein, Ph.D., The early appearance of this relationship suggests that developmental events occurring in utero may have a lasting influence on an individual's preference for salty taste.

A similar relationship was found in a subset of the same children at preschool age, suggesting that the relationship between salty taste preference and birth weight persists at least through early childhood, a critical time for the formation of flavor and food preferences.

By studying individual differences in liking for salty taste, scientists hope to obtain needed insights into the underlying factors driving salt preference and intake. Such information could potentially be used in programs designed to reduce salt intake, which is believed by many to contribute to the development and maintenance of high blood pressure.

Although salty taste is intrinsically appealing to humans, the basic mechanisms underlying detection and acceptance of salty taste are not well understood. According to Monell Director Gary Beauchamp, Ph.D., a co-author on the study, The development of practical and successful methods to reduce salt intake likely will not be possible without a more thorough understanding of exactly how humans detect salty taste and the factors that modify salty taste acceptance.

In the study, 80 healthy babies weighing at least 5.5 lb. (2.5 kg) at birth were given separate bottles containing plain water and salt water. When the amount of salt water the babies drank was compared to the amount of plain water, preference for the salt water was greater in lower-birth weight babies, while higher birth weight babies tended to reject the salty water.

When salty taste acceptance was assessed in 38 of the same children at preschool age (3-4 years), measures of salty taste acceptance were once again related to birth weight, with increased liking and preference for salty foods evident in lower birth weight children.

Stein, a biopsychologist, notes, Because similar relationships were not found for sweet foods, the data suggest that there is a specific and enduring relationship between birth weight and salty taste acceptance. Now additional studies are needed to determine whether birth weight predicts salt preference and, even more importantly, salt intake, in older children and adults.

A working 'aftertaste' hypothesis: certain tastants block the natural taste 'off-switch'

Tue, 30 Aug 2005 19:18:00 PST

( from http://www.rxpgnews.com ) It's no secret that George Bush the Elder doesn't like broccoli. That he's not alone is no surprise. But the range of foods that many people won't eat because they are sensitive to "bitter" taste, or, in the case of non-sugar sweeteners, an "unacceptable aftertaste," is longer than you might think. These include spinach, lettuce and for some, even citrus fruits and juices.

"This is not just an esthetic or parenting issue, but a major dietary and economic issue," according to Michael Naim, a professor at the Hebrew University of Jerusalem. Naim pointed out that the food industry and individual cooks use such "tricks as masking the bitter taste of healthy greens with salad dressing or sugar, or in the case of other foods, just taking out the offending taste. From the viewpoint of nutrition and health promotion, including removal of antioxidants, these are undesirable stopgap solutions."

Responding to popular demands for lower-calorie foods, scientists together with the food industry over the past few decades have developed numerous sugar substitutes, but most share a common failing: bad aftertaste. "Unfortunately for the industry and we consumers," Naim said, "sucrose is regarded by humans as the optimal sweetener. In contrast to all the artificial sweeteners it has a pure sweet taste, no aftertaste and no add-on attributes other than sweetness."

A working 'aftertaste' hypothesis: certain tastants block the natural taste 'off-switch'

Despite the obvious need for improved artificial sweeteners, progress in finding acceptable sugar substitutes is slow, and uncovering even a hint of the physiology of "aftertaste" has been even slower. But on the basis of recent experiments, Naim's team has developed a working hypothesis that certain bitter and artificial sweet tastants somehow enter the taste-bud cells where they inhibit the natural termination of the taste-receptor signal resulting in what we call aftertaste.

The paper describing their work, "Inhibition of signal termination-kinases by membrane-permeant bitter and sweet tastants: potential role in taste signal termination," appears in the August issue of the American Journal of Physiology-Cell Physiology, published by the American Physiological Society. Research is by Meirav Zubare-Samuelov, Merav E. Shaul, Irena Peri, Alexander Aliluiko, Oren Tirosh and Michael Naim at the Hebrew University of Jerusalem, Israel.

In their experiments, Naim's team found that oral stimulation of rats by certain bitter and artificial sweet taste molecules (or artificial sweeteners), are able to enter taste bud cells. Furthermore, they interfere with the natural shutoff switch in receptors when tested in isolated form in the test tube. Naim's team hypothesized that "by inhibiting the phosphorylation of the taste sensors, the receptors continue to be active, and so we continue to taste what is often an unwelcome sensation to begin with," Naim said. "Of course there may be more than one mechanism at work and theoretically there are other possible approaches to this complex phenomenon," he concedes, "but so far this hypothesis has held up to experimentation."

First breakthrough: identification of sweet and bitter receptors

In recent years, researchers have identified receptors for sweet and bitter tastes. These receptors belong to the family of G protein coupled receptors (GPCRs) and are found on the plasma membrane of taste cells. In general, stimulation of this type of receptor leads to intracellular formation of such second messengers as IP3, cAMP, cGMP as well as activation of some ionic channels.

"Termination of this signaling in most cases is initiated by receptor phosphorylation, a kind of common physiological 'on/off switch,'" Naim explained. In many cases, the activity of GPCRs is terminated due to phosphorylation by G protein coupled receptor kinases (GRKs) located in the cytosol (cell fluid) or in the cytosolic side of the plasma membrane. Inhibition of this phosphorylation delays signal termination in vision and some other systems.

GRKs found in taste cells, switch-off inhibited by nonsugar sweeteners, bitter tastants

"In experiments reported in this paper, we showed that GRK5 and perhaps GRK2 and GRK6 are present in taste-bud cells," Naim reported. "Furthermore, we show that the phosphorylation of rhodopsin, which we used as a model for GPCR, by GRK5, GRK2 was inhibited in vitro by a variety of non-sugar sweeteners and bitter tastants."

The tastants included: (artificial sweeteners) saccharin, NHD, cyclamate, D-tryptophan and acesulfame K, and (in the bitter spectrum) cyclo(Leu-Trp), caffeine, quinine, L-tryptophan, limonin and naringin. The phosphoryalization activity of protein kinase A (PKA), another receptor-related kinase, was also inhibited by these tastants.

On the basis of these findings, Naim's group "hypothesized that some non-sugar sweeteners and bitter tastants, in addition to stimulating taste GPCRs on the extracellular surface, permeate the cytosolic side to inhibit GRK (and perhaps other kinases), thus delaying receptor phosphorylation and signal termination, and therefore may extend the taste response."

Next steps and other theoretical considerations

Though the results to date seem quite positive, Naim warned that much remains to be proven.

# According to the paper: "Additional studies using the newly discovered taste GPCRs are needed to show their interaction with GRKs and possibly with other kinases, such as in intact cells in vivo, before anything can be unequivocally stated."

# Furthermore, the "novelty of the proposed mechanism of signal termination may lie in the fact that the ligands themselves not only interact extracellularly with GPCRs to initiate the transduction chain, but may concomitantly interact intracellularly with downstream shutoff components to affect signal termination."

# Also, the fact "that tastants inhibit PKA and not just GRKs suggests that they inhibit other kinases as well. Because these tastants are components of our daily diets and may access other tissues along the gastrointestinal tract, these results may have implications for cellular signaling in tissues other than those involved in taste."

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