Making sense of scents

For many animals, making sense of the clutter of sensory stimuli is often a matter or literal life or death.

Exactly how animals separate objects of interest, such as food sources or the scent of predators, from background information, however, remains largely unknown. Even the extent to which animals can make such distinctions, and how differences between scents might affect the process were largely a mystery – until now.

A new study, described in an August 3 paper in Nature Neuroscience, a team of researchers led by Venkatesh Murthy, Professor of Molecular and Cellular Biology, showed that while mice can be trained to detect specific odorants embedded in random mixtures, their performance drops steadily with increasing background components. The team included Dan Rokni, Vikrant Kapoor and Vivian Hemmelder, all from Harvard University.

"There is a continuous stream of information constantly arriving at our senses, coming from many different sources," Murthy said. "The classic example would be a cocktail party – though it may be noisy, and there may be many people talking, we are able to focus our attention on one person, while ignoring the background noise.

"Is the same also true for smells?" he continued. "We are bombarded with many smells all jumbled up. Can we pick out one smell "object" – the smell of jasmine, for example, amidst a riot of other smells? Our experience tells us indeed we can, but how do we pick out the ones that we need to pay attention to, and what are the limitations?"

To find answers to those, and other, questions, Murthy and colleagues turned to mice.

After training mice to detect specific scents, researchers presented the animals with a combination of smells – sometimes including the “target” scent, sometimes not. Though previous studies had suggested animals are poor at individual smells, and instead perceived the mixture as a single smell, their findings showed that mice were able to identify when a target scent was present with 85 percent accuracy or better.

"Although the mice do well overall, they perform progressively poorer when the number of background odors increases," Murthy explained.

Understanding why, however, meant first overcoming a problem particular to olfaction.

While the relationship between visual stimuli is relatively easy to understand – differences in color can be easily described as differences in the wavelength of light – no such system exists to describe how two odors relate to each other. Instead, the researchers sought to describe scents according to how they activated neurons in the brain.

Using fluorescent proteins, they created images that show how each of 14 different odors stimulated neurons in the olfactory bulb. What they found, Murthy said, was that the ability of mice to identify a particular smell was markedly diminished if background smells activated the same neurons as the target odor.

"Each odor gives rise to a particular spatial pattern of neural responses," Murthy said. "When the spatial pattern of the background odors overlapped with the target odor, the mice did much more poorly at detecting the target. Therefore, the difficulty of picking out a particular smell among a jumble of other odors, depends on how much the background interferes with your target smell. So, we were able to give a neural explanation for how well you can solve the cocktail party problem.

"This study is interesting because it first shows that smells are not always perceived as one whole object – they can be broken down into their pieces," he added. "This is perhaps not a surprise – there are in fact coffee or wine specialists that can detect faint whiffs of particular elements within the complex mixture of flavors in each coffee or wine. But by doing these studies in mice, we can now get a better understanding of how the brain does this. One can also imagine that understanding how this is done may also allow us to build artificial olfactory systems that can detect specific chemicals in the air that are buried amidst a plethora of other odors."

New research links bad diet to loss of smell

Could stuffing yourself full of high-fat foods cause you to lose your sense of smell?

A new study from Florida State University neuroscientists says so, and it has researchers taking a closer look at how our diets could impact a whole range of human functions that were not traditionally considered when examining the impact of obesity.

"This opens up a lot of possibilities for obesity research," said Florida State University post-doctoral researcher Nicolas Thiebaud, who led the study examining how high-fat foods impacted smell.

Thiebaud led the study in the lab of Biological Science Professor Debra Ann Fadool. Their work is published in the Journal of Neuroscience and shows that a high-fat diet is linked to major structural and functional changes in the olfactory system, which gives us our sense of smell.

It was the first time researchers had been able to demonstrate a solid link between a bad diet and a loss of smell.

The research was conducted over a six-month period where mice were given a high-fat daily diet, while also being taught to associate between a particular odor and a reward (water).

Mice that were fed the high-fat diets were slower to learn the association than the control population. And when researchers introduced a new odor to monitor their adjustment, the mice with the high-fat diets could not rapidly adapt, demonstrating reduced smell capabilities.

"Moreover, when high-fat-reared mice were placed on a diet of control chow during which they returned to normal body weight and blood chemistry, mice still had reduced olfactory capacities," Fadool said. "Mice exposed to high-fat diets only had 50 percent of the neurons that could operate to encode odor signals."

For Thiebaud and his colleagues, the results are opening up a whole new line of research. They will begin looking at whether exercise could slow down a high-fat diet’s impact on smell and whether a high-sugar diet would also yield the same negative results on smell as a high-fat diet.

Funded by the National Institutes of Health (NIH), the study comes at an important time with obesity rates at all-time highs throughout the world. According to the NIH, more than two in three adults in the United States are considered to be overweight or obese. Additionally, about one-third of children and adolescents ages 6 to 19 are considered to be overweight or obese.

(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: Olfactory sensory neurons (green and magenta) located in the olfactory epithelium. Credit: Image courtesy of Limei Ma, Ph.D., Stowers Institute for Medical Research)

Finding the target: how timing is critical in establishing an olfactory wiring map

The human nose expresses nearly 400 odorant receptors, which allow us to distinguish a large number of scents. In mice the number of odor receptors is closer to 1000. Each olfactory neuron displays only a single type of receptor and all neurons with the same receptors are connected to the same spot, a glomerulus, in the brain. This convergence, or wiring pattern, is often described as an olfactory map. The map is important because it serves as a code book for odorants that allows the brain to distinguish between food odors and the scent of a predator, among others.

Unlike photoreceptors in the retina or hair cells in the inner ear, which cannot be replaced once damaged, olfactory neurons have the unique capacity to regenerate throughout the life. More remarkably, the regenerated neurons must dispatch their axons on a path through the nasal epithelium to the brain through a distance a thousand times the length of the cell, where they make the proper connections. If regenerating neurons are mis-wired to different glomeruli, odor perception would be altered.

In the April 11, 2014 issue of Science, Associate Investigator C. Ron Yu, Ph.D. and colleagues at the Stowers Institute of Medical Research identify a developmental window during which olfactory neurons of newborn mice can form a proper wiring map. They show that if incorrect neuronal connections are maintained after this period, renewing cells will also be mis-wired.

Their results also hint at how the olfactory neurons connect to their targets. Although scientists can induce stem cells to become neurons, they know little about how to precisely steer them to make the proper connections. This work suggests additional targeting skills that stem cell-generated neurons need to acquire to repair the brain or spinal cord.

Previously, researchers thought that since olfactory neurons exhibited lifelong regeneration, they likewise retained the ability to re-establish correct connections. “We show that this is not the case,” says Yu. In the report, his team uses a number of transgenic mouse lines to demonstrate that the first week after birth is a critical window of time during which incorrect projections can be restored to normal. “If mis-targeting does not get corrected within this period, cells still regenerate but many get locked onto the wrong tracks.” Yu adds.

Neuronal wiring has intrigued Yu since he was a post-doc in the lab of Richard Axel, M.D., at Columbia University. Back then Yu created a genetically engineered mouse in which he could temporarily muffle the firing of olfactory neurons. He found that inactivating neurons caused them to connect to the wrong glomeruli. After joining the Stowers Institute in 2005, Yu began to wonder whether an incorrectly wired olfactory map could be restored in mice.

In this new work, Yu’s team, led by first author Limei Ma, Ph.D., reports that if the silenced sensory neurons are reactivated within a week of a mouse’s birth, erroneous olfactory neuron connections are restored. Beyond that critical period, however, neurons appeared to lose the capacity to make the right connections and in fact maintained connections to the wrong glomeruli.

“After the first week, we believe that newly generated neurons follow pre-existing tracks to their target,” says Ma, Senior Research Specialist in the Yu lab. A key finding in the report supports this idea. The team provoked a temporary identity crisis in olfactory neurons by broadly mis-expressing an odorant receptor called M71 in cells where it would not normally be displayed. Surprisingly, only the neurons that normally express the M71 receptor targeted the “wrong” glomeruli, not the neurons that express different odorant receptors. 

An interpretation of this experiment is that late-born olfactory neurons expressing a particular receptor recognize and follow a track laid down earlier by neurons expressing the very same receptor—even if the latter expressed that receptor due to experimental manipulation. “These olfactory neurons have identity tags,” says Ma, referring to the receptors. “And they like to follow others displaying the same tag.”

As yet, investigators have not identified the molecular basis for the targeting switch occurring at the end of one-week period. “We don’t know what keeps these late stage cells from re-establishing the right connections,” explains Ma. “Either the cues that guide them disappear or their axons encounter a physical barrier to the target.”

Yu envisions the studies in the olfactory system will provide clues on how a regenerated neuron, either through a natural process in the case of the olfactory neuron, or by stem technology, find their target and make the right connection. “To repair a damaged spinal cord, you will need to ensure that newly generated motor neurons target the right muscle,” says Yu. “The next goal is to identify the molecular cues that enable correct projections to be established.”

(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.

Sniff study suggests humans can distinguish more than 1 trillion scents

The human sense of smell does not get the respect it deserves, new research suggests. In an experiment led by Andreas Keller, of Rockefeller’s Laboratory of Neurogenetics and Behavior, researchers tested volunteers’ ability to distinguish between complex mixtures of scents. Based on the sensitivity of these people’s noses and brains, the team calculated the human sense of smell can detect more than 1 trillion odor mixtures, far more discrete stimuli than previous smell studies have estimated.

The existing generally accepted number is just 10,000, says Leslie Vosshall, Robert Chemers Neustein Professor and head of the laboratory. “Everyone in the field had the general sense that this number was ludicrously small, but Andreas was the first to put the number to a real scientific test,” Vosshall says.

In fact, even 1 trillion may be understating it, says Keller. “The message here is that we have more sensitivity in our sense of smell than for which we give ourselves credit. We just don’t pay attention to it and don’t use it in everyday life,” he says.

The quality of an odor has multiple dimensions, because the odors we encounter in real life are composed of complex mixes of molecules. For instance, the characteristic scent of rose has 275 components, but only a small percentage of those dominate the perceived smell. That makes odor much more difficult to study than vision and hearing, which require us to detect variations in a single dimension. For comparison, researchers estimate the number of colors we can distinguish at between 2.3 and 7.5 million and audible tones at about 340,000.

To overcome this complexity, Keller combined odors and asked volunteers whether they could distinguish between mixtures with some components in common. “Our trick is we use mixtures of odor molecules, and we use the percentage of overlap between two mixtures to measure the sensitivity of a person’s sense of smell,” Keller says. To create his mixtures, Keller drew upon 128 odor molecules responsible for scents such as orange, anise and spearmint. He mixed these in combinations of 10, 20 and 30 with different proportions of components in common. The volunteers received three vials, two of which contained identical mixes, and they were asked to pick out the odd one.

This approach was inspired by previous work at the Weizmann Institute in Israel, in which researchers combined odors at similar intensities to create neutral smelling “olfactory white.” In that experiment and in Keller’s study, the researchers were interested in the perception of odor qualities, such as fishy, floral or musky — not their intensity. But since intensity can interfere with the perceived qualities, both had to account for it.

The results, published this week in Science, show that while individual volunteers’ performance varied greatly, on average they could tell the difference between mixtures containing as much as 51 percent of the same components. Once the mixes shared more than half of their components, fewer volunteers could tell the difference between them. This was true for mixes of 10, 20 and 30 odors.

By analyzing the data, the researchers could calculate the total number of distinguishable mixtures.

“It turns out that the resolution of the olfactory system is not extraordinary – you need to change a fair fraction of the components before the change can be reliably detected by more than 50 percent of the subjects,” says collaborator Marcelo O. Magnasco, head of the Laboratory of Mathematical Physics at Rockefeller. “However, because the number of combinations is quite literally astronomical, even after accounting for this limitation the total number of distinguishable odor combinations is quite large.” The 1 trillion estimate is almost certainly too low, the researchers say, because there are many, many more odor molecules in the real world that can be mixed in many more ways.

Keller theorizes that our ancestors had much more use and appreciation for our sense of smell than we do. Humans’ upright posture lifted our noses far from the ground where most smells originate, and more recently, conveniences such as refrigerators and daily showers, have effectively limited odors in the modern world. “This could explain our attitude that smell is unimportant, compared to hearing and vision,” he says.

Nevertheless, the sense of smell remains closely linked to human behavior, and studying it can tell us a lot about how our brains process complex information. The results of this study are a step toward an elusive quantitative science of odor perception that can help drive further research, Keller says.

Mice can ‘warn’ sons, grandsons of dangers via sperm

Lab mice trained to fear a particular smell can transfer the impulse to their unborn sons and grandsons through a mechanism in their sperm, a study reveals.

The research claims to provide evidence for the concept of animals “inheriting” a memory of their ancestors’ traumas, and responding as if they had lived the events themselves.

It is the latest find in the study of epigenetics, in which environmental factors are said to cause genes to start behaving differently without any change to their underlying DNA encoding.

"Knowing how ancestral experiences influence descendant generations will allow us to understand more about the development of neuropsychiatric disorders that have a transgenerational basis," says study co-author Brian Dias of the Emory University School of Medicine in Atlanta, Georgia.

And it may one day lead to therapies that can soften the memory “inheritance”.

For the study, Dias and co-author Kerry Ressler trained mice, using foot shocks, to fear an odour that resembles cherry blossoms.

Later, they tested the extent to which the animals’ offspring startled when exposed to the same smell. The younger generation had not even been conceived when their fathers underwent the training, and had never smelt the odour before the experiment.

The offspring of trained mice were “able to detect and respond to far less amounts of odour… suggesting they are more sensitive” to it, says Ressler co-author of the study published in the journal Nature Neuroscience.

They did not react the same way to other odours, and compared to the offspring of non-trained mice, their reaction to the cherry blossom whiff was about 200 percent stronger, he says.

The scientists then looked at a gene (M71) that governs the functioning of an odour receptor in the nose that responds specifically to the cherry blossom smell.

Epigenetic marks

The gene, inherited through the sperm of trained mice, had undergone no change to its DNA encoding, the team found.

But the gene did carry epigenetic marks that could alter its behaviour and cause it to be “expressed more” in descendants, says Dias.

This in turn caused a physical change in the brains of the trained mice, their sons and grandsons, who all had a larger glomerulus - a section in the olfactory (smell) unit of the brain.

"This happens because there are more M71 neurons in the nose sending more axons" into the brain, says Dias.

Similar changes in the brain were seen even in offspring conceived with artificial insemination from the sperm of cherry blossom-fearing fathers.

The sons of trained mouse fathers also had the altered gene expression in their sperm.

"Such information transfer would be an efficient way for parents to ‘inform’ their offspring about the importance of specific environmental features that they are likely to encounter in their future environments," says Ressler.

Happening in humans?

Commenting on the findings, British geneticist Marcus Pembrey says they could be useful in the study of phobias, anxiety and post-traumatic stress disorders.

"It is high time public health researchers took human transgenerational responses seriously," he said in a statement issued by the Science Media Centre.

"I suspect we will not understand the rise in neuropsychiatric disorders or obesity, diabetes and metabolic disruptions generally without taking a multigenerational approach."

Wolf Reik, epigenetics head at the Babraham Institute in England, says such results were “encouraging” as they suggested that transgenerational inheritance does exist, but cannot yet be extrapolated to humans.

Discoveries in How Memories Form Could Help Treat Dementia

Do fruit flies hold the key to treating dementia? Researchers at the University of Houston (UH) have taken a significant step forward in unraveling the mechanisms of Pavlovian conditioning. Their work will help them understand how memories form and, ultimately, provide better treatments to improve memory in all ages.

Gregg Roman, an associate professor of biology and biochemistry at UH, and Shixing Zhang, his postdoctoral associate, describe their findings in a paper titled “Presynaptic Inhibition of Gamma Lobe Neurons Is Required for Olfactory Learning in Drosophila,” appearing Nov. 27 in Current Biology, a scientific bimonthly journal published by Cell Press.

“Memory is essential to our daily function and is also central to our sense of self,” Roman said. “To a large degree, we are the sum of our experiences. When memories can no longer be retrieved or we have difficulty in forming new memories, the effects are frequently tragic. In the future, our work will enable us to have a better understanding of how human memories form.”

Roman and Zhang set about to unravel some of these mysteries by studying the brains of fruit flies (Drosophila). Within the fly brain, Roman says, there are nerve cells that play a role in olfactory learning and memory. Olfactory learning, he says, is an example of classical conditioning first described by Pavlov in his experiment with dogs. In their study, the flies were trained to associate a weak electric shock with an odor. After training, the flies avoided that odor.

“We found that these particular nerve cells – the gamma lobe neurons of the mushroom bodies in the insect brain – are activated by odors. Training the flies to associate an odor with an electric shock changed how these cells responded to odors by developing a modification in gamma lobe neuron activity, known as a memory trace,” he said. “Interestingly, we found that training caused the gamma lobe neurons to be more weakly activated by odors that were not paired with an electric shock, while the odors paired with electric shock maintained a strong activation of these neurons. Thus, the gamma lobe neurons responded more strongly to the trained odor than to the untrained odor.”

The team also showed that a specific protein – the heterotrimeric G(o) protein – is naturally involved in inhibiting gamma lobe neurons. Roman says removing the activity of this protein only within the gamma lobe neurons resulted in a loss of the memory trace and, thus, poor learning. Therefore, inhibiting the release of neurotransmitters from these neurons through the actions of the G(o) protein is key to forming the memory trace and associative memories.

The significance of using fruit flies is that while their brain structure is much simpler with far fewer neurons, the mushroom body is analogous to the perirhinal cortex in humans, which serves the same function of sensory integration and learning. This simplicity allows scientists to gain insights into how memories are acquired, stored and retrieved.

“Drosophila represents the Goldilocks principle of neural research, with sufficient behavioral complexity, while maintaining a huge advantage in neural simplicity,” Roman said. “The complex behaviors allow us to examine many behavioral processes like learning, attention, aggression and addiction-like behaviors, while the simplicity allows us to dissect the crucial neural activities down to single cells. Additionally, Drosophila has the most powerful genetic toolkit available for behavioral experimentation. In using these tools, we are genetically identifying the molecules necessary to perform these behaviors and dissecting the logic of the neural circuits that allow for changes in behavior to occur.”

The pair says all their experience to date suggests the molecules and logic will translate to most animals, including humans, leading to a more complete understanding of how memories form in humans, both at the level of molecules and through the activity of neural circuits.