(Image caption: Making “scents” of new cells in the brain’s odor-processing area. Adult-born cells travel through the thin rostral migratory stream before settling into the olfactory bulb, the large structure in the upper right of the image. Courtesy of the Belluscio Lab, NINDS)

Scientists sniff out unexpected role for stem cells in the brain

For decades, scientists thought that neurons in the brain were born only during the early development period and could not be replenished. More recently, however, they discovered cells with the ability to divide and turn into new neurons in specific brain regions. The function of these neuroprogenitor cells remains an intense area of research. Scientists at the National Institutes of Health (NIH) report that newly formed brain cells in the mouse olfactory system — the area that processes smells — play a critical role in maintaining proper connections. The results were published in the October 8 issue of the Journal of Neuroscience. 

“This is a surprising new role for brain stem cells and changes the way we view them,” said Leonardo Belluscio, Ph.D., a scientist at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and lead author of the study.

The olfactory bulb is located in the front of the brain and receives information directly from the nose about odors in the environment. Neurons in the olfactory bulb sort that information and relay the signals to the rest of the brain, at which point we become aware of the smells we are experiencing. Olfactory loss is often an early symptom in a variety of neurological disorders, including Alzheimer’s and Parkinson’s diseases.

In a process known as neurogenesis, adult-born neuroprogenitor cells are generated in the subventricular zone deep in the brain and migrate to the olfactory bulb where they assume their final positions. Once in place, they form connections with existing cells and are incorporated into the circuitry.

Dr. Belluscio, who studies the olfactory system, teamed up with Heather Cameron, Ph.D., a neurogenesis researcher at the NIH’s National Institute of Mental Health, to better understand how the continuous addition of new neurons influences the circuit organization of the olfactory bulb. Using two types of specially engineered mice, they were able to specifically target and eliminate the stem cells that give rise to these new neurons in adults, while leaving other olfactory bulb cells intact. This level of specificity had not been achieved previously.    

In the first set of mouse experiments, Dr. Belluscio’s team first disrupted the organization of olfactory bulb circuits by temporarily plugging a nostril in the animals, to block olfactory sensory information from entering the brain. His lab previously showed that this form of sensory deprivation causes certain projections within the olfactory bulb to dramatically spread out and lose the precise pattern of connections that show under normal conditions. These studies also showed that this widespread disrupted circuitry could re-organize itself and restore its original precision once the sensory deprivation was reversed.

However, in the current study, Dr. Belluscio’s lab reveals that once the nose is unblocked, if new neurons are prevented from forming and entering the olfactory bulb, the circuits remain in disarray. “We found that without the introduction of the new neurons, the system could not recover from its disrupted state,” said Dr. Belluscio.

To further explore this idea, his team also eliminated the formation of adult-born neurons in mice that did not experience sensory deprivation. They found that the olfactory bulb organization began to break down, resembling the pattern seen in animals blocked from receiving sensory information from the nose. And they observed a relationship between the extent of stem cell loss and amount of circuitry disruption, indicating that a greater loss of stem cells led to a larger degree of disorganization in the olfactory bulb.

According to Dr. Belluscio, it is generally assumed that the circuits of the adult brain are quite stable and that introducing new neurons alters the existing circuitry, causing it to re-organize. “However, in this case, the circuitry appears to be inherently unstable requiring a constant supply of new neurons not only to recover its organization following disruption but also to maintain or stabilize its mature structure. It’s actually quite amazing that despite the continuous replacement of cells within this olfactory bulb circuit, under normal circumstances its organization does not change,” he said.

Dr. Belluscio and his colleagues speculate that new neurons in the olfactory bulb may be important to maintain or accommodate the activity-dependent changes in the system, which could help animals adapt to a constantly varying environment.

“It’s very exciting to find that new neurons affect the precise connections between neurons in the olfactory bulb. Because new neurons throughout the brain share many features, it seems likely that neurogenesis in other regions, such as the hippocampus, which is involved in memory, also produce similar changes in connectivity,” said Dr. Cameron.

The underlying basis of the connection between neurological disease and changes in the olfactory system is also unknown but may come from a better understanding of how the sense of smell works. “This is an exciting area of science,” said Dr. Belluscio, “I believe the olfactory system is very sensitive to changes in neural activity and given its connection to other brain regions, it could lend insight into the relationship between olfactory loss and many brain disorders.”

(Image caption: On these images, the cerebral activation detected by ultrasound imaging is shown in red. During odor presentation, specific areas are activated in the olfactory bulb but not in the piriform cortex. Credit: © Mickael Tanter / Hirac Gurden)

Ultrasound tracks odor representation in the brain

A new ultrasound imaging technique has provided the first ever in vivo visualization of activity in the piriform cortex of rats during odor perception. This deep-seated brain structure plays an important role in olfaction, and was inaccessible to functional imaging until now. This work also sheds new light on the still poorly known functioning of the olfactory system, and notably how information is processed in the brain. This study is the result of a collaboration between the team led by Mickael Tanter at the Institut Langevin (CNRS/INSERM/ESPCI ParisTech/UPMC/Université Paris Diderot) and that led by Hirac Gurden in the Laboratoire Imagerie et Modélisation en Neurobiologie et Cancérologie (CNRS/Université Paris-Sud/Université Paris Diderot). Their findings are published in NeuroImage.

How can the perception of the senses help represent the external environment? How, for example, does the brain process food-or perfume-related olfactory data? Although the organization of the olfactory system is well known - it is similar in organisms ranging from insects to mammals - its functioning remains unclear. To answer these questions, the scientists focused on the two brain structures that act as major olfactory relays: the olfactory bulb and the piriform cortex. In the rat, the olfactory bulb is located between the eyes, just behind the nasal bone. The piriform cortex, meanwhile, is deep-seated in the brain of rodents, which made it impossible to obtain any functional images in a living animal until now.

Yet the neurofunctional ultrasound imaging technique developed by Mickael Tanter’s team, called fUS(functional Ultrasound), allows the monitoring of neuronal activity in the piriform cortex. It is based on the transmission of ultrasonic plane waves into the brain tissue. After data processing, the echoes returned by the structures crossed by these waves can provide images with unequalled spatial and temporal resolution: 80 micrometers and a few tens of milliseconds. The contrast on these images is due to variations in the brain’s blood flow. Indeed, the activity of nerve cells requires an input of energy: it is therefore coupled to an influx of blood into the zone concerned. By recording volume variations in the blood vessels irrigating the different brain structures, it is there fore possible to determine the location of activated neurons.

Several imaging techniques, such as MRI, are already based on the link between blood volume and neuronal activity. But fUS offers advantages in terms of cost, ease of use and resolution. Furthermore, it provides easier access to the deepest structures that are often located several centimeters beneath the cranium.

The recordings performed by Hirac Gurden’s team using this technique made it possible to observe the spatial distribution of activity within the olfactory bulb. When an odor was perceived, blood volume increased in clearly defined areas: each odor thus corresponded to a specific pattern of activated neurons. In addition to these findings, and for the first time, the images revealed an absence of spatial distribution in the piriform cortex. At this level, two different odors triggered the same activation throughout the region.

The cellular mechanisms responsible for the disappearance of a spatial signature are not yet clearly defined, but these findings lead to the formulation of several hypotheses. The piriform cortex could be a structure that serves not only to process olfactory stimuli but rather to integrate and memorize different types of data. By making abstraction of the strict odor-induced patterns, it would be possible to make associations and achieve a global concept. For example, based on the perception of the hundreds of odorant molecules found in coffee, the piriform cortex would be able to recognize a single odor, that of
coffee.

This work opens new perspectives for both imaging and neurobiology. The researchers will now be focusing on the effects of learning on cortical activity in order to elucidate its role and the specificities of the olfactory system.

(Image caption: A window of plasticity. Native neurons (green) that express the odorant receptor MOR28 attach to known glomeruli (above). Neurons expressing engineered MOR28 (red) may attach to other glomeruli. Growing side-by-side, the red neurons could redirect some of the green, but only in the perinatal period. Neuron wiring established early remained stable in adults. Credit: Barnea lab/Brown University)

Early neural wiring for smell persists

A new study in Science reveals that the fundamental wiring of the olfactory system in mice sets up shortly after birth and then remains stable but adaptable. The research highlights how important early development can be throughout life and provides insights that may be important in devising regenerative medical therapies in the nervous system.

To accommodate a lifetime of scents and aromas, mammals have hundreds of genes that each produce a different odorant receptor. The complex and diverse olfactory system they build remains adaptable, but a new study in the journal Science shows that the system’s flexibility, or plasticity, has its limits. Working in mice, Brown University scientists found that the fundamental neural wiring map between the nose and the brain becomes established in a critical period of early development and then regenerates the same map thereafter.

The findings not only reveal a key moment with lifelong consequences in the development of a vital sensory system, but also may provide a “heads up” for bioengineers and doctors looking to develop regenerative therapies for the central nervous system. As flexible as the brain is, it also has mechanisms — at least in the olfactory system — to ensure that the connections established early will be maintained for life.

“Our experiments enabled us to reveal that the system has some ‘memory’,” said Gilad Barnea, the Robert and Nancy Carney Assistant Professor of Neuroscience and corresponding author of the study.

Tracking connections

Lead author Lulu Tsai, now a postdoctoral fellow at Drexel University, conducted the experiments under Barnea’s supervision while she was a graduate student at Brown. Tsai and Barnea are the paper’s only authors.

“Lulu really sweated for this,” Barnea said. “These experiments were very complicated.”

Tsai and Barnea sought to track the development of sensory neurons that express an odorant receptor, MOR28, through space and time in the mouse olfactory system. They did so by engineering a version of the receptor that could be expressed or suppressed at key developmental times. Neurons that express the engineered version of MOR28 would glow red under the microscope. In addition, the researchers tweaked the native version of the receptor gene such that neurons that express it would glow green.

In a typical mammalian olfactory system, neurons expressing a receptor gene like MOR28 will be found randomly sprinkled around the lining of the nose, but their long, wiry axons will all connect to just two symmetrical pairs of structures called glomeruli within the brain’s olfactory bulb. The glomeruli relay odor signals to the rest of the brain.

Barnea and Tsai’s mice developed similarly, with most native MOR28-expressing neurons connecting their axons into the typical glomeruli during early development. But when the researchers let the engineered MOR28 become expressed, those connected into other nearby glomeruli. Significantly, native MOR28 axons sometimes ended up becoming rerouted to these alternate glomeruli with their engineered brethren. Under the microscope, green mixed with red.

It’s a novel finding that some engineered MOR28-expressing neurons could reroute native MOR28-expressing neurons to join them outside the standard four MOR28 glomeruli. It suggests that olfactory neurons influence each other during early development as they find their way to glomeruli and don’t, as current neurodevelopmental models suggest, do so autonomously.

Timing is everything

But the main finding of a critical period where wiring becomes locked in came about as Tsai controlled the timing of engineered MOR28 receptor expression. She induced that on the day some mice were born, a week later in other mice, and two weeks later in still others. In mice where engineered MOR28 expression was allowed at birth, one in nine mice showed rerouting of native MOR28 axons to glomeruli with engineered MOR28. A week out only one in 17 mice showed any rerouting. After two weeks it never happened.

“We conclude that there is a critical period for the formation of rerouted-MOR28 glomeruli that ends at birth or shortly thereafter,” Tsai and Barnea wrote in Science.

The researchers also looked at this in other ways. In one experiment, they found that they didn’t need to maintain expression of the engineered MOR28 for the rerouted connections to persist into adulthood. Once established, they remained.

They also tested whether the rerouting seen in developing mice could occur in adults. They let native MOR28-expressing axons grow alone, and then wiped them out. Then they let native and engineered MOR28-expressing neurons regrow fresh connections to the olfactory bulb together when the mice were adults. They never saw rerouting in the adult mice as connections regrew, suggesting that the ability to reroute is lost in adulthood.

In yet another experiment, they found that if they let rerouted glomeruli become established and then wiped out olfactory neurons, the regrowing connections would return to the rerouted glomeruli even when the engineered receptor was no longer expressed. So although adults can’t create new rerouted glomeruli, they will restore existing ones.

All of the experiments together showed that the fundamental wiring diagram of the olfactory system is laid out and implemented early in life. Whatever pattern is established then stays there for life.

These observations suggest that the course of early development has lifelong consequences, Barnea said, providing insight into understanding of neurodevelopmental and psychiatric disorders.

These observations may also have implications for regenerative medicine, Barnea said. Once neural circuits are established, it may be difficult to induce subsequent fundamental alterations to them. On the other hand, learning more about the differences between early development and the adult system may help to devise better regenerative strategies.

“It is clear that there is much more for us to learn about the development of neural circuits,” he said.

Memory Accuracy and Strength Can Be Manipulated During Sleep

The sense of smell might seem intuitive, almost something you take for granted. But researchers from NYU Langone Medical Center have found that memory of specific odors depends on the ability of the brain to learn, process and recall accurately and effectively during slow-wave sleep — a deep sleep characterized by slow brain waves.

The sense of smell is one of the first things to fail in neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia. Indeed, down the road, if more can be learned from better understanding of how the brain processes odors, researchers believe it could lead to novel therapies that target specific neurons in the brain, perhaps enhancing memory consolidation and memory accuracy.

Reporting in the Journal of Neuroscience online April 9, researchers in the lab of Donald A. Wilson, PhD, a professor in the departments of Child and Adolescent Psychiatry and Neuroscience and Physiology at NYU Langone, and a research scientist at the NYU-affiliated Nathan Kline Institute for Psychiatric Research, showed in experiments with rats that odor memory was strengthened when odors sensed the previous day were replayed during sleep. Memories deepened more when odor reinforcement occurred during sleep than when rats were awake.

When the memory of a specific odor learned when the rats were awake was replayed during slow-wave sleep, they achieved a stronger memory for that odor the next day, compared to rats that received no replay, or only received replay when they were awake.

However, when the research team exposed the rats to replay during sleep of an odor pattern that they had not previously learned, the rats had false memories to many different odors. When the research team pharmacologically prevented neurons from communicating to each other during slow-wave sleep, the accuracy of memory of the odor was also impaired.

The rats were initially trained to recognize odors through conditioning. Using electrodes in the olfactory bulb, a part of the brain responsible for perceiving smells, the researchers stimulated different smell perceptions, according to precise patterns of electrical stimulation. Then, by replaying the patterns electrically, they were able to test the effects of slow-wave sleep manipulation.

Replay of learned electrical odors during slow-wave sleep enhanced the memory for those odors. When the learned smells were replayed while the rats were awake, the strength of the memory decreased. Finally, when a false pattern that the rat never learned was incorporated, the rats could not discriminate the smell accurately from the learned odor.

“Our findings confirm the importance of brain activity during sleep for both memory strength and accuracy,” says Dr. Wilson, the study’s senior author. “What we think is happening is that during slow-wave sleep, neurons in the brain communicate with each other, and in doing so, strengthen their connections, permitting storage of specific information.”

Dr. Wilson says these findings are the first to demonstrate that memory accuracy, not just memory strength, is altered during short-wave sleep. In future research, Dr. Wilson and his team hope to examine how sleep disorders affect memory and perception.

Research reveals first glimpse of a brain circuit that helps experience to shape perception

Odors have a way of connecting us with moments buried deep in our past. Maybe it is a whiff of your grandmother’s perfume that transports you back decades. With that single breath, you are suddenly in her living room, listening as the adults banter about politics. The experiences that we accumulate throughout life build expectations that are associated with different scents. These expectations are known to influence how the brain uses and stores sensory information. But researchers have long wondered how the process works in reverse: how do our memories shape the way sensory information is collected?

In work published today in Nature Neuroscience, scientists from Cold Spring Harbor Laboratory (CSHL) demonstrate for the first time a way to observe this process in awake animals. The team, led by Assistant Professor Stephen Shea, was able to measure the activity of a group of inhibitory neurons that links the odor-sensing area of the brain with brain areas responsible for thought and cognition. This connection provides feedback so that memories and experiences can alter the way smells are interpreted. 

The inhibitory neurons that forget the link are known as granule cells. They are found in the core of the olfactory bulb, the area of the mouse brain responsible for receiving odor information from the nose. Granule cells in the olfactory bulb receive inputs from areas deep within the brain involved in memory formation and cognition. Despite their importance, it has been almost impossible to collect information about how granule cells function. They are extremely small and, in the past, scientists have only been able to measure their activity in anesthetized animals. But the animal must be awake and conscious in order to for experiences to alter sensory interpretation. Shea worked with lead authors on the study, Brittany Cazakoff, graduate student in CSHL’s Watson School of Biological Sciences, and Billy Lau, Ph.D., a postdoctoral fellow. They engineered a system to observe granule cells for the first time in awake animals. 

Granule cells relay the information they receive from neurons involved in memory and cognition back to the olfactory bulb. There, the granule cells inhibit the neurons that receive sensory inputs. In this way, “the granule cells provide a way for the brain to ‘talk’ to the sensory information as it comes in,” explains Shea. “You can think of these cells as conduits which allow experiences to shape incoming data.”

Why might an animal want to inhibit or block out specific parts of a stimulus, like an odor? Every scent is made up of hundreds of different chemicals, and “granule cells might help animals to emphasize the important components of complex mixtures,” says Shea. For example, an animal might have learned through experience to associate a particular scent, such as a predator’s urine, with danger. But each encounter with the smell is likely to be different. Maybe it is mixed with the smell of pine on one occasion and seawater on another. Granule cells provide the brain with an opportunity to filter away the less important odors and to focus sensory neurons only on the salient part of the stimulus. 

Now that it is possible to measure the activity of granule cells in awake animals, Shea and his team are eager to look at how sensory information changes when the expectations and memories associated with an odor change. “The interplay between a stimulus and our expectations is truly the merger of ourselves with the world. It exciting to see just how the brain mediates that interaction,” says Shea.

Odor receptors discovered in lungs

Your nose is not the only organ in your body that can sense cigarette smoke wafting through the air. Scientists at Washington University in St. Louis and the University of Iowa have shown that your lungs have odor receptors as well.

Unlike the receptors in your nose, which are located in the membranes of nerve cells, the ones in your lungs are in the membranes of neuroendocrine cells. Instead of sending nerve impulses to your brain that allow it to “perceive” the acrid smell of a burning cigarette somewhere in the vicinity, they trigger the flask-shaped neuroendocrine cells to dump hormones that make your airways constrict.

The newly discovered class of cells expressing olfactory receptors in human airways, called pulmonary neuroendocrine cells, or PNECs, were found by a team led by Yehuda Ben-Shahar, PhD, assistant professor of biology, in Arts & Sciences, and of medicine at Washington University in St. Louis, and including colleagues Steven L. Brody, MD, and Michael J. Holtzman, MD, of the Washington University School of Medicine, and Michel J. Welsh, MD, of the University of Iowa Carver College of Medicine.

“We forget,” said Ben-Shahar, “that our body plan is a tube within a tube, so our lungs and our gut are open to the external environment. Although they’re inside us, they’re actually part of our external layer. So they constantly suffer environmental insults,” he said, “and it makes sense that we evolved mechanisms to protect ourselves.”

In other words, the PNECs, described in the March issue of the American Journal of Respiratory Cell and Molecular Biology, are sentinels, guards whose job it is to exclude irritating or toxic chemicals.

The cells might be responsible for the chemical hypersensitivity that characterizes respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. Patients with these diseases are told to avoid traffic fumes, pungent odors, perfumes and similar irritants, which can trigger airway constriction and breathing difficulties.

The odor receptors on the cells might be a therapeutic target, Ben-Shahar suggests. By blocking them, it might be possible to prevent some attacks, allowing people to cut down on the use of steroids or bronchodilators.

Every breath you take
When a mammal inhales, volatile chemicals flow over two patches of specialized epithelial tissue high up in the nasal passages. These patches are rich in nerve cells with specialized odorant-binding molecules embedded in their membranes.

If a chemical docks on one of these receptors, the neuron fires, sending impulses along the olfactory nerve to the olfactory bulb in the brain, where the signal is integrated with those from hundreds of other similar cells to conjure the scent of old leather or dried lavender.

Aware that airway diseases are characterized by hypersensitivity to volatile stimuli, Ben-Shahar and his colleagues realized that the lungs, like the nose, must have some means of detecting inhaled chemicals.

Earlier, a team at the University of Iowa, where Ben-Shahar was a postdoctoral research associate, had searched for genes expressed by patches of tissue from lung transplant donors. They found a group of ciliated cells that express bitter taste receptors. When offending substances were detected, the cilia beat more strongly to sweep them out of the airway. This result was featured on the cover of the Aug. 28, 2009, issue of Science.

But since people are sensitive to many inhaled substances, not just bitter ones, Ben-Shahar decided to look again. This time he found that these tissues also express odor receptors, not on ciliated cells but instead on neuroendocrine cells, flask-shaped cells that dump serotonin and various neuropeptides when they are stimulated.

This made sense. “When people with airway disease have pathological responses to odors, they’re usually pretty fast and violent,” said Ben-Shahar. “Patients suddenly shut down and can’t breathe, and these cells may explain why.”

Ben-Shahar stresses the differences between chemosensation in the nose and in the lung. The cells in the nose are neurons, he points out, each with a narrowly tuned receptor, and their signals must be woven together in the brain to interpret our odor environment.

The cells in the airways are secretory, not neuronal, cells, and they may carry more than one receptor, so they are broadly tuned. Instead of sending nerve impulses to the brain, they flood local nerves and muscles with serotonin and neuropeptides. “They are possibly designed,” he said, “to elicit a rapid, physiological response if you inhale something that is bad for you.”

The different mechanisms explain why cognition plays a much stronger role in taste and smell than in coughing in response to an irritant. It is possible, for example, to develop a taste for beer. But nobody learns not to cough; the response is rapid and largely automatic.

The scientists suspect these pulmonary neuroscretory cells contribute to the hypersensitivity of patients with COPD to airborne irritants. COPD is a group of diseases, including emphysema, that is characterized by coughing, wheezing, shortness of breath and chest tightness.

When the scientists looked at the airway tissues from patients with COPD, they discovered that they had more of these neurosecretory cells than airway tissues from healthy donors.

Of mice and men
As a geneticist, Ben-Shahar would like to go farther, knocking out genes to make sure that the derangement of neurosecretory cells isn’t just correlated with airway diseases but instead suffices to produce it.

But there is a problem. “For example, a liver from a mouse and a liver from a human are pretty similar, they express the same types of cells. But the lungs from different mammalian species are often very different; you can see it at a glance,” Ben-Shahar said.

“Clearly, primates have evolved distinct cell lineages and signaling systems for respiratory-specific functions.”

This makes it challenging to unravel the biomolecular mechanisms of respiratory diseases. 

Still, he is hopeful that the PNEC pathways will provide targets for drugs that would better control asthma, COPD and other respiratory diseases. They would be welcome. There has been a steep rise in these diseases in the past few decades, treatment options have been limited, and there are no cures.

Sense of smell: The nose and the brain make quite a team… in disconnection

Alan Carleton’s team from the Neuroscience Department at the University of Geneva (UNIGE) Faculty of Medicine has just shown that the representation of an odor evolves after the first breath, and that an olfactory retentivity persists at the central level. The phenomenon is comparable to what occurs in other sensory systems, such as vision or hearing. These movements undoubtedly enable the identification of new odors in complex environments or participate in the process of odor memorization. This research is the subject of a publication in the latest online edition of the journal PNAS (Proceedings of the National Academy of Sciences of the United States of America).

Rodents can identify odors in a single breath, which is why research on sense of smell in mammals focuses on that first inhalation. Yet we must remember that from a neurological standpoint, sensory representations change during and after the stimuli. To understand the evolution of these mental representations, an international team of researchers led by Professor Alan Carleton at the University of Geneva (UNIGE) Faculty of Medicine conducted the following experiment: by observing the brain of an alert mouse, the neuroscientists recorded the electrical activity emitted by the olfactory bulb of animals inhaling odors.

They were surprised to find that in mitral cells, some representations evolved during the first inhalations, and others persisted and remained stable well after the odor ceased. The cohort subjected to these analyses revealed that the post-odor responses contained an odor retentivity—a specific piece of information about the nature of odor and its concentration.

Will odor memory soon be understood?

Using cerebral imaging, researchers discovered that the majority of sensory activity is visible only during the presentation of odors, which implies that retentivity is essentially internal to the brain. Therefore, odor retentivity would not be dependent upon odorous physicochemical properties. Finally, to artificially induce retentivity, the team photostimulated mitral cells using channelrhodopsin, then recorded the persistent activity maintained at the central level. The strength and persistence of the retentivity were found to be dependent on the duration of the stimulation, both artificial and natural.

In summary, the neuroscientists were able to show that the representation of an odor changes after the first breath, and that an olfactory retentivity persists at the central level, a phenomenon comparable to what occurs in other sensory systems, such as vision and hearing. These movements undoubtedly enable the identification of new odors in complex environments or participate in the process of odor memorization.

(Image: photos.com)

Sugar solution makes tissues see-through

Japanese researchers have developed a new sugar and water-based solution that turns tissues transparent in just three days, without disrupting the shape and chemical nature of the samples. Combined with fluorescence microscopy, this technique enabled them to obtain detailed images of a mouse brain at an unprecedented resolution.

The team from the RIKEN Center for Developmental biology reports their finding today in Nature Neuroscience.

Over the past few years, teams in the USA and Japan have reported a number of techniques to make biological samples transparent, that have enabled researchers to look deep down into biological structures like the brain.

“However, these clearing techniques have limitations because they induce chemical and morphological damage to the sample and require time-consuming procedures,” explains Dr. Takeshi Imai, who led the study.

SeeDB, an aqueous fructose solution that Dr. Imai developed with colleagues Drs. Meng-Tsen Ke and Satoshi Fujimoto, overcomes these limitations.

Using SeeDB, the researchers were able to make mouse embryos and brains transparent in just three days, without damaging the fine structures of the samples, or the fluorescent dyes they had injected in them.

They could then visualize the neuronal circuitry inside a mouse brain, at the whole-brain scale, under a customized fluorescence microscope without making mechanical sections through the brain.

They describe the detailed wiring patterns of commissural fibers connecting the right and left hemispheres of the cerebral cortex, in three dimensions, for the first time. They also report that they were able to visualize in three dimensions the wiring of mitral cells in the olfactory bulb, which is involved the detection of smells, at single-fiber resolution.

“Because SeeDB is inexpensive, quick, easy and safe to use, and requires no special equipment, it will prove useful for a broad range of studies, including the study of neuronal circuits in human samples,” explain the authors.

Cat and Mouse: A Single Gene Matters

When a mouse smells a cat, it instinctively avoids the feline or risks becoming dinner. How? A Northwestern University study involving olfactory receptors, which underlie the sense of smell, provides evidence that a single gene is necessary for the behavior.

A research team led by neurobiologist Thomas Bozza has shown that removing one olfactory receptor from mice can have a profound effect on their behavior. The gene, called TAAR4, encodes a receptor that responds to a chemical that is enriched in the urine of carnivores. While normal mice innately avoid the scent marks of predators, mice lacking the TAAR4 receptor do not.

The study, published April 28 in the journal Nature, reveals something new about our sense of smell: individual genes matter.

Unlike our sense of vision, much less is known about how sensory receptors contribute to the perception of smells. Color vision is generated by the cooperative action of three light-sensitive receptors found in sensory neurons in the eye. People with mutations in even one of these receptors experience color blindness.

“It is easy to understand how each of the three color receptors is important and maintained during evolution,” said Bozza, an author of the paper, “but the olfactory system is much more complex.”

In contrast to the three color receptors, humans have 380 olfactory receptor genes, while mice have more than 1,000. Common smells like the fragrance of coffee and perfumes typically activate many receptors.

“The general consensus in the field is that removing a single olfactory receptor gene would not have a significant effect on odor perception,” said Bozza, an assistant professor of neurobiology in the Weinberg College of Arts and Sciences.

Bozza and his colleagues tested this assumption by genetically removing a specific subset of olfactory receptors called trace amine-associated receptors, or TAARs, in mice. Mice have 15 TAARs. One is expressed in the brain and responds to amine neurotransmitters and common drugs of abuse such as amphetamine. The other 14 are found in the nose and have been coopted to detect odors.

Bozza’s group has shown that the TAARs are extremely sensitive to amines — a class of chemicals that is ubiquitous in biological systems and is enriched in decaying materials and rotting flesh. Mice and humans typically avoid amines since they have a strongly unpleasant, fishy quality.

Bozza’s team, including the paper’s lead authors, postdoctoral fellow Adam Dewan and graduate student Rodrigo Pacifico, generated mice that lack all 14 olfactory TAAR genes. These mice showed no aversion to amines. In a second experiment, the researchers removed only the TAAR4 gene. TAAR4 responds selectively to phenylethylamine (PEA), an amine that is concentrated in carnivore urine. They found that mice lacking TAAR4 fail to avoid PEA, or the smell of predator cat urine, but still avoid other amines.

“It is amazing to see such a selective effect,” Dewan said. “If you remove just one olfactory receptor in mice, you can affect behavior.”

The TAAR genes are found in all mammals studied so far, including humans. “The fact that TAARs are highly conserved means they are likely important for survival,” Bozza said.

One idea is that the TAARs may make animals very sensitive to the smell of amines. Humans may have TAAR genes to avoid rotting foods, which become enriched in amines during the decomposition process. In fact, the TAARs may relay information to a specific part of the brain that elicits innately aversive behavior in animals.

Bozza’s lab has recently shown that neurons in the nose that express the TAARs connect to with a specific region of the olfactory bulb — the part of the brain that first receives olfactory information. This suggests that the TAARs may elicit hardwired responses to amines in mice, and perhaps humans.

“We hope this work will reveal specific brain circuits that underlie instinctive behaviors in mammals,” Bozza said. “Doing so will help us understand how neural circuits contribute to behavior.”