Zebrafish use surprising strategy to regrow spinal cord

Zebrafish are members of a rarefied group of vertebrates capable of fully healing a severed spinal cord. A clear understanding of how this regeneration takes place could provide clues toward strategies for healing spinal cord injuries in people. Such injuries can be devastating, causing permanent loss of sensation and movement.

A new study from Washington University School of Medicine in St. Louis maps out a detailed atlas of all the cells involved -- and how they work together -- in regenerating the zebrafish spinal cord. In an unexpected finding, the researchers showed that survival and adaptability of the severed neurons themselves is required for full spinal cord regeneration. Surprisingly, the study showed that stem cells capable of forming new neurons -- and typically thought of as central to regeneration -- play a complementary role but don't lead the process.

The study is published Thursday, Aug. 15, in the journal Nature Communications.

Unlike humans' and other mammals' spinal cord injuries, in which damaged neurons always die, the damaged neurons of zebrafish dramatically alter their cellular functions in response to injury, first to survive and then to take on new and central roles in orchestrating the precise events that govern healing, the researchers found. Scientists knew that zebrafish neurons survive spinal cord injury, and this new study reveals how they do it.

"We found that most, if not all, aspects of neural repair that we're trying to achieve in people occur naturally in zebrafish," said senior author Mayssa Mokalled, PhD, an associate professor of developmental biology. "The surprising observation we made is that there are strong neuronal protection and repair mechanisms happening right after injury. We think these protective mechanisms allow neurons to survive the injury and then adopt a kind of spontaneous plasticity -- or flexibility in their functions -- that gives the fish time to regenerate new neurons to achieve full recovery. Our study has identified genetic targets that will help us promote this type of plasticity in the cells of people and other mammals."

By mapping out the evolving roles of various cell types involved in regeneration, Mokalled and her colleagues found that the flexibility of the surviving injured neurons and their capacity to immediately reprogram after injury lead the chain of events that are required for spinal cord regeneration. If these injury-surviving neurons are disabled, zebrafish do not regain their normal swim capacity, even though regenerative stem cells remain present.

When the long wiring of the spinal cord is crushed or severed in people and other mammals, it sets off a chain of toxicity events that kills the neurons and makes the spinal cord environment hostile against repair mechanisms. This neuronal toxicity could provide some explanation for the failure of attempts to harness stem cells to treat spinal cord injuries in people. Rather than focus on regeneration with stem cells, the new study suggests that any successful method to heal spinal cord injuries in people must start with saving the injured neurons from death.

"Neurons by themselves, without connections to other cells, do not survive," Mokalled said. "In zebrafish, we think severed neurons can overcome the stress of injury because their flexibility helps them establish new local connections immediately after injury. Our research suggests this is a temporary mechanism that buys time, protecting neurons from death and allowing the system to preserve neuronal circuitry while building and regenerating the main spinal cord."

There is some evidence that this capacity is present but dormant in mammalian neurons, so this may be a route to new therapies, according to the researchers.

"We are hopeful that identifying the genes that orchestrate this protective process in zebrafish -- versions of which also are present in the human genome -- will help us find ways to protect neurons in people from the waves of cell death that we see following spinal cord injuries," she said.

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New research demonstrates potential for increasing effectiveness of popular diabetes, weight-loss drugs

A network of proteins found in the central nervous system could be harnessed to increase the effectiveness and reduce the side effects of popular diabetes and weight-loss drugs, according to new research from the University of Michigan.

The study, appearing today in the Journal of Clinical Investigation, focused on two proteins called melanocortin 3 and melanocortin 4 found primarily on the surface of neurons in the brain that play a central role in regulating feeding behavior and maintaining the body's energy balance.

Melanocortin 3 and melanocortin 4 impact everything from sensing long-term energy stores to processing signals from the gut regarding short-term fullness, or satiety, said U-M physiologist Roger Cone, who led the study.

The class of drugs known as GLP-1 agonists, which includes semaglutides (e.g., Ozempic) and tirzepatides (e.g., Mounjaro), have received substantial attention recently for their effectiveness in treating not only type 2 diabetes, but also obesity, heart disease and potentially addiction. They work by mimicking a natural hormone that the gut produces when it is full, triggering the brain to reduce feeding behavior.

"So the obvious question for us was: How do these GLP-1 drugs, which work by manipulating satiety signals, function when we prime the melanocortin system?" said Cone, professor of molecular and integrative physiology at the U-M Medical School and director of the U-M Life Sciences Institute where his lab is located.

Working in mouse models, Cone and his colleagues tested the effects of several hormones that reduce food intake. They compared the results in normal mice with mice that genetically lacked the MC3R protein, in mice that were given chemicals to block the activity of MC3R, and in mice that were given a drug to increase the activity of MC4R. (Because MC3R is a natural negative regulator of MC4R, meaning it decreases the activity of MC4R, blocking MC3R and increasing MC4R activity has similar effects.)

In all cases, Naima Dahir, first author of the study and a postdoctoral research fellow in Cone's lab, and colleagues found that adjusting the melanocortin system -- either by inhibiting MC3R or increasing MC4R activity -- made the mice more sensitive to GLP-1 drugs and other hormones that affect feeding behavior. The mice that were given a GLP-1 drug in combination with an MC4R agonist or MC3R antagonist showed up to five times more weight loss and reduced feeding than mice receiving only the GLP-1 drugs.

"We found that activating the central melanocortin system hypersensitizes animals to the effects of not just GLP-1s, but to every anti-feeding hormone we tested," Cone said.

The researchers also measured activity in parts of the brain thought to trigger nausea in response to GLP-1 drugs and observed no increased activation when GLP-1 drugs were combined with alterations to the melanocortin system. In contrast, priming of the melanocortin neurons significantly increased GLP-1 drug activation of neurons in hypothalamic feeding centers in the brain.

The findings indicate that pairing the existing GLP-1 drugs with an MC4R agonist could increase sensitivity to the desired effects of the drugs by up to fivefold, without increasing unwanted side effects.Ultimately, this approach could enable patients who are sensitive to the side effects to take a lower dose, or could improve the results in patients who have not responded to the existing drug dosages. Further drug development and clinical testing are needed before this can occur.

While this research has been conducted only in mouse models, Cone is optimistic that the results will translate well to humans.

"The melanocortin system is highly conserved in humans," he said. "Everything we've observed in the mouse over the past decades studying these proteins has also been found in humans, so I suspect that these results would also be translatable to patients."

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Sleep resets brain connections -- but only for first few hours

During sleep, the brain weakens the new connections between neurons that had been forged while awake -- but only during the first half of a night's sleep, according to a new study in fish by UCL scientists.

The researchers say their findings, published in Nature, provide insight into the role of sleep, but still leave an open question around what function the latter half of a night's sleep serves.

The researchers say the study supports the Synaptic Homeostasis Hypothesis, a key theory on the purpose of sleep which proposes that sleeping acts as a reset for the brain.

Lead author Professor Jason Rihel (UCL Cell & Developmental Biology) said: "When we are awake, the connections between brain cells get stronger and more complex. If this activity were to continue unabated, it would be energetically unsustainable. Too many active connections between brain cells could prevent new connections from being made the following day.

"While the function of sleep remains mysterious, it may be serving as an 'off-line' period when those connections can be weakened across the brain, in preparation for us to learn new things the following day."

For the study, the scientists used optically translucent zebrafish, with genes enabling synapses (structures that communicate between brain cells) to be easily imaged. The research team monitored the fish over several sleep-wake cycles.

The researchers found that brain cells gain more connections during waking hours, and then lose them during sleep. They found that this was dependent on how much sleep pressure (need for sleep) the animal had built up before being allowed to rest; if the scientists deprived the fish from sleeping for a few extra hours, the connections continued to increase until the animal was able to sleep.

Professor Rihel added: "If the patterns we observed hold true in humans, our findings suggest that this remodelling of synapses might be less effective during a mid-day nap, when sleep pressure is still low, rather than at night, when we really need the sleep."

The researchers also found that these rearrangements of connections between neurons mostly happened in the first half of the animal's nightly sleep. This mirrors the pattern of slow-wave activity, which is part of the sleep cycle that is strongest at the beginning of the night.

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Illusion helps demystify the way vision works

For the first time, research shows that a certain kind of visual illusion, neon color spreading, works on mice. The study is also the first to combine the use of two investigative techniques called electrophysiology and optogenetics to study this illusion. Results from experiments on mice settle a long-standing debate in neuroscience about which levels of neurons within the brain are responsible for the perception of brightness.

We're all familiar with optical illusions; some are novelties, while some are all around us. Even as you look at the screen in front you, you are being fooled into thinking that you're seeing the color white. What you're really seeing is lots of red, green and blue elements packed so tightly together it gives the impression of being white. Another example is a fast rotating wheel or propeller, which can briefly look like it's reversing direction while it's accelerating to full speed. In any case, it might be surprising to know that optical illusions are not just fun to look at but can also be a useful tool to learn more about eyes, nerves, minds and brains.

Associate Professor Masataka Watanabe from the Department of Systems Innovation at the University of Tokyo is on a mission to understand more about the nature of consciousness. It's a vast subject area so naturally there are many ways to explore it, and amongst other things, he uses optical illusions. His most recent research looked at whether a certain kind of illusion that works on humans would also work on mice. And it turns out, it does. But why is this significant?

"Knowing this kind of illusion, called a neon-color-spreading illusion, works on mice as well as humans, is useful for neuroscientists like myself, as it means that mice can serve as useful test subjects for cases where humans cannot," said Watanabe. "To really understand what goes on inside the brain during perceptual experiences, we need to use certain methods that we cannot use on people. These include electrophysiology, the recording of neural activity with electrodes, and optogenetics, where light pulses enable or disable firing of specific neurons in a living brain."

Watanabe's experiment was the first of its kind to make use of both electrophysiology and optogenetics at the same time in animal test subjects exposed to the neon-color-spreading illusion, which allowed his team to see precisely what structures within the brain are responsible for processing the illusion.

"After a visual stimulus lands on the eye, it's carried to the brain by nerves and is then received by a series of layers of neurons called V1, V2 and so on, where V1 is the first and most basic layer, and V2 and above are considered higher layers," said Watanabe. "There is a long-standing debate in neuroscience about the role higher levels play in the perception of brightness and it was not an easy thing to study. Our experiment on mice has shown us that neurons in V1 responded not just to the illusion, but also to a nonillusory version of the same kind of pattern shown. But only when the illusory version was shown to the mice did neurons in V2 also play a crucial role: that of modulating the activity of neurons in V1, thus proving that V2 neurons do in fact play a role in the perception of brightness."

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RNA that doesn't age

Certain RNA molecules in the nerve cells in the brain last a life time without being renewed. Neuroscientists from Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) have now demonstrated that this is the case together with researchers from Germany, Austria and the USA. RNAs are generally short-lived molecules that are constantly reconstructed to adjust to environmental conditions. With their findings that have now been published in the journal Science, the research group hopes to decipher the complex aging process of the brain and gain a better understanding of related degenerative diseases.

Most cells in the human body are regularly renewed, thereby retaining their vitality.

However, there are exceptions: the heart, the pancreas and the brain consist of cells that do not renew throughout the whole lifespan, and yet still have to remain in full working order.

"Aging neurons are an important risk factor for neurodegenerative illnesses such as Alzheimer's," says Prof.

Dr. Tomohisa Toda, Professor of Neural Epigenomics at FAU and at the Max Planck Center for Physics and Medicine in Erlangen.

"A basic understanding of the aging process and which key components are involved in maintaining cell function is crucial for effective treatment concepts:"

In a joint study conducted together with neuroscientists from Dresden, La Jolla (USA) and Klosterneuburg (Austria), the working group led by Toda has now identified a key component of brain aging: the researchers were able to demonstrate for the first time that certain types of ribonucleic acid (RNA) that protect genetic material exist just as long as the neurons themselves.

"This is surprising, as unlike DNA, which as a rule never changes, most RNA molecules are extremely short-lived and are constantly being exchanged," Toda explains.

In order to determine the life span of the RNA molecules, the Toda group worked together with the team from Prof.

Dr. Martin Hetzer, a cell biologist at the Institute of Science and Technology Austria (ISTA). "We succeeded in marking the RNAs with fluorescent molecules and tracking their lifespan in mice brain cells," explains Tomohisa Toda, who has unique expertise in epigenetics and neurobiology and who was awarded an ERC Consolidator Grant for his research in 2023.

"We were even able to identify the marked long-lived RNAs in two year old animals, and not just in their neurons, but also in somatic adult neural stem cells in the brain."

In addition, the researchers discovered that the long-lived RNAs, that they referred to as LL-RNA for short, tend to be located in the cells' nuclei, closely connected to chromatin, a complex of DNA and proteins that forms chromosomes.

This indicates that LL-RNA play a key role in regulating chromatin.

In order to confirm this hypothesis, the team reduced the concentration of LL-RNA in an in-vitro experiment with adult neural stem cell models, with the result that the integrity of the chromatin was strongly impaired.

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Researchers map how the brain regulates emotions

Ever want to scream during a particularly bad day, but then manage not to? Thank the human brain and how it regulates emotions, which can be critical for navigating everyday life. As we perceive events unfolding around us, the ability to be flexible and reframe a situation impacts not only how we feel, but also our behavior and decision-making.

In fact, some of the problems associated with mental health relate to individuals' inability to be flexible, such as when persistent negative thoughts make it hard to perceive a situation differently.

To help address such issues, a new Dartmouth-led study is among the first of its kind to separate activity relating to emotion generation from emotion regulation in the human brain. The findings are published in Nature Neuroscience.

"As a former biomedical engineer, it was exciting to identify some brain regions that are purely unique to regulating emotions," says lead author Ke Bo, a postdoctoral researcher in the Cognitive and Affective Neuroscience Lab (CANlab) at Dartmouth. "Our results provide new insight into how emotion regulation works by identifying targets which could have clinical applications."

For example, the systems the researchers identified could be good targets for brain stimulation to enhance the regulation of emotion.

Using computational methods, the researchers examined two independent datasets of fMRI studies obtained earlier by co-author Peter Gianaros at the University of Pittsburgh. Participants' brain activity was recorded in an fMRI scanner as they viewed images that were likely to draw a negative reaction such as a bloody scene or scary- looking animals.

The participants were then asked to recontextualize the stimulus by generating new kinds of thoughts about an image to make it less aversive, before a neutral image was presented followed by another dislikable image.

By examining the neural activity, researchers could identify the brain areas that are more active when emotions are regulated versus when emotions are generated.

The new study reveals that emotion regulation, also known in neuroscience as "reappraisal," involves particular areas of the anterior prefrontal cortex and other higher-level cortical hierarchies whose role in emotion regulation had not previously been isolated with this level of precision. These regions are involved in other high-level cognitive functions and are important for abstract thought and long-term representations of the future.

The more people are able to activate these emotion regulation-selective brain regions, the more resilient they are to experiencing something negative without letting it affect them personally. These findings build on other research linking these areas to better mental health and the ability to resist temptations and avoid drug addiction.

The results also demonstrated that the amygdala, which is known as the threat-related brain region responsible for negative emotion and has long been considered an ancient subcortical threat center, responds to aversive experiences the same way, whether people are using their thoughts to self-regulate down-regulate negative emotion or not. "It's really the cortex that is responsible for generating people's emotional responses, by changing the way we see and attach meaning to events in our environments," says Bo.

The researchers were also interested in identifying the neurochemicals that interact with emotion regulation systems. Neurotransmitters like dopamine and serotonin shape how networks of neurons communicate and are targets for both illicit drugs and therapeutic treatments alike. Some neurotransmitters may be important for enabling the ability to self-regulate or "down-regulate."

The team compared the emotion regulation brain maps from the two datasets to neurotransmitter binding maps from 36 other studies. The systems involved in regulating negative emotion overlapped with particular neurotransmitter systems.

"Our results showed that receptors for cannabinoids, opioids, and serotonin, including 5H2A, were especially rich in areas that are involved in emotion regulation," says senior author Tor Wager, the Diana L. Taylor Distinguished Professor in Neuroscience and director of the Dartmouth Brain Imaging Center at Dartmouth. "When drugs that bind to these receptors are taken, they are preferentially affecting the emotion regulation system, which raises questions about their potential for long-term effects on our capacity to self-regulate."

Serotonin is well-known for its role in depression, as the most widely used antidepressant drugs inhibit its reuptake in synapses, which transmit signals from one neuron to another.

5H2A is the serotonin receptor most strongly affected by another exciting new type of treatment for mental health -- psychedelic drugs. The study's findings suggest that the effects of drugs on depression and other mental health disorders may work in part by altering how we think about life events and our ability to self-regulate. This may help explain why drugs, particularly psychedelics, are likely to be ineffective without the right kind of psychological support. The study could help improve therapeutic approaches by increasing our understanding of why and how psychological and pharmaceutical approaches need to be combined into integrated treatments.

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Researchers identify gene involved in neuronal vulnerability in Alzheimer's disease

Early stages of neurodegenerative disorders are characterized by the accumulation of proteins in discrete populations of brain cells and degeneration of these cells. For most diseases, this selective vulnerability pattern is unexplained, yet it could yield major insight into pathological mechanisms. Alzheimer's disease (AD), the world-leading cause of dementia, is defined by the appearance of two hallmark pathological lesions, amyloid plaques (extracellular aggregates of Aβ peptides) and neurofibrillary tangles (intracellular aggregates of hyperphosphorylated tau, or NFTs). While plaques are widespread in the neocortex and hippocampus, NFTs follow a well-defined regional pattern that starts in principal neurons from the entorhinal cortex.

In a new study from Boston University Chobanian & Avedisian School of Medicine, researchers have identified a gene they believe may lead to the degeneration of the neurons that are most vulnerable to AD.

"We are trying to understand why certain neurons in the brain are particularly vulnerable during the earliest stages of AD. Why they accumulate and degenerate very early is unknown. We believe elucidating this vulnerability would allow for a new therapeutic avenue for AD," said corresponding author Jean-Pierre Roussarie, PhD, assistant professor of anatomy & neurobiology at the school.

In collaboration with leading computational genomic experts from Rice University, the BU researchers along with co-corresponding author, Patricia Rodriguez-Rodriguez, PhD, from Karolinska Institute, used cutting-edge analysis tools with machine learning to identify the gene DEK as possibly responsible for vulnerability of entorhinal cortex neurons.

They injected viruses into the entorhinal cortex of experimental models and neurons grown in the lab to manipulate levels of the DEK gene.

When they reduced the levels of the DEK gene, vulnerable neurons started to accumulate tau and to degenerate.

According to the researchers, preventing these neurons from degeneration by targeting DEK or proteins that collaborate with DEK, would prevent patients from developing memories loss and would curtail the disease before it spreads to larger areas of the brain.

"Given that entorhinal cortex neurons are necessary for the formation of new memories and since they are so vulnerable and the first to die, this explains why the first symptom of AD is the inability to form new memories," said Roussarie.

The researchers believe these findings are the first step in understanding how these fragile neurons die, yet they hope to uncover additional genes to fully understand what leads to the death of critical memory-forming neurons.

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Surprisingly simple model explains how brain cells organize and connect

A new study by physicists and neuroscientists from the University of Chicago, Harvard and Yale describes how connectivity among neurons comes about through general principles of networking and self-organization, rather than the biological features of an individual organism.

The research, published on January 17, 2024 in Nature Physics, accurately describes neuronal connectivity in a variety of model organisms and could apply to non-biological networks like social interactions as well.

"When you're building simple models to explain biological data, you expect to get a good rough cut that fits some but not all scenarios," said Stephanie Palmer, PhD, Associate Professor of Physics and Organismal Biology and Anatomy at UChicago and senior author of the paper.

"You don't expect it to work as well when you dig into the minutiae, but when we did that here, it ended up explaining things in a way that was really satisfying."

Understanding how neurons connect

Neurons form an intricate web of connections between synapses to communicate and interact with each other.

While the vast number of connections may seem random, networks of brain cells tend to be dominated by a small number of connections that are much stronger than most.

This "heavy-tailed" distribution of connections (so-called because of the way it looks when plotted on a graph) forms the backbone of circuitry that allows organisms to think, learn, communicate and move.

Despite the importance of these strong connections, scientists were unsure if this heavy-tailed pattern arises because of biological processes specific to different organisms, or due to basic principles of network organization.

To answer these questions, Palmer and Christopher Lynn, PhD, Assistant Professor of Physics at Yale University, and Caroline Holmes, PhD, a postdoctoral researcher at Harvard University, analyzed connectomes, or maps of brain cell connections.

The connectome data came from several different classic lab animals, including fruit flies, roundworms, marine worms and the mouse retina.

To understand how neurons form connections to one another, they developed a model based on Hebbian dynamics, a term coined by Canadian psychologist Donald Hebb in 1949 that essentially says, "neurons that fire together, wire together." This means the more two neurons activate together, the stronger their connection becomes.

Across the board, the researchers found these Hebbian dynamics produce "heavy-tailed" connection strengths just like they saw in the different organisms.

The results indicate that this kind of organization arises from general principles of networking, rather than something specific to the biology of fruit flies, mice, or worms.

The model also provided an unexpected explanation for another networking phenomenon called clustering, which describes the tendency of cells to link with other cells via connections they share.

A good example of clustering occurs in social situations. If one person introduces a friend to a third person, those two people are more likely to become friends with them than if they met separately.

"These are mechanisms that everybody agrees are fundamentally going to happen in neuroscience," Holmes said.

"But we see here that if you treat the data carefully and quantitatively, it can give rise to all of these different effects in clustering and distributions, and then you see those things across all of these different organisms."

Accounting for randomness

As Palmer pointed out, though, biology doesn't always fit a neat and tidy explanation, and there is still plenty of randomness and noise involved in brain circuits.

Neurons sometimes disconnect and rewire with each other -- weak connections are pruned, and stronger connections can be formed elsewhere.

This randomness provides a check on the kind of Hebbian organization the researchers found in this data, without which strong connections would grow to dominate the network.

The researchers tweaked their model to account for randomness, which improved its accuracy.

"Without that noise aspect, the model would fail," Lynn said.

"It wouldn't produce anything that worked, which was surprising to us. It turns out you actually need to balance the Hebbian snowball effect with the randomness to get everything to look like real brains."

Since these rules arise from general networking principles, the team hopes they can extend this work beyond the brain.

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Amnesia caused by head injury reversed in early mouse study

A mouse study designed to shed light on memory loss in people who experience repeated head impacts, such as athletes, suggests the condition could potentially be reversed. The research in mice finds that amnesia and poor memory following head injury is due to inadequate reactivation of neurons involved in forming memories.

The study, conducted by researchers at Georgetown University Medical Center in collaboration with Trinity College Dublin, Ireland, is reported January 16, 2024, in the Journal of Neuroscience.

Importantly for diagnostic and treatment purposes, the researchers found that the memory loss attributed to head injury was not a permanent pathological event driven by a neurodegenerative disease.

Indeed, the researchers could reverse the amnesia to allow the mice to recall the lost memory, potentially allowing cognitive impairment caused by head impact to be clinically reversed.

The Georgetown investigators had previously found that the brain adapts to repeated head impacts by changing the way the synapses in the brain operate.

This can cause trouble in forming new memories and remembering existing memories.

In their new study, investigators were able to trigger mice to remember memories that had been forgotten due to head impacts.

"Our research gives us hope that we can design treatments to return the head-impact brain to its normal condition and recover cognitive function in humans that have poor memory caused by repeated head impacts," says the study's senior investigator, Mark Burns, PhD, a professor and Vice-Chair in Georgetown's Department of Neuroscience and director of the Laboratory for Brain Injury and Dementia.

In the new study, the scientists gave two groups of mice a new memory by training them in a test they had never seen before.

One group was exposed to a high frequency of mild head impacts for one week (similar to contact sport exposure in people) and one group were controls that didn't receive the impacts.

The impacted mice were unable to recall the new memory a week later.

"Most research in this area has been in human brains with chronic traumatic encephalopathy (CTE), which is a degenerative brain disease found in people with a history of repetitive head impact," said Burns.

"By contrast, our goal was to understand how the brain changes in response to the low-level head impacts that many young football players regularly experience."

Researchers have found that, on average, college football players receive 21 head impacts per week with defensive ends receiving 41 head impacts per week.

The number of head impacts to mice in this study were designed to mimic a week of exposure for a college football player, and each single head impact by itself was extraordinarily mild.

Using genetically modified mice allowed the researchers to see the neurons involved in learning new memories, and they found that these memory neurons (the "memory engram") were equally present in both the control mice and the experimental mice.

To understand the physiology underlying these memory changes, the study's first author, Daniel P. Chapman, Ph.D., said, "We are good at associating memories with places, and that's because being in a place, or seeing a photo of a place, causes a reactivation of our memory engrams. This is why we examined the engram neurons to look for the specific signature of an activated neuron. When the mice see the room where they first learned the memory, the control mice are able to activate their memory engram, but the head impact mice were not. This is what was causing the amnesia."

The researchers were able to reverse the amnesia to allow the mice to remember the lost memory using lasers to activate the engram cells.

"We used an invasive technique to reverse memory loss in our mice, and unfortunately this is not translatable to humans," Burns adds.

"We are currently studying a number of non-invasive techniques to try to communicate to the brain that it is no longer in danger, and to open a window of plasticity that can reset the brain to its former state."

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A trillion scents, one nose

The mammalian nose is a work of evolutionary art. Its millions of nerve cells, each tailored with just one of thousands of specific odor-chemical receptors encoded in the genome, can collectively distinguish a trillion distinct scents. Those sensations, in turn, inform many behaviors, from assessing food options to discerning friends from foes to sparking memories.

Today, in the journal Nature, a research team led by scientists at Columbia's Zuckerman Institute describes a previously undetected mechanism in mice -- starring the genetic molecule RNA -- that could explain how each sensory cell, or neuron, in mammalian noses becomes tailored to detect a specific odor chemical.

For example, there are sensory neurons in our noses that bear receptors uniquely tuned to detect ethyl vanillin, the main odorant in vanilla, and other cells with receptors for limonene, lemon's signature odorant.

"How sensory cells in the nose make their receptor choices has been one of the most vexing mysteries about olfaction," said Stavros Lomvardas, PhD, a Roy and Diana Vagelos Professor and Chair of Biochemistry and Molecular Biophysics and Herbert and Florence Irving Professor of Neuroscience at Columbia's Zuckerman Institute and the Vagelos College of Physicians and Surgeons, and corresponding author on the paper.

"Now, the story behind our sense of smell, or olfaction, is becoming clearer, and also more dramatic."

The sense-refining drama he is referring to unfolds entirely within the minuscule confines of each olfactory neuron's nucleus, where the cell's chromosomes and genes reside.

There, in a Squid Games-style, winner-takes-all competition, a developing cell's myriad olfactory receptor genes vie with each other in a process that winnow them down, in stages, first to handful of finalists and then to a single winner.

The prevailing gene is the one that determines the cell's odorant sensitivity.

In their study, Dr. Lomvardas and his team uncover details of the final stage of this process when the winner emerges from the finalist genes.

"It's basically a battle between a 1000 contenders," said Ariel Pourmorady, the paper's first author and an M.D.-Ph.D. candidate at the Zuckerman Institute in the Lomvardas lab.

The action is exceedingly complex and involves a dizzying cast of molecular characters.

Playing roles that either dial up or down each gene's ability to produce olfactory receptors are a variety of gene-regulating molecules.

By gathering into various alliances within the genome, these molecular players help turn specific genes on or off.

Also in the fray is another set of molecular hubs that reshape portions of the genome in ways that favor specific receptor genes.

When his team first observed these in the genome in 2014, Dr. Lomvardas dubbed them "Greek Islands" because they reminded him of islands in the Aegean Sea.

"It turns out that the genome has a certain spatial organization in the nucleus and changes in this structure are pivotal when it comes to which genes are expressed into proteins, like olfactory receptors," said Pourmorady.

"We are learning just how important this process is within maturing olfactory cells."

In their new Nature paper, the researchers summon a trove of data from mouse studies pointing toward RNA as the linchpin molecule in the olfactory system's gene-choosing mechanism.

RNA is most known as the go-between molecule that translates the genetic code embodied in DNA into protein molecules with specific cellular jobs, like detecting odorants.

Using sophisticated techniques for analyzing changes in genome structure as cells mature, however, the researchers say their evidence points to a pivotal second role for the RNA.

"It looks like the RNA the cell makes during gene expression also is altering the genome's architecture in ways that bolster the expression of one olfactory receptor gene while also shutting down all the others," Pourmorady said.

Big gaps in this genome-controlling story remain, but the researchers say the outline

is becoming more defined. It starts with maturing olfactory cells, which initially express many receptor genes at those genomic hubs where gene-regulating molecules and complexes, including Greek Islands, converge.

Then the RNA winnows the contending olfactory-receptor genes down to one.

The particular hub in each cell where the molecular stars align to produce the highest amount of RNA wins the competition.

At this hub, receptor-gene expression soars. But, like a slinky saboteur, RNA from that same hub may wind its way to all the other hubs.

In those locations, the RNA causes shape changes in the genome that shut down gene expression.

The result is a nose's worth of mature olfactory neurons, each of which bears on its surface only one odorant receptor.

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From the first bite, our sense of taste helps pace our eating

When you eagerly dig into a long-awaited dinner, signals from your stomach to your brain keep you from eating so much you'll regret it -- or so it's been thought. That theory had never really been directly tested until a team of scientists at UC San Francisco recently took up the question.

The picture, it turns out, is a little different.

The team, led by Zachary Knight, PhD, a UCSF professor of physiology in the Kavli Institute for Fundamental Neuroscience, discovered that it's our sense of taste that pulls us back from the brink of food inhalation on a hungry day. Stimulated by the perception of flavor, a set of neurons -- a type of brain cell -- leaps to attention almost immediately to curtail our food intake.

"We've uncovered a logic the brainstem uses to control how fast and how much we eat, using two different kinds of signals, one coming from the mouth, and one coming much later from the gut," said Knight, who is also an investigator with the Howard Hughes Medical Institute and a member of the UCSF Weill Institute for Neurosciences. "This discovery gives us a new framework to understand how we control our eating."

The study, which appears Nov. 22, 2023 in Nature, could help reveal exactly how weight-loss drugs like Ozempic work, and how to make them more effective.

New views into the brainstem

Pavlov proposed over a century ago that the sight, smell and taste of food are important for regulating digestion. More recent studies in the 1970s and 1980s have also suggested that the taste of food may restrain how fast we eat, but it's been impossible to study the relevant brain activity during eating because the brain cells that control this process are located deep in the brainstem, making them hard to access or record in an animal that's awake.

Over the years, the idea had been forgotten, Knight said.

New techniques developed by lead author Truong Ly, PhD, a graduate student in Knight's lab, allowed for the first-ever imaging and recording of a brainstem structure critical for feeling full, called the nucleus of the solitary tract, or NTS, in an awake, active mouse. He used those techniques to look at two types of neurons that have been known for decades to have a role in food intake.

The team found that when they put food directly into the mouse's stomach, brain cells called PRLH (for prolactin-releasing hormone) were activated by nutrient signals sent from the GI tract, in line with traditional thinking and the results of prior studies.

However, when they allowed the mice to eat the food as they normally would, those signals from the gut didn't show up. Instead, the PRLH brain cells switched to a new activity pattern that was entirely controlled by signals from the mouth.

"It was a total surprise that these cells were activated by the perception of taste," said Ly. "It shows that there are other components of the appetite-control system that we should be thinking about."

While it may seem counterintuitive for our brains to slow eating when we're hungry, the brain is actually using the taste of food in two different ways at the same time. One part is saying, "This tastes good, eat more," and another part is watching how fast you're eating and saying, "Slow down or you're going to be sick."

"The balance between those is how fast you eat," said Knight.

The activity of the PRLH neurons seems to affect how palatable the mice found the food, Ly said. That meshes with our human experience that food is less appetizing once you've had your fill of it.

Brain cells that inspire weight-loss drugs

The PRLH-neuron-induced slowdown also makes sense in terms of timing. The taste of food triggers these neurons to switch their activity in seconds, from keeping tabs on the gut to responding to signals from the mouth.

Meanwhile, it takes many minutes for a different group of brain cells, called CGC neurons, to begin responding to signals from the stomach and intestines. These cells act over much slower time scales -- tens of minutes -- and can hold back hunger for a much longer period of time.

"Together, these two sets of neurons create a feed-forward, feed-back loop," said Knight. "One is using taste to slow things down and anticipate what's coming. The other is using a gut signal to say, 'This is how much I really ate. Ok, I'm full now!'"

The CGC brain cells' response to stretch signals from the gut is to release GLP-1, the hormone mimicked by Ozempic, Wegovy and other new weight-loss drugs.

These drugs act on the same region of the brainstem that Ly's technology has finally allowed researchers to study. "Now we have a way of teasing apart what's happening in the brain that makes these drugs work," he said.

A deeper understanding of how signals from different parts of the body control appetite would open doors to designing weight-loss regimens designed for the individual ways people eat by optimizing how the signals from the two sets of brain cells interact, the researchers said.

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Scientists regenerate neurons that restore walking in mice after paralysis from spinal cord injury

In a new study in mice, a team of researchers from UCLA, the Swiss Federal Institute of Technology, and Harvard University have uncovered a crucial component for restoring functional activity after spinal cord injury. The neuroscientists have shown that re-growing specific neurons back to their natural target regions led to recovery, while random regrowth was not effective.

In a 2018 study published in Nature, the team identified a treatment approach that triggers axons -- the tiny fibers that link nerve cells and enable them to communicate -- to regrow after spinal cord injury in rodents. But even as that approach successfully led to the regeneration of axons across severe spinal cord lesions, achieving functional recovery remained a significant challenge.

For the new study, published this week in Science, the team aimed to determine whether directing the regeneration of axons from specific neuronal subpopulations to their natural target regions could lead to meaningful functional restoration after spinal cord injury in mice. They first used advanced genetic analysis to identify nerve cell groups that enable walking improvement after a partial spinal cord injury.

The researchers then found that merely regenerating axons from these nerve cells across the spinal cord lesion without specific guidance had no impact on functional recovery. However, when the strategy was refined to include using chemical signals to attract and guide the regeneration of these axons to their natural target region in the lumbar spinal cord, significant improvements in walking ability were observed in a mouse model of complete spinal cord injury.

"Our study provides crucial insights into the intricacies of axon regeneration and requirements for functional recovery after spinal cord injuries," said Michael Sofroniew, MD, PhD, professor of neurobiology at the David Geffen School of Medicine at UCLA and a senior author of the new study. "It highlights the necessity of not only regenerating axons across lesions but also of actively guiding them to reach their natural target regions to achieve meaningful neurological restoration."

The authors say understanding that re-establishing the projections of specific neuronal subpopulations to their natural target regions holds significant promise for the development of therapies aimed at restoring neurological functions in larger animals and humans. However, the researchers also acknowledge the complexity of promoting regeneration over longer distances in non-rodents, necessitating strategies with intricate spatial and temporal features. Still, they conclude that applying the principles laid out in their work "will unlock the framework to achieve meaningful repair of the injured spinal cord and may expedite repair after other forms of central nervous system injury and disease."

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Cracking the code that relates brain and behavior in a simple animal

To understand the full relationship between brain activity and behavior, scientists have needed a way to map this relationship for all of the neurons across a whole brain -- a so far insurmountable challenge. But after inventing new technologies and methods for the purpose, a team of scientists in The Picower Institute for Learning and Memory at MIT has produced a rigorous accounting of the neurons in the tractably tiny brain of a humble C. elegans worm, mapping out how its brain cells encode almost all of its essential behaviors, such as movement and feeding.

In the journal Cell, the team presents new brain-wide recordings and a mathematical model that accurately predicts the versatile ways that neurons represent the worm's behaviors. Applying that model specifically to each cell, the team produced an atlas of how most cells, and the circuits they take part in, encode the animal's actions. The atlas therefore reveals the underlying "logic" of how the worm's brain produces a sophisticated and flexible repertoire of behaviors, even as its environmental circumstances change.

"This study provides a global map of how the animal's nervous system is organized to control behavior," said senior author Steven Flavell, Associate Professor in MIT's Department of Brain and Cognitive Sciences. "It shows how the many defined nodes that make up the animal's nervous system encode precise behavioral features, and how this depends on factors like the animal's recent experience and current state."

Graduate students Jungsoo Kim and Adam Atanas, who each earned their PhDs this spring for the research, are the study's co-lead authors. They've also made all their data, and the findings of their model and atlas, freely available to fellow researchers at a website called the WormWideWeb.

Microscopes to models

To make the measurements needed to develop their model, Flavell's lab invented a new microscope and software system that automatically tracks almost all behaviors of the worm (movement, feeding, sleeping, egg-laying, etc.) and the activity of every neuron in its head (cells are engineered to flash when calcium ions build up). Reliably distinguishing and tracking separate neurons as the worm wriggles around and bends required writing custom software, utilizing the latest tools from machine learning. It proved to be 99.7 percent accurate in sampling individual neuron's activities with greatly improved signal-to-noise compared to previous systems, the scientists report.

The team used the system to record simultaneous behavior and neural data from more than 60 worms as they roved about their dishes, doing whatever they wanted.

Data analysis revealed three novel observations about neural activity in the worm: Neurons track behavior not only of the present moment but also the recent past; they tune their encoding of behaviors, such as motion, based on a surprising variety of factors; and many neurons simultaneously encode multiple behaviors.

For example, while the behavior of wriggling around one's little laboratory dish might seem like a very simple act, neurons represented factors such as speed, steering, and whether the worm is eating or not. In some cases they represented the animal's motion spanning back in time by about a minute. By encoding recent, rather than just current motion, these neurons could help the worm compute how its past actions influenced its current outcome. Many neurons also combined behavioral information to execute more complex maneuvers. Much like a human driver must remember to steer the car in the opposite way when going in reverse versus going forward, certain neurons in the worm's brain integrated the animal's direction of motion and steering direction.

By carefully analyzing these kinds of patterns of how neural activity correlated with behaviors the scientists developed the C. elegans Probabilistic Neural Encoding Model. The model, encapsulated in a single equation, accounts for how each neuron represents various factors to accurately predict whether and how the neural activity reflects behavior. Nearly 60 percent of the neurons in the worm's head indeed accounted for at least one behavior.

In fitting the model, the research team used a probabilistic modeling approach that allowed them to understand how certain they were about each fit model parameter, an approach pioneered by co-author Vikash Mansinghka, a principal research scientist who leads MIT's Probabilistic Computing Project.

Making an atlas

In creating a model that could quantify and predict how any brain cell would represent behavior, the team initially gathered data from neurons without tracking the cells' specific identities. But a key goal of studying the worms is to understand how each cell and circuit contributes to behavior. So to apply the model's capability to each of the worm's specific neurons, which have all been previously mapped out, the team's next step was to relate neural activity and behavior for each cell on the map. Doing that required labeling each neuron with a unique color so that its activity could be associated with its identity. The team did this in dozens of freely-moving animals, which provided them with information of how almost all of the defined neurons in the worm's head related to the animal's behavior.

The atlas resulting from this work revealed many insights, more fully mapping out the neural circuits that control each of the animal's behaviors. These new findings will enable a more holistic understanding of how these behaviors are controlled, Flavell said.

"It allowed us to complete the circuits," he said. "Our hope is that as our colleagues study aspects of neural circuit function, they can refer to this atlas to obtain a fairly complete view of the key neurons involved."

Built for flexibility

Another major outcome of the team's work was the finding that while most neurons always obeyed the predictions of the model, a smaller set of neurons in the worm's brain -- about 30 percent of those that encode behavior -- was able to flexibly remap their behavior encoding, essentially taking on new jobs. The neurons in this group were reliably similar across animals, and were well connected with one another in the worm's synaptic wiring diagram.

Theoretically these remapping events could occur for any number of reasons, so the team ran further experiments to see if they could cause neurons to remap. As the worms wriggled around their dishes, the researchers applied a quick laser zap that heated the agar around the worm's head. The heat was harmless but enough to annoy the worms for a while, inducing a change in the animal's behavior state that lasted for minutes. From these recordings the team was able to see that many neurons remapped their behavioral encoding right as animals switched behavioral states.

"Behavioral information is richly expressed across the brain in many different forms -- with distinct tunings, timescales, and levels of flexibility -- that map onto the defined neuron classes of the C. elegans connectome," the authors wrote.

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Scientists discover external protein network can help stabilize neural connections

The Noelin family of secreted proteins bind to the external portion of AMPA glutamate receptors and stabilize them on the neuronal cellular membrane, a process necessary for transmission of full-strength signals between neurons, according to a study in mice from the National Eye Institute (NEI) and the University of Freiberg, Germany. Without this external, stabilizing protein network, the AMPA receptors are no longer retained at the synapse, leading to weak, short-lived synaptic signals. The findings not only provide insight into processes such as learning and memory but also the development of blinding conditions like glaucoma. The study was published in the journal Neuron. NEI is part of the National Institutes of Health.

"This study shows that Noelins have a crucial job in supporting synapse function in the brain and other neural tissues like the eye's retina," said Stanislav Tomarev, Ph.D., chief of NEI's Section on Retinal Ganglion Cell Biology and co-senior author of the report.

Neurons pass signals from one cell to the next via synapses, specialized connection points between the two cells. The main excitatory synapses in the brain are glutamatergic, meaning that they use the chemical messenger glutamate to transmit their signals across the synapse. The presynaptic "sending" cell emits glutamate, which travels across the synaptic cleft and is sensed by glutamate receptors on the postsynaptic "receiving" cell. These glutamate receptors are ion channels; when the channels sense glutamate, they open, generating a new neuronal signal within the postsynaptic cell. In order to generate a strong signal, sufficient receptors must be present in the correct location of the cell's surface at the synapse.

In a new study, a team of researchers led by Tomarev and Bernd Fakler, M.D., University of Freiberg, used biochemical and genetic methods to explore the complex network of extracellular proteins maintaining the localization of AMPA-type glutamate receptors at neural synapses.

The researchers first took mouse brain tissue, and isolated cellular membranes and their attached proteins. Using mass spectroscopy and specialized analytic techniques, the team worked out which proteins were associating with AMPA receptors in these membranes. The Noelin family of proteins (primarily Noelin 1, but also Noelins 2 and 3, also known as Olfactomedins 1, 2, and 3, respectively), were strongly associated with the AMPA receptors. The researchers also found secreted and membrane-anchored proteins like Neuritin and Brorin, which are known to be present at synapses.

To better understand how the Noelins help regulate neuronal activity, the researchers developed mice lacking all three Noelin proteins. Without Noelins present, synapses in the mouse hippocampus had many fewer AMPA glutamate receptors. And when the researchers attempted to stimulate neurons lacking Noelins, the neuronal signals were much lower than normal.

However, the neuronal signals weren't just lower. One of the key steps in memory formation is long-term neuron signaling, also known as long-term potentiation. This is achieved through recruitment and stabilization of additional glutamate receptors at the synapse over time, leading to a sustained signal through the neuron. In the brains of mice lacking Noelins, this stabilization didn't take place, meaning that not only were the neural signals low, they were short-lived as well.

"While this first study showed the Noelins' role in the brain, these proteins are highly prevalent in the retina as well," Tomarev said. "Our next task is to understand how changes in these secreted protein networks contribute to the development of retinal disorders, including glaucoma."

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How psychedelic drugs affect a rat's brain

Researchers at Lund University have developed a technique for simultaneously measuring electrical signals from 128 areas of the brain in awake rats. They have then used the information to measure what happens to the neurons when the rats are given psychedelic drugs. The results show an unexpected and simultaneous synchronisation among neurons in several regions of the brain.

The idea that electrical oscillations in the brain could be used to teach us more about our experiences was conceived several years ago. Pär Halje and the research team was studying rats with Parkinson's disease that had problems with involuntary movements. The researchers discovered a tone -- an oscillation or wave in the electrical fields -- of 80 hertz in the brains of the rats with Parkinson's disease. It turned out that the wave was closely connected to the involuntary movements.

"A Polish researcher had observed similar waves after giving rats the anaesthetic ketamine. The ketamine was given at a low dose so that the rats were conscious, and the equivalent dose in a human causes psychedelic experiences. The waves they saw were in more cognitive regions of the brain than in the rats with Parkinson's, and the frequency was higher, but that still made us consider whether there were links between the two phenomena. Perhaps excessive brain waves in the motor regions of the brain cause motor symptoms, while excessive waves in cognitive regions give cognitive symptoms," says Pär Halje, researcher in neurophysiology at Lund University.

The research team that Pär Halje belongs to has developed a method that uses electrodes to simultaneously measure oscillations from 128 separate areas of the brain in awake rats. The electrical waves are caused by the cumulative activity in thousands of neurons, but the researchers also succeeded in isolating signals from individual neurons.

"For several of these areas, it is the first time anyone has successfully shown how individual neurons are affected by LSD in awake animals. When we gave the rats the psychedelic substances LSD and ketamine, the waves were clearly registered."

Collective wave patterns

Despite ketamine and LSD affecting different receptors in the brain -- they have completely different ways into the nervous system -- they resulted in the same wave patterns even if the signals from individual cells differed. When the rats were given LSD, researchers saw that their neurons were inhibited -- they signalled less -- in all parts of the brain. Ketamine seemed to have a similar effect on the large neurons -- pyramidal cells -- which saw their expression inhibited, while interneurons, which are smaller neurons that are only collected locally in tissue, increased their signalling.

Pär Halje interprets the results seen in the study, which is published in Communication Biology, to mean that the wave phenomenon is connected to the psychedelic experience.

"Activity in the individual neurons caused by ketamine and LSD looks quite different, and as such cannot be directly linked to the psychedelic experience. Instead, it seems to be this distinctive wave phenomenon -- how the neurons behave collectively -- that is most strongly linked to the psychedelic experience."

Research model for psychoses

Even if what is happening in individual cells is interesting, Pär Halje argues that the whole is bigger and more exciting than the individual parts.

"The oscillations behave in a strange way. One might think that a strong wave starts somewhere, which then spreads to other parts of the brain. But instead, we see that the neurons' activity synchronises itself in a special way -- the waves in the brain go up and down essentially simultaneously in all parts of the brain where we are able to take measurements. This suggests that there are other ways in which the waves are communicated than through chemical synapses, which are relatively slow."

Pär Halje emphasises that it is difficult to know whether the waves cause hallucinations or are merely an indication of them. But, he argues, it opens up the possibility that this could be used as a research model for psychoses, where no good models exist today.

"Given how drastically a psychosis manifests itself, there ought to be a common pattern that we can measure. So far, we have not had that, but we now see a very specific oscillation pattern in rats that we are able to measure."

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New study links brain waves directly to memory

Neurons produce rhythmic patterns of electrical activity in the brain. One of the unsettled questions in the field of neuroscience is what primarily drives these rhythmic signals, called oscillations. University of Arizona researchers have found that simply remembering events can trigger them, even more so than when people are experiencing the actual event.

The researchers, whose findings are published in the journal Neuron, specifically focused on what are known as theta oscillations, which emerge in the brain's hippocampus region during activities like exploration, navigation and sleep. The hippocampus plays a crucial role in the brain's ability to remember the past.

Prior to this study, it was believed that the external environment played a more important role in driving theta oscillations, said Arne Ekstrom, professor of cognition and neural systems in the UArizona Department of Psychology and senior author of the study. But Ekstrom and his collaborators found that memory generated in the brain is the main driver of theta activity.

"Surprisingly, we found that theta oscillations in humans are more prevalent when someone is just remembering things, compared to experiencing events directly," said lead study author Sarah Seger, a graduate student in the Department of Neuroscience.

The results of the study could have implications for treating patients with brain damage and cognitive impairments, including patients who have experienced seizures, stroke and Parkinson's disease, Ekstrom said. Memory could be used to create stimulations from within the brain and drive theta oscillations, which could potentially lead to improvements in memory over time, he said.

UArizona researchers collaborated on the study with researchers from the University of Texas Southwestern Medical Center in Dallas, including neurosurgeon Dr. Brad Lega and research technician Jennifer Kriegel. The researchers recruited 13 patients who were being monitored at the center in preparation for epilepsy surgery. As part of the monitoring, electrodes were implanted in the patients' brains for detecting occasional seizures. The researchers recorded the theta oscillations in the hippocampus of the brain.

The patients participated in a virtual reality experiment, in which they were given a joystick to navigate to shops in a virtual city on a computer. When they arrived at the correct destination, the virtual reality experiment was paused. The researchers asked the participants to imagine the location at which they started their navigation and instructed them to mentally navigate the route they just passed through. The researchers then compared theta oscillations during initial navigation to participants' subsequent recollection of the route.

During the actual navigation process using the joystick, the oscillations were less frequent and shorter in duration compared to oscillations that occurred when participants were just imagining the route. So, the researchers conclude that memory is a strong driver of theta oscillations in humans.

One way to compensate for impaired cognitive function is by using cognitive training and rehabilitation, Ekstrom said.

"Basically, you take a patient who has memory impairments, and you try to teach them to be better at memory," he said.

In the future, Ekstrom is planning to conduct this research in freely walking patients as opposed to patients in beds and find how freely navigating compares to memory with regard to brain oscillations.

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Fear is in the eye of the beholder

Averting our eyes from things that scare us may be due to a specific cluster of neurons in a visual region of the brain, according to new research at the University of Tokyo. Researchers found that in fruit fly brains, these neurons release a chemical called tachykinin which appears to control the fly's movement to avoid facing a potential threat. Fruit fly brains can offer a useful analogy for larger mammals, so this research may help us better understand our own human reactions to scary situations and phobias. Next, the team want to find out how these neurons fit into the wider circuitry of the brain so they can ultimately map out how fear controls vision.

Do you cover your eyes during horror movies? Or perhaps the sight of a spider makes you turn and run? Avoiding looking at things which scare us is a common experience, for humans and animals. But what actually makes us avert our gaze from the things we fear? Researchers have found that it may be due to a group of neurons in the brain which regulates vision when feeling afraid.

"We discovered a neuronal mechanism by which fear regulates visual aversion in the brains of Drosophila (fruit flies). It appears that a single cluster of 20-30 neurons regulates vision when in a state of fear. Since fear affects vision across animal species, including humans, the mechanism we found may be active in humans as well," explained Assistant Professor Masato Tsuji from the Department of Biological Sciences at the University of Tokyo.

The team used puffs of air to simulate a physical threat and found that the flies' walking speed increased after being puffed at. The flies also would choose a puff-free route if offered, showing that they perceived the puffs as a threat (or at least preferred to avoid them). Next the researchers placed a small black object, roughly the size of a spider, 60 degrees to the right or left of the fly. On its own the object didn't cause a change in behavior, but when placed following puffs of air, the flies avoided looking at the object and moved so that it was positioned behind them.

To understand the molecular mechanism underlying this aversion behavior, the team then used mutated flies in which they altered the activity of certain neurons. While the mutated flies kept their visual and motor functions, and would still avoid the air puffs, they did not respond in the same fearful manner to visually avoid the object.

"This suggested that the cluster of neurons which releases the chemical tachykinin was necessary for activating visual aversion," said Tsuji. "When monitoring the flies' neuronal activity, we were surprised to find that it occurred through an oscillatory pattern, i.e., the activity went up and down similar to a wave. Neurons typically function by just increasing their activity levels, and reports of oscillating activity are particularly rare in fruit flies because up until recently the technology to detect this at such a small and fast scale didn't exist."

By giving the flies genetically encoded calcium indicators, the researchers could make the flies' neurons shine brightly when activated. Thanks to the latest imaging techniques, they then saw the changing, wavelike pattern of light being emitted, which was previously averaged out and missed.

Next, the team wants to figure out how these neurons fit into the broader circuitry of the brain. Although the neurons exist in a known visual region of the brain, the researchers do not yet know from where the neurons are receiving inputs and to where they are transmitting them, to regulate visual escape from objects perceived as dangerous.

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Astrocyte cells critical for learning skilled movements

From steering a car to swinging a tennis racket, we learn to execute all kinds of skilled movements during our lives. You might think this learning is only implemented by neurons, but a new study by researchers at The Picower Institute for Learning and Memory at MIT shows the essential role of another brain cell type: astrocytes.

Just as teams of elite athletes train alongside staffs of coaches, ensembles of neurons in the brain's motor cortex depend on nearby astrocytes to help them learn to encode when and how to move, and the optimal timing and trajectory of a motion, the study shows. Describing a series of experiments in mice, the new paper in the Journal of Neuroscience reveals two specific ways that astrocytes directly impact motor learning, maintaining an optimal molecular balance in which the neuronal ensembles can properly refine movement performance.

"This finding is part of a body of work from our lab and other labs that elevate the importance of astrocytes to neuronal encoding and hence to behavior," said senior author Mriganka Sur, Newton Professor of Neuroscience in The Picower Institute and MIT's Department of Brain and Cognitive Sciences. "This shows that while the population coding of behaviors is a neuronal function, we need to include astrocytes as partners with them."

Picower Institute Postdoc Jennifer Shih and former Sur Lab postdocs Chloe Delepine and Keji Li are the paper's co-lead authors.

"This research highlights the complexity of astrocytes and the importance of astrocyte-neuron interactions in fine-tuning brain function by providing concrete evidence of these mechanisms in the motor cortex," Delepine said.

Messing with motor mastery

The team gave their mice a simple motor task to master. When cued with a tone, the mice had to reach for and push down a lever within five seconds. The rodents showed they could learn the task over a few days and master it within a couple of weeks. They not only performed the task more accurately, but also their reactions quickened and the trajectory of their reaching and pushing became smoother and more uniform.

In some of the mice, however, the team employed precision molecular interventions to disrupt two specific functions of astrocytes in the motor cortex. In some mice, they disrupted the astrocytes' ability to soak up the neurotransmitter glutamate, a chemical that excites neural activity when it is received at connections called synapses. In other mice they hyperactivated the astrocytes' calcium signals, which affected how they function. In both ways, the interventions disrupted the normal process by which neurons would form or change their connections with each other, a process called "plasticity" that enables learning.

The interventions each affected the performance of the mice. The first one (a knockdown of the glutamate transporter GLT1) didn't affect whether the mice pushed the lever or how quickly they did so. Instead it disrupted the smoothness of the motion. Mice with GLT1 disrupted remained erratic and shaky, as if unable to refine their technique. Mice subjected to the second intervention (activation of Gq signaling) showed deficits not only in the smoothness of their motion trajectory but also in their understanding of when to push the lever and their quickness in doing so.

The team dug deeper into how these deficits emerged. Using a two-photon microscope they tracked neural activity in the motor cortex in unaltered mice and mice treated with each intervention. Compared to what they saw in normal mice, the mice with GLT1 disrupted showed less correlated activity among neurons. Mice with Gq activation showed excessive correlated activity compared to the normal mice.

"The data suggest that an optimal level of neuronal correlation is required for the emergence of functional neuronal ensembles that drive task performance," the authors wrote. "Meaningful correlations that carry information are what drive motor learning rather than the absolute magnitude of potentially non-specific correlations."

The team dug even deeper still. They carefully isolated astrocytes from the motor cortex of mice, including some who were untrained in the motor task as well as ones who were trained, including mice who were unaltered and mice who underwent each intervention. In all these samples of purified astrocytes, they then sequenced RNA to assess how they differed in their expression of genes. They found that in trained vs. untrained mice, astrocytes exhibited greater expression of genes related to GLT1. In mice where they intervened they saw lowered expression. That evidence further suggested that the glutamate transporter process is indeed fundamental to training in motor tasks.

"Here we show that astrocytes have an important role in enabling neurons to encode information properly, both the learning and the execution of a movement for example," Sur said.

Read more at Science Daily

How the brain senses infection

A new study led by researchers at Harvard Medical School illuminates how the brain becomes aware that there is an infection in the body.

Studying mice, the team discovered that a small group of neurons in the airway plays a pivotal role in alerting the brain about a flu infection. They also found signs of a second pathway from the lungs to the brain that becomes active later in the infection.

The study was published March 8 in Nature.

Although most people are sick several times a year, scientific knowledge of how the brain evokes the feeling of sickness has lagged behind research on other bodily states such as hunger and thirst. The paper represents a key first step in understanding the brain-body connection during an infection.

"This study helps us begin to understand a basic mechanism of pathogen detection and how that's related to the nervous system, which until now has been largely mysterious," said senior author Stephen Liberles, professor of cell biology in the Blavatnik Institute at HMS and an investigator at Howard Hughes Medical Institute.

The findings also shed light on how nonsteroidal anti-inflammatory drugs such as ibuprofen and aspirin alleviate influenza symptoms.

If the results can be translated into humans, the work could have important implications for developing more-effective flu therapies.

An infectious state of mind

The Liberles lab is interested in how the brain and body communicate to control physiology. For example, it has previously explored how the brain processes sensory information from internal organs, and how sensory cues can evoke or suppress the sensation of nausea.

In the new paper, the researchers turned their attention to another important type of sickness that the brain controls: sickness from a respiratory infection.

During an infection, Liberles explained, the brain orchestrates symptoms as the body mounts an immune response. These can include broad symptoms such as fever, decreased appetite, and lethargy, as well as specific symptoms such as congestion or coughing for a respiratory illness or vomiting or diarrhea for a gastrointestinal bug.

The team decided to focus on influenza, a respiratory virus that is the source of millions of illnesses and medical visits and causes thousands of deaths in the United States every year.

Through a series of experiments in mice, first author Na-Ryum Bin, HMS research fellow in the Liberles lab, identified a small population of neurons embedded in the glossopharyngeal nerve, which runs from the throat to the brain.

Importantly, he found that these neurons are necessary to signal to the brain that a flu infection is present and have receptors for lipids called prostaglandins. These lipids are made by both mice and humans during an infection, and they are targeted by drugs such as ibuprofen and aspirin.

Cutting the glossopharyngeal nerve, eliminating the neurons, blocking the prostaglandin receptors in those neurons, or treating the mice with ibuprofen similarly reduced influenza symptoms and increased survival.

Together, the findings suggest that these airway neurons detect the prostaglandins made during a flu infection and become a communication conduit from the upper part of the throat to the brain.

"We think that these neurons relay the information that there's a pathogen there and initiate neural circuits that control the sickness response," Liberles said.

The results provide an explanation for how drugs like ibuprofen and aspirin work to reduce flu symptoms -- and suggest that these drugs may even boost survival.

The researchers discovered evidence of another potential sickness pathway, this one traveling from the lungs to the brain. They found that it appears to become active in the second phase of infection as the virus infiltrates deeper into the respiratory system.

This additional pathway doesn't involve prostaglandins, the team was surprised to find. Mice in the second phase of infection didn't respond to ibuprofen.

The findings suggest an opportunity for improving flu treatment if scientists are able to develop drugs that target the additional pathway, the authors said.

A foundation for future research

The study raises a number of questions that Liberles and colleagues are eager to investigate.

One is how well the findings will translate to humans. Although mice and humans share a lot of basic sensory biology, including having a glossopharyngeal nerve, Liberles emphasized that researchers need to conduct further genetic and other experiments to confirm that humans have the same neuron populations and pathways seen in the mouse study.

If the findings can be replicated in humans, it raises the possibility of developing treatments that address both the prostaglandin- and nonprostaglandin pathways of flu infection.

"If you can find a way to inhibit both pathways and use them in synergy, that would be incredibly exciting and potentially transformative," Liberles said.

Bin is already delving into the details of the nonprostaglandin pathway, including the neurons involved, with the goal of figuring out how to block it. He also wants to identify the airway cells that produce prostaglandins in the initial pathway and study them in more depth.

Read more at Science Daily

Silent synapses are abundant in the adult brain

MIT neuroscientists have discovered that the adult brain contains millions of "silent synapses" -- immature connections between neurons that remain inactive until they're recruited to help form new memories.

Until now, it was believed that silent synapses were present only during early development, when they help the brain learn the new information that it's exposed to early in life. However, the new MIT study revealed that in adult mice, about 30 percent of all synapses in the brain's cortex are silent.

The existence of these silent synapses may help to explain how the adult brain is able to continually form new memories and learn new things without having to modify existing conventional synapses, the researchers say.

"These silent synapses are looking for new connections, and when important new information is presented, connections between the relevant neurons are strengthened. This lets the brain create new memories without overwriting the important memories stored in mature synapses, which are harder to change," says Dimitra Vardalaki, an MIT graduate student and the lead author of the new study.

Mark Harnett, an associate professor of brain and cognitive sciences, is the senior author of the paper, which appears today in Nature. Kwanghun Chung, an associate professor of chemical engineering at MIT, is also an author.

A surprising discovery

When scientists first discovered silent synapses decades ago, they were seen primarily in the brains of young mice and other animals. During early development, these synapses are believed to help the brain acquire the massive amounts of information that babies need to learn about their environment and how to interact with it. In mice, these synapses were believed to disappear by about 12 days of age (equivalent to the first months of human life).

However, some neuroscientists have proposed that silent synapses may persist into adulthood and help with the formation of new memories. Evidence for this has been seen in animal models of addiction, which is thought to be largely a disorder of aberrant learning.

Theoretical work in the field from Stefano Fusi and Larry Abbott of Columbia University has also proposed that neurons must display a wide range of different plasticity mechanisms to explain how brains can both efficiently learn new things and retain them in long-term memory. In this scenario, some synapses must be established or modified easily, to form the new memories, while others must remain much more stable, to preserve long-term memories.

In the new study, the MIT team did not set out specifically to look for silent synapses. Instead, they were following up on an intriguing finding from a previous study in Harnett's lab. In that paper, the researchers showed that within a single neuron, dendrites -- antenna-like extensions that protrude from neurons -- can process synaptic input in different ways, depending on their location.

As part of that study, the researchers tried to measure neurotransmitter receptors in different dendritic branches, to see if that would help to account for the differences in their behavior. To do that, they used a technique called eMAP (epitope-preserving Magnified Analysis of the Proteome), developed by Chung. Using this technique, researchers can physically expand a tissue sample and then label specific proteins in the sample, making it possible to obtain super-high-resolution images.

While they were doing that imaging, they made a surprising discovery. "The first thing we saw, which was super bizarre and we didn't expect, was that there were filopodia everywhere," Harnett says.

Filopodia, thin membrane protrusions that extend from dendrites, have been seen before, but neuroscientists didn't know exactly what they do. That's partly because filopodia are so tiny that they are difficult to see using traditional imaging techniques.

After making this observation, the MIT team set out to try to find filopodia in other parts of the adult brain, using the eMAP technique. To their surprise, they found filopodia in the mouse visual cortex and other parts of the brain, at a level 10 times higher than previously seen. They also found that filopodia had neurotransmitter receptors called NMDA receptors, but no AMPA receptors.

A typical active synapse has both of these types of receptors, which bind the neurotransmitter glutamate. NMDA receptors normally require cooperation with AMPA receptors to pass signals because NMDA receptors are blocked by magnesium ions at the normal resting potential of neurons. Thus, when AMPA receptors are not present, synapses that have only NMDA receptors cannot pass along an electric current and are referred to as "silent."

Unsilencing synapses

To investigate whether these filopodia might be silent synapses, the researchers used a modified version of an experimental technique known as patch clamping. This allowed them to monitor the electrical activity generated at individual filopodia as they tried to stimulate them by mimicking the release of the neurotransmitter glutamate from a neighboring neuron.

Using this technique, the researchers found that glutamate would not generate any electrical signal in the filopodium receiving the input, unless the NMDA receptors were experimentally unblocked. This offers strong support for the theory the filopodia represent silent synapses within the brain, the researchers say.

The researchers also showed that they could "unsilence" these synapses by combining glutamate release with an electrical current coming from the body of the neuron. This combined stimulation leads to accumulation of AMPA receptors in the silent synapse, allowing it to form a strong connection with the nearby axon that is releasing glutamate.

The researchers found that converting silent synapses into active synapses was much easier than altering mature synapses.

"If you start with an already functional synapse, that plasticity protocol doesn't work," Harnett says. "The synapses in the adult brain have a much higher threshold, presumably because you want those memories to be pretty resilient. You don't want them constantly being overwritten. Filopodia, on the other hand, can be captured to form new memories."

"Flexible and robust"

The findings offer support for the theory proposed by Abbott and Fusi that the adult brain includes highly plastic synapses that can be recruited to form new memories, the researchers say.

"This paper is, as far as I know, the first real evidence that this is how it actually works in a mammalian brain," Harnett says. "Filopodia allow a memory system to be both flexible and robust. You need flexibility to acquire new information, but you also need stability to retain the important information."

The researchers are now looking for evidence of these silent synapses in human brain tissue. They also hope to study whether the number or function of these synapses is affected by factors such as aging or neurodegenerative disease.

"It's entirely possible that by changing the amount of flexibility you've got in a memory system, it could become much harder to change your behaviors and habits or incorporate new information," Harnett says. "You could also imagine finding some of the molecular players that are involved in filopodia and trying to manipulate some of those things to try to restore flexible memory as we age."

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