Mitochondria are flinging their DNA into our brain cells

As direct descendants of ancient bacteria, mitochondria have always been a little alien.

Now a study shows that mitochondria are possibly even stranger than we thought.

Mitochondria in our brain cells frequently fling their DNA into the nucleus, the study found, where the DNA becomes integrated into the cells' chromosomes. And these insertions may be causing harm: Among the study's nearly 1,200 participants, those with more mitochondrial DNA insertions in their brain cells were more likely to die earlier than those with fewer insertions.

"We used to think that the transfer of DNA from mitochondria to the human genome was a rare occurrence," says Martin Picard, mitochondrial psychobiologist and associate professor of behavioral medicine at Columbia University Vagelos College of Physicians and Surgeons and in the Robert N. Butler Columbia Aging Center. Picard led the study with Ryan Mills of the University of Michigan.

"It's stunning that it appears to be happening several times during a person's lifetime, Picard adds. "We found lots of these insertions across different brain regions, but not in blood cells, explaining why dozens of earlier studies analyzing blood DNA missed this phenomenon."

Mitochondrial DNA behaves like a virus

Mitochondria live inside all our cells, but unlike other organelles, mitochondria have their own DNA, a small circular strand with about three dozen genes. Mitochondrial DNA is a remnant from the organelle's forebears: ancient bacteria that settled inside our single-celled ancestors about 1.5 billion years ago.

In the past few decades, researchers discovered that mitochondrial DNA has occasionally "jumped" out of the organelle and into human chromosomes.

"The mitochondrial DNA behaves similar to a virus in that it makes use of cuts in the genome and pastes itself in, or like jumping genes known as retrotransposons that move around the human genome," says Mills.

The insertions are called nuclear-mitochondrial segments -- NUMTs ("pronounced new-mites") -- and have been accumulating in our chromosomes for millions of years.

"As a result, all of us are walking around with hundreds of vestigial, mostly benign, mitochondrial DNA segments in our chromosomes that we inherited from our ancestors," Mills says.

Mitochondrial DNA insertions are common in the human brain

Research in just the past few years has shown that "NUMTogenesis" is still happening today.

"Jumping mitochondrial DNA is not something that only happened in the distant past," says Kalpita Karan, a postdoc in the Picard lab who conducted the research with Weichen Zhou, a research investigator in the Mills lab. "It's rare, but a new NUMT becomes integrated into the human genome about once in every 4,000 births. This is one of many ways, conserved from yeast to humans, by which mitochondria talk to nuclear genes."

The realization that new inherited NUMTs are still being created made Picard and Mills wonder if NUMTs could also arise in brain cells during our lifespan.

"Inherited NUMTs are mostly benign, probably because they arise early in development and the harmful ones are weeded out," says Zhou. But if a piece of mitochondrial DNA inserts itself within a gene or regulatory region, it could have important consequences on that person's health or lifespan. Neurons may be particularly susceptible to damage caused by NUMTs because when a neuron is damaged, the brain does not usually make a new brain cell to take its place.

To examine the extent and impact of new NUMTs in the brain, the team worked with Hans Klein, assistant professor in the Center for Translational and Computational Neuroimmunology at Columbia, who had access to DNA sequences from participants in the ROSMAP aging study (led by David Bennett at Rush University). The researchers looked for NUMTs in different regions of the brain using banked tissue samples from more than 1,000 older adults.

Their analysis showed that nuclear mitochondrial DNA insertion happens in the human brain -- mostly in the prefrontal cortex -- and likely several times over during a person's lifespan.

They also found that people with more NUMTs in their prefrontal cortex died earlier than individuals with fewer NUMTs. "This suggests for the first time that NUMTs may have functional consequences and possibly influence lifespan," Picard says. "NUMT accumulation can be added to the list of genome instability mechanisms that may contribute to aging, functional decline, and lifespan."

Stress accelerates NUMTogenesis

What causes NUMTs in the brain, and why do some regions accumulate more than others?

To get some clues, the researchers looked at a population of human skin cells that can be cultured and aged in a dish over several months, enabling exceptional longitudinal "lifespan" studies.

These cultured cells gradually accumulated several NUMTs per month, and when the cells' mitochondria were dysfunctional from stress, the cells accumulated NUMTs four to five times more rapidly.

"This shows a new way by which stress can affect the biology of our cells," Karan says. "Stress makes mitochondria more likely to release pieces of their DNA and these pieces can then 'infect' the nuclear genome," Zhou adds. It's just one way mitochondria shape our health beyond energy production.

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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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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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How tasty is the food?

To know when it's time for a meal -- and when to stop eating again -- is important to survive and to stay healthy, for humans and animals alike. Researchers at the Max Planck Institute for Biological Intelligence investigated how the brain regulates feeding behavior in mice. The team found that the hormone ghrelin activates specialized nerve cells in a brain region known as the amygdala. Here, the interaction between ghrelin and the specialized neurons promotes food consumption and conveys hunger and the pleasant and rewarding feelings associated with eating.

Hunger is a powerful sensation with important biological underpinnings. It signals the body to look for food, which is a crucial behavior to prevent starvation and ensure survival. When we're hungry, we crave for food -- and when we finally get to eat, our body rewards us with pleasant feelings and a general state of happiness.

A network of brain circuits and signaling pathways orchestrates the eating behavior of humans and animals and elicits the associated sensations. One of the central players in this network is the hormone ghrelin. It is released by stomach cells when humans and animals are hungry or fasting, and promotes feeding behavior.

The department of Rüdiger Klein at the Max Planck Institute for Biological Intelligence studies the brain networks that underly feeding behavior in mice. To this end, the researchers conducted a thorough analysis of the different cell types in a brain region known as the central amygdala. "Previously, the amygdala had mostly been studied in the context of feelings like fear and reward, while the regulation of feeding was thought to happen in different parts of the brain, such as the hypothalamus," says Christian Peters, a postdoctoral researcher in the department.

Nine cell clusters

Peters and his colleagues analyzed individual cells in the central amygdala, studying messenger RNA molecules -- the cell's working copies of their genes. The analysis revealed that the cells are organized into nine different cell clusters. Some of these clusters promote appetite while others inhibit it, and they adjust their production of messenger RNAs when the mice are fed or fasting.

"We now have a much better understanding of the diversity of cell types and the physiological processes that promote feeding in the central amygdala," says Rüdiger Klein. "Our research uncovers for the first time that the 'hunger hormone' ghrelin also acts on cells in the central amygdala." There, it activates a small subset of cell clusters, collectively marked by the presence of the protein Htr2a, to increase feeding.

Multiple functions for ghrelin

The scientists found that the Htr2a neurons became active after an overnight fast or when stimulated by the hormone ghrelin. The cells also responded when the researchers presented food to the mice. "We think that ghrelin performs multiple functions," explains Christian Peters. "When mice are hungry, ghrelin activates the appetitive brain regions to predispose the animals for eating. In addition, the hormone enhances the activity in brain circuits, such as the amygdala, that confer rewards, which is likely an incentive to eat additional food." This way, ghrelin increases the palatability of food in proportion to how satiated the mice currently are.

After a fasting diet, when the animals were very hungry the activity of Htr2a neurons was not needed to start feeding, presumably because the tastiness of food is less important under these conditions. "Other brain circuits, for example the hypothalamus, which regulate the body's metabolism, take over and signal the mice that it's important to eat in order to survive," says Christian Peters.

Feeling hungry or satiated has profound impacts on physical but also on emotional wellbeing, as probably everyone knows by the pleasures associated with eating tasty food. "The neuronal networks that convey these feelings are obviously linked to those that control eating, yet it is not fully understood how exactly they influence each other," says Rüdiger Klein.

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Organoids reveal how SARS-CoV-2 damages brain cells -- and a potential treatment

Using human brain organoids, an international team of researchers, led by scientists at University of California San Diego School of Medicine and Sanford Consortium, has shown how the SARS-CoV-2 virus that causes COVID-19 infects cortical neurons and specifically destroys their synapses -- the connections between brain cells that allow them to communicate with each other.

The findings, published in the November 3, 2022 issue of PLOS Biology, also report that the antiviral drug sofosbuvir, already an approved treatment for hepatitis C, effectively inhibited SARS-CoV-2 replication and reversed neuronal alterations in infected brain organoids.

"Vaccines and emerging treatments have reduced the health consequences of COVID-19 in most patients," said senior study author Alysson R. Muotri, PhD, professor in departments of Pediatrics and Cellular and Molecular at UC San Diego School of Medicine. "But the phenomenon of Long COVID, characterized by persisting symptoms that include neurological impairment, remains poorly understood and without any specific remedy.

"This work helps explain some of the neurological symptoms of COVID-19 and, more importantly, it suggests that an FDA-approved antiviral drug might be repurposed to restore infected brain cells to health and address long-term neurological outcomes of COVID-19."

Though primarily considered to be a respiratory disease, COVID-19 can cause temporary or long-lasting neurological symptoms in some patients, ranging from loss of taste and smell, impaired concentration (brain fog), and psychological effects such as depression to stroke, epilepsy, and encephalopathy (a change in brain function or structure).

With evidence accumulating that the SARS-CoV-2 virus can infect and alter brain cells (including in developing fetuses), the research team focused on using organoids -- self-organizing, three-dimensional tissues derived from cultured stem cells that can mimic some organ functions.

Researchers exposed the brain organoids to SARS-CoV-2, observed viral infection and replication and noted that the virus rapidly decreased the number of excitatory synapses in neurons within seven days post-infection. Excitatory synapses increase the firing action potential of a neuron, while their counterparts, called inhibitory synapses, decrease that potential.

However, when infected organoids were treated with sofosbuvir, viral replication was inhibited, and observed neurological impairments rescued or restored. The findings echo earlier computational models that suggested sofosbuvir could be a treatment and previous research by Muotri and colleagues that found sofosbuvir effectively protected and rescued neural cells infected by the Zika virus.

"The bottom line is that sofosbuvir appears to have the potential to arrest or prevent the development of neurological symptoms in COVID-19 patients," Muotri said. "And because it has been shown to present no safety concerns in pregnant women, it might also be an option for preventing SARS-CoV-2 transmission to their unborn children.

"Further studies and clinical trials are needed, of course, but these findings offer a path forward for treating a condition (Long COVID) that has so far stymied remedy for millions of people wordwide."

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The brain cells that slow us down when we're sick

We tend to eat, drink, and move less when we're feeling under the weather. And we're not alone -- most animals reduce those same three behaviors when they're fighting an infection.

Now, a new study pinpoints the cluster of neurons that control these responses, referred to as sickness behaviors. By provoking immune responses in mice, researchers demonstrated that a specific population of cells in the brainstem potently induce three telltale sickness behaviors. In addition, inhibiting these neurons blunts each of these behavioral elements of the sickness response. The findings, published in Nature, directly link inflammation to neural pathways regulating behavior, offering insight into how the immune system interacts with the brain.

"We are still in the early days of trying to understand the brain's role in infection," says Jeffrey M. Friedman, Marilyn M. Simpson Professor at The Rockefeller University. "But with these results, we now have a unique opportunity to ask: What does your brain look like when you're sick?"

Sickness behaviors have been shown to play an important role in an animal's recovery from an infection. Prior studies have bolstered that theory by demonstrating that animals forced to eat when they're sick showed a significantly increased mortality. "These behavioral changes during infection are really important for survival," says lead author Anoj Ilanges, a former graduate student in Friedman's lab, now a group leader at the HHMI Janelia Research Campus

But it has never been clear how the brain coordinates that near-universal urge to refuse meals and curl up under the covers with the onset of infection. So Friedman and Ilanges set out to map the brain regions behind sickness behaviors in mice.

The team began by exposing mice to LPS, a piece of bacterial cell wall that activates the immune system and potently induces sickness behavior. Shortly after an injection of LPS, there was a spike in activity in a brainstem region known as the dorsal vagal complex, among a population of neurons expressing the neuropeptide ADCYAP1. To confirm that they had found the right brain cells, the researchers then activated those neurons in healthy mice and they found that the animals ate, drank, and moved around less. In contrast, when the ADCYAP1 neurons were deactivated , the effect of LPS on these behaviors was significantly reduced.

"We didn't know if the same or different neurons regulated each of these behaviors," Friedman says, "We found it surprising that a single neuronal population appears to regulate each of these components of the sickness response."

The authors were not, however, altogether surprised that this brainstem region was involved in mediating sickness behaviors. The dorsal vagal complex is one of a precious few physiological crossroads of the central nervous system, where an absence of the blood brain barrier enables circulating factors in the blood to pass information directly to the brain. "This region has emerged as a kind of alert center for the brain, conveying information about aversive or noxious substances that, more often than not, reduce food intake," Friedman says.

In the coming months, Friedman's team at Rockefeller intends to incorporate these findings into their overall goal of understanding the physiological signals and neural circuitry that regulate feeding behavior. They are specifically interested in understanding why even mice engineered to eat voraciously will nonetheless stop eating when exposed to bacterial infections.

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Human brain cells in a dish learn to play Pong in real time

Human and mouse neurons in a dish learned to play the video game Pong, researchers report October 12 in the journal Neuron. The experiments are evidence that even brain cells in a dish can exhibit inherent intelligence, modifying their behavior over time.

"From worms to flies to humans, neurons are the starting block for generalized intelligence," says first author Brett Kagan (@ANeuroExplorer), chief scientific officer at Cortical Labs in Melbourne, Australia. "So, the question was, can we interact with neurons in a way to harness that inherent intelligence?"

To start, the researchers connected the neurons to a computer in such a way where the neurons received feedback on whether their in-game paddle was hitting the ball. They monitored the neuron's activity and responses to this feedback using electric probes that recorded "spikes" on a grid.

The spikes got stronger the more a neuron moved its paddle and hit the ball. When neurons missed, their playstyle was critiqued by a software program created by Cortical Labs. This demonstrated that the neurons could adapt activity to a changing environment, in a goal-oriented way, in real time.

"We chose Pong due to its simplicity and familiarity, but, also, it was one of the first games used in machine learning, so we wanted to recognize that," says Kagan, who worked with collaborators from 10 other institutions on the project.

"An unpredictable stimulus was applied to the cells, and the system as a whole would reorganize its activity to better play the game and to minimize having a random response," he says. "You can also think that just playing the game, hitting the ball and getting predictable stimulation, is inherently creating more predictable environments."

The theory behind this learning is rooted in the free-energy principle. Simply put, the brain adapts to its environment by changing either its world view or its actions to better fit the world around it.

Pong wasn't the only game the research team tested. "You know when the Google Chrome browser crashes and you get that dinosaur that you can make jump over obstacles (Project Bolan). We've done that and we've seen some nice preliminary results, but we still have more work to do building new environments for custom purposes," says Kagan.

Future directions of this work have potential in disease modeling, drug discoveries, and expanding the current understanding of how the brain works and how intelligence arises.

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Brains cells born together wire and fire together for life

Brain cells with the same "birthdate" are more likely to wire together into cooperative signaling circuits that carry out many functions, including the storage of memories, a new study finds.

Led by researchers from NYU Grossman School of Medicine, the new study on the brains of mice developing in the womb found that brain cells (neurons) with the same birthdate showed distinct connectivity and activity throughout the animals' adult lives, whether they were asleep or awake.

Published online August 22 in Nature Neuroscience, the findings suggest that evolution took advantage of the orderly birth of neurons -- by gestational day -- to form localized microcircuits in the hippocampus, the brain region that forms memories. Rather than attempting to create each new memory from scratch, the researchers suggest, the brain may exploit the stepwise formation of neuronal layers to establish neural templates, like "Lego pieces," that match each new experience to an existing template as it is remembered.

These rules of circuit assembly would suggest that cells born together are more likely to encode memories together, and to fail together, potentially implicating neuronal birthdate in diseases like autism and Alzheimer's, say the authors. With changes to the number of cells born at different days, the developing brain may be more vulnerable on some gestational days to viral infections, toxins, or alcohol.

"Our study's results suggest that which day a hippocampal neuron is born strongly influences both how that single cell performs, and how populations of such cells signal together throughout life," says senior study author György Buzsáki, MD, PhD, the Biggs Professor in the Department of Neuroscience and Physiology at NYU Langone Health. "This work may reshape how we study neurodevelopmental disorders, which have traditionally been looked at through a molecular or genetic, rather than a developmental, lens," says Buzsáki, also a faculty member in the Neuroscience Institute at NYU Langone."

New Understanding

The current study's innovation rests on tracking the activity of neurons of a given birthdate into adulthood. To accomplish this, the researchers relied on a technique that allowed them to transfer DNA into cells that were undergoing division into neurons in the womb. The DNA expressed markers that tagged brain cells that were born on same day, akin to a barcode. This labeling method then enabled the researchers to study these neurons in the adult animal.

Using a combination of techniques, the new study found that neurons of the same birthdate tend to "co-fire" together, characterized by synchronized swings in their positive and negative charges, allowing them to transmit electrical signals collectively. A likely reason for the co-firing, say the authors, is that neurons with the same birthdate are connected via shared neurons.

Past work had shown that activity in the hippocampus can be described in terms patterns of collective neuronal activity during waking and sleep. During sleep, for instance, when each day's memories are consolidated for long-term memory storage, hippocampal neurons engage in a cyclical burst of activity called the "sharp wave-ripple," named for the shape it takes when captured graphically by EEG, a technology that records brain activity with electrodes.

"Our results show that neurons born on the same day become part of the same cooperating assemblies, and participate in the same sharp wave-ripples and represent the same memories," says first author Roman Huszár, a graduate student in Buzsáki's lab. "These relationships, and the pre-set templates they encode, have a key implication for hippocampal function: the storage of a memory about a place or event."

Moving forward, the team plans additional experiments to identify the genes active in the same birthdate neurons in different brain regions, and to test their role in memory formation and behavior.

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Boost in nerve-growth protein helps explain why running supports brain health

Exercise increases levels of a chemical involved in brain cell growth, which bolsters the release of the "feel good" hormone dopamine, a new study shows. Dopamine is known to play a key role in movement, motivation, and learning.

Experts have long understood that regular running raises dopamine activity in the brain and may protect nerve cells from damage. In addition, past research has tied exercise-driven boosts in the dopamine-triggering chemical called brain-derived neurotrophic factor (BDNF) and in dopamine levels to improvements in learning and memory. However, the precise way these three factors interact has until now remained unclear.

Led by researchers at NYU Grossman School of Medicine, the investigation showed that mice running on a wheel for 30 days had a 40% increase in dopamine release in the dorsal stratium, the part of the brain involved in movement, compared to levels in mice that did not exercise. The runners also showed a nearly 60% increase in BDNF levels compared to their non-running counterparts. Notably, the increase in dopamine release remained elevated even after a week of rest. Additionally, when BDNF levels were artificially reduced, running did not lead to additional dopamine release.

"Our findings suggest that BDNF plays a key role in the long-lasting changes that occur in the brain as a result of running," says study lead author and neurobiologist Guendalina Bastioli, PhD. "Not only do these results help explain why exercise makes you move, think, and feel better, they also show that these benefits continue even if you do not work out every day," adds Bastioli, a postdoctoral fellow in the Department of Neuroscience at NYU Langone Health.

While researchers have previously measured dopamine activity during running, the new investigation provides insight into the longer-term behavior of the hormone and its effects on the brain well after exercise stops, according to Bastioli. The report is publishing online May 16 in the Journal of Neuroscience.

For the investigation, researchers provided dozens of male mice with unlimited access to either a freely rotating wheel or a locked wheel that could not move. After one month, the team measured dopamine release and BDNF levels in brain slices. They repeated this same process on a new group of rodents, some of which had been genetically modified to produce half as much BDNF as regular mice.

The study authors note that patients with Parkinson's disease and other movement disorders are often treated with drugs that mimic dopamine's effects on motor neurons. However, the mechanism behind dopamine's role in this protective benefit of exercise had not been thoroughly explored.

"Our results help us understand why exercise alleviates the symptoms of Parkinson's disease, as well as those of neuropsychiatric disorders such as depression," says study senior author and neuroscientist Margaret Rice, PhD. "Now that we know why physical activity helps, we can explore it as a means of augmenting or even replacing the use of dopamine-enhancing drugs in these patients."

Rice, a professor in the Departments of Neurosurgery and Neuroscience and Physiology at NYU Langone, cautions that while the preliminary findings in rodents were promising, future studies in humans will be required to fully understand the role of BDNF and dopamine in Parkinson's disease.

She adds that the study team next plans to investigate the relationship between exercise and these chemicals in female mice, which notably run more frequently than males. In addition, the researchers intend to directly examine whether active mice indeed have improved motor skills compared with those with limited physical activity.

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New sleep molecule discovered: 'It shows just how complex the machinery of sleep is'

Researchers from the University of Copenhagen and Aalborg University presents a new study demonstrating that a small molecule in brain cells affects the level of hypocretin, which is responsible for making us feel awake during the day and tired at night. People with a genetic variation of this molecule have a higher risk of suffering from daytime sleepiness.

When brain scientist Birgitte Kornum from the Department of Neuroscience recently arrived in Rome for one of the largest sleep conferences in the world, she was completely taken aback. There were pharmaceutical companies everywhere -- with stands, information material and campaigns.

They all wanted to treat daytime sleepiness or to turn off the brain at night. And a lot of them focussed on hypocretin, which is a protein found in brain cells and which has recently attracted a lot of attention within sleep research.

This is because hypocretin is suspected to play a role in both insomnia, which is a decreased ability to fall asleep at night, and in narcolepsy, which is a decreased ability to stay awake during the day. People suffering from insomnia may have too much hypocretin in the brain, while people suffering from narcolepsy have too little. Researchers also suspect hypocretin to play a role in depression, ADHD and other mental disorders.

A lot is already known about the hypocretin system in the brain. There is even a new drug for insomnia countering the effect of hypocretin, latest introduced in Canada in 2018. According to Birgitte Kornum, though, the problem is that we know very little about how hypocretin is regulated inside the cells.

Therefore, Associate Professor Birgitte Kornum and her colleagues set out to shed light on the issue in a new study, which has recently been published in the reputed journal PNAS. The study combines tests on mice, zebrafish and human cells, and the researchers cooperated with their neighbours at the University of Copenhagen's Department of Cellular and Molecular Medicine, among others.

MicroRNA associated with sleep regulation

The team of researchers have spent several years studying one of the cellular mechanisms that affect hypocretin levels. Here they have focussed on a small molecule called microRNA-137 (miR-137).

"We discovered that miR-137 helps regulate hypocretin. To experience normal sleep, you need to have the right amount of hypocretin in the brain at the right time, and miR-137 helps with that. Though MiR-137 is also found in other parts of the body, it is especially pronounced in the brain," Birgitte Kornum says about the new study, which she has headed together with Assistant Professor Anja Holm from Aalborg University.

MicroRNA regulates various cellular processes, including hypocretin levels. Therefore, there is considerable research interest in microRNAs, as they could be targeted in order to regulate such processes.

Previously, the scientists knew very little about the role played by miR-137 in the brain, but now Birgitte Kornum's research team has demonstrated that it is associated with hypocretin regulation and thus with sleep.

"This is the first time a microRNA is associated with sleep regulation. Drawing on the UK Biobank, we discovered some genetic mutations in miR-137 which cause daytime sleepiness. The study demonstrates this connection in both mice and zebrafish, and we are able to prove the connection with hypocretin. Our discovery shows just how complex the machinery of sleep is. Imagine inheriting a variant of miR-137 that puts you at higher risk of feeling sleepy during the day," says Birgitte Kornum.

Hypocretin affects sleep stages

Hypocretin, which has caught the attention of the pharmaceutical companies, also affects the order of the sleep stages.

Our sleep is usually divided into four stages. The stages follow a specific order, and this order is vital to the quality of our sleep.

"Narcolepsy patients suffering from low levels of hypocretin experience muddled sleep stages. We know this from mice tests demonstrating that hypocretin affects the order of these stages," explains Anja Holm from Aalborg University, who is first author of the study and who did the tests together with Birgitte Kornum.

Existing research suggests that to solve the problem we need to gain more knowledge of hypocretin regulation. And here the Danish researchers point to a different, but equally important piece of the puzzle, namely the immune system.

"Most people know that when you are ill you often feel tired. And when you have a fever and the immune system is hard at work, you often suffer from poor sleep. So we know that something happens to the hypocretin level when the body is trying to fight off a virus infection, for example, and we are trying to understand this process," says Birgitte Kornum.

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How does the brain make memories?

Researchers have discovered two types of brain cells that play a key role in dividing continuous human experience into distinct segments that can be recalled later. The discovery provides new promise as a path toward development of novel treatments for memory disorders such as dementia and Alzheimer's disease.

In a study led by Cedars-Sinai, researchers have discovered two types of brain cells that play a key role in dividing continuous human experience into distinct segments that can be recalled later. The discovery provides new promise as a path toward development of novel treatments for memory disorders such as dementia and Alzheimer's disease.

The study, part of a multi-institutional BRAIN Initiative consortium funded by the National Institutes of Health and led by Cedars-Sinai, was published in the peer-reviewed journal Nature Neuroscience. As part of ongoing research into how memory works, Ueli Rutishauser, PhD, professor of Neurosurgery, Neurology, and Biomedical Sciences at Cedars-Sinai, and co-investigators looked at how brain cells react as memories are formed.

"One of the reasons we can't offer significant help for somebody who suffers from a memory disorder is that we don't know enough about how the memory system works," said Rutishauser, senior author of the study, adding that memory is foundational to us as human beings.

Human experience is continuous, but psychologists believe, based on observations of people's behavior, that memories are divided by the brain into distinct events, a concept known as event segmentation. Working with 19 patients with drug-resistant epilepsy, Rutishauser and his team were able to study how neurons perform during this process.

Patients participating in the study had electrodes surgically inserted into their brains to help locate the focus of their epileptic seizures, allowing investigators to record the activity of individual neurons while the patients viewed film clips that included cognitive boundaries.

While these boundaries in daily life are nuanced, for research purposes, the investigators focused on "hard" and "soft" boundaries.

"An example of a soft boundary would be a scene with two people walking down a hallway and talking, and in the next scene, a third person joins them, but it is still part of the same overall narrative," said Rutishauser, interim director of the Center for Neural Science and Medicine and the Board of Governors Chair in Neurosciences at Cedars-Sinai.

In the case of a hard boundary, the second scene might involve a completely different set of people riding in a car. "The difference between hard and soft boundaries is in the size of the deviation from the ongoing narrative," Rutishauser said. "Is it a totally different story, or like a new scene from the same story?"

When study participants watched film clips, investigators noted that certain neurons in the brain, which they labeled "boundary cells," increased their activity after both hard and soft boundaries. Another group of neurons, labeled "event cells," increased their activity only in response to hard boundaries, but not soft boundaries.

Rutishauser and his co-investigators theorize that peaks in the activity of boundary and event cells -- which are highest after hard boundaries, when both types of cells fire -- send the brain into the proper state for initiating a new memory.

"A boundary response is kind of like creating a new folder on your computer," said Rutishauser. "You can then deposit files in there. And when another boundary comes around, you close the first folder and create another one."

To retrieve memories, the brain uses boundary peaks as what Rutishauser calls "anchors for mental time travel."

"When you try to remember something, it causes brain cells to fire," Rutishauser said. "The memory system then compares this pattern of activity to all the previous firing peaks that happened shortly after boundaries. If it finds one that is similar, it opens that folder. You go back for a few seconds to that point in time, and things that happened then come into focus."

To test their theory, investigators gave study participants two memory tests.

They first showed participants a series of still images and asked them whether or not they had seen them in the film clips they had viewed. Study participants were more likely to remember images that closely followed a hard or soft boundary, when a new "memory folder" would have been created.

Investigators also showed participants pairs of images from film clips they had viewed and asked which of the images appeared first. Participants had difficulty remembering the correct order of images that appeared on opposite sides of a hard boundary, possibly because the brain had segmented those images into separate memory folders.

Rutishauser said that therapies that improve event segmentation could help patients with memory disorders. Even something as simple as a change in atmosphere can amplify event boundaries, he explained.

"The effect of context is actually quite strong," Rutishauser said. "If you study in a new place, where you have never been before, instead of on your couch where everything is familiar, you will create a much stronger memory of the material."

The research team included postdoctoral fellow Jie Zheng, PhD, and neuroscientist Gabriel Kreiman, PhD, from Boston Children's Hospital; neurosurgeon Taufik A. Valiante, MD, PhD, of the University of Toronto; and Adam Mamelak, MD, professor of Neurosurgery and director of the Functional Neurosurgery Program at Cedars-Sinai.

In follow-up studies, the team plans to test the theory that boundary and event cells activate dopamine neurons when they fire, and that dopamine, a chemical that sends messages between cells, might be used as a therapy to strengthen memory formation.

Rutishauser and his team also noted during this study that when event cells fired in time with one of the brain's internal rhythms, the theta rhythm -- a repetitive pattern of activity linked to learning, memory and navigation -- subjects were better able to remember the order of images they had seen. This is an important new insight because it shows that deep brain stimulation that adjusts theta rhythms could prove therapeutic for memory disorders.

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Neuroscientists roll out first comprehensive atlas of brain cells

When you clicked to read this story, a band of cells across the top of your brain sent signals down your spine and out to your hand to tell the muscles in your index finger to press down with just the right amount of pressure to activate your mouse or track pad.

A slew of new studies now shows that the area of the brain responsible for initiating this action -- the primary motor cortex, which controls movement -- has as many as 116 different types of cells that work together to make this happen.

The 17 studies, appearing online Oct. 6 in the journal Nature, are the result of five years of work by a huge consortium of researchers supported by the National Institutes of Health's Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative to identify the myriad of different cell types in one portion of the brain. It is the first step in a long-term project to generate an atlas of the entire brain to help understand how the neural networks in our head control our body and mind and how they are disrupted in cases of mental and physical problems.

"If you think of the brain as an extremely complex machine, how could we understand it without first breaking it down and knowing the parts?" asked cellular neuroscientist Helen Bateup, a University of California, Berkeley, associate professor of molecular and cell biology and co-author of the flagship paper that synthesizes the results of the other papers. "The first page of any manual of how the brain works should read: Here are all the cellular components, this is how many of them there are, here is where they are located and who they connect to."

Individual researchers have previously identified dozens of cell types based on their shape, size, electrical properties and which genes are expressed in them. The new studies identify about five times more cell types, though many are subtypes of well-known cell types. For example, cells that release specific neurotransmitters, like gamma-aminobutyric acid (GABA) or glutamate, each have more than a dozen subtypes distinguishable from one another by their gene expression and electrical firing patterns.

While the current papers address only the motor cortex, the BRAIN Initiative Cell Census Network (BICCN) -- created in 2017 -- endeavors to map all the different cell types throughout the brain, which consists of more than 160 billion individual cells, both neurons and support cells called glia. The BRAIN Initiative was launched in 2013 by then-President Barack Obama.

"Once we have all those parts defined, we can then go up a level and start to understand how those parts work together, how they form a functional circuit, how that ultimately gives rise to perceptions and behavior and much more complex things," Bateup said.

Together with former UC Berkeley professor John Ngai, Bateup and UC Berkeley colleague Dirk Hockemeyer have already used CRISPR-Cas9 to create mice in which a specific cell type is labeled with a fluorescent marker, allowing them to track the connections these cells make throughout the brain. For the flagship journal paper, the Berkeley team created two strains of "knock-in" reporter mice that provided novel tools for illuminating the connections of the newly identified cell types, she said.

"One of our many limitations in developing effective therapies for human brain disorders is that we just don't know enough about which cells and connections are being affected by a particular disease and therefore can't pinpoint with precision what and where we need to target," said Ngai, who led UC Berkeley's Brain Initiative efforts before being tapped last year to direct the entire national initiative. "Detailed information about the types of cells that make up the brain and their properties will ultimately enable the development of new therapies for neurologic and neuropsychiatric diseases."

Ngai is one of 13 corresponding authors of the flagship paper, which has more than 250 co-authors in all.

Bateup, Hockemeyer and Ngai collaborated on an earlier study to profile all the active genes in single dopamine-producing cells in the mouse's midbrain, which has structures similar to human brains. This same profiling technique, which involves identifying all the specific messenger RNA molecules and their levels in each cell, was employed by other BICCN researchers to profile cells in the motor cortex. This type of analysis, using a technique called single-cell RNA sequencing, or scRNA-seq, is referred to as transcriptomics.

The scRNA-seq technique was one of nearly a dozen separate experimental methods used by the BICCN team to characterize the different cell types in three different mammals: mice, marmosets and humans. Four of these involved different ways of identifying gene expression levels and determining the genome's chromatin architecture and DNA methylation status, which is called the epigenome. Other techniques included classical electrophysiological patch clamp recordings to distinguish cells by how they fire action potentials, categorizing cells by shape, determining their connectivity, and looking at where the cells are spatially located within the brain. Several of these used machine learning or artificial intelligence to distinguish cell types.

"This was the most comprehensive description of these cell types, and with high resolution and different methodologies," Hockemeyer said. "The conclusion of the paper is that there's remarkable overlap and consistency in determining cell types with these different methods."

A team of statisticians combined data from all these experimental methods to determine how best to classify or cluster cells into different types and, presumably, different functions based on the observed differences in expression and epigenetic profiles among these cells. While there are many statistical algorithms for analyzing such data and identifying clusters, the challenge was to determine which clusters were truly different from one another -- truly different cell types -- said Sandrine Dudoit, a UC Berkeley professor and chair of the Department of Statistics. She and biostatistician Elizabeth Purdom, UC Berkeley associate professor of statistics, were key members of the statistical team and co-authors of the flagship paper.

"The idea is not to create yet another new clustering method, but to find ways of leveraging the strengths of different methods and combining methods and to assess the stability of the results, the reproducibility of the clusters you get," Dudoit said. "That's really a key message about all these studies that look for novel cell types or novel categories of cells: No matter what algorithm you try, you'll get clusters, so it is key to really have confidence in your results."

Bateup noted that the number of individual cell types identified in the new study depended on the technique used and ranged from dozens to 116. One finding, for example, was that humans have about twice as many different types of inhibitory neurons as excitatory neurons in this region of the brain, while mice have five times as many.

"Before, we had something like 10 or 20 different cell types that had been defined, but we had no idea if the cells we were defining by their patterns of gene expression were the same ones as those defined based on their electrophysiological properties, or the same as the neuron types defined by their morphology," Bateup said.

"The big advance by the BICCN is that we combined many different ways of defining a cell type and integrated them to come up with a consensus taxonomy that's not just based on gene expression or on physiology or morphology, but takes all of those properties into account," Hockemeyer said. "So, now we can say this particular cell type expresses these genes, has this morphology, has these physiological properties, and is located in this particular region of the cortex. So, you have a much deeper, granular understanding of what that cell type is and its basic properties."

Dudoit cautioned that future studies could show that the number of cell types identified in the motor cortex is an overestimate, but the current studies are a good start in assembling a cell atlas of the whole brain.

"Even among biologists, there are vastly different opinions as to how much resolution you should have for these systems, whether there is this very, very fine clustering structure or whether you really have higher level cell types that are more stable," she said. "Nevertheless, these results show the power of collaboration and pulling together efforts across different groups. We're starting with a biological question, but a biologist alone could not have solved that problem. To address a big challenging problem like that, you want a team of experts in a bunch of different disciplines that are able to communicate well and work well with each other."

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Think a census of humans is hard? Try counting their brain cells!

In 2013, the U.S. government began investing $100 million to decipher how the human brain works in a collaborative project called the BRAIN Initiative. Cold Spring Harbor Laboratory (CSHL) and other researchers built tools and set standards for describing all the cells in the brain. On October 7, 2021 the initiative reached a major milestone, publishing a comprehensive census of cell types in the mouse, monkey, and human primary motor cortex in Nature.

The BRAIN Initiative Cell Census Network (BICCN) is the consortium of neuroscientists, computational scientists, physicists, geneticists, and instrument makers within the BRAIN Initiative tasked with counting and mapping all the cells in the brain.

Z. Josh Huang, an adjunct professor at CSHL, leads one branch of the BICCN that includes five principal investigators from CSHL and researchers from other institutions. His lab outlined ways to classify new cell subtypes within the mouse forebrain based on their shapes, connections, and the genes they use.

CSHL Professor Partha Mitra and other CSHL collaborators taught a computer to recognize different parts of neurons, then mapped the cells onto a topological world to see how those neurons are likely to connect.

CSHL Associate Professor Jesse Gillis' lab developed a statistics-based computer tool to categorize cells based on similarities in their component parts. This program, called MetaNeighbor, uses RNA transcripts (the instructions to build the components) to compare and categorize mammalian brain cells.

CSHL Professor Anthony Zador's lab developed MAPseq to map how different brain cells connect and interact. Several years later, Zador and his team developed BARseq and BARseq2, which can map connections and gene-use in thousands of neurons in a single mouse at single-neuron resolution.

CSHL Associate Professor Pavel Osten leads another branch of the BICCN dedicated to finding anatomical differences between female and male mouse brains. He and his lab developed qBrain, a method that combines brain imaging techniques to map cells and connections of the mouse primary motor cortex in three dimensions.

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Mutated enzyme weakens connection between brain cells that help control movement

In one type of a rare, inherited genetic disorder that affects control of body movement, scientists have found a mutation in an enzyme impairs communication between neurons and what should be the inherent ability to pick up our pace when we need to run, instead of walk, across the street.

The disorder is spinocerebellar ataxia, or SCA, a neurodegenerative condition resulting from different genetic mutations whose debilitating bottom line can include ataxia -- loss of control of body movement -- and atrophy of the cerebellum, a small part of the brain jam packed with neurons, which coordinates movement and balance, says Dr. Ferenc Deak, neuroscientist at the Medical College of Georgia at Augusta University.

The enzyme is ELOVL4, which produces very long chain fatty acids, and its mutation is known to cause the specific SCA type 34. Animal models with this SCA type have problems with motor control by age two months, and scientists from MCG and the University of Oklahoma Health Sciences Center wanted to know precisely why.

"We found a dramatically diminished synaptic response. The information was to go faster, go faster and they never really got the message," Deak, co-corresponding author of the study in the journal Molecular Neurobiology, says of these communication connections between neurons. "They were transmitting the signal, but when they had to adjust their synaptic connection to coordinate the different movement, that did not happen in the mutant knock-in rat," he says of the SCA34 model generated using the gene editing technique CRISPR cas9.

Despite the different gene mutations that are causative in SCA, a common bottom line appears to be altered output of the cerebellum and an impact on Purkinje cells, big brain cells in the cerebellum, which can receive about 100 times the input of usual neurons. The big cells also exclusively inhibit communication, so they shut down signals that would interfere with something like a muscle being activated. Loss of these key cells is clear in many forms of SCA, Deak says.

Much like an air traffic controller at a busy airport, these big brain cells obviously monitor a lot of different input simultaneously, and they are the only neuron sending out messages from that part of the brain.

Purkinje cells get a lot of their input from granule cells, one of the smallest neurons in the brain but largest in number. Both cell types express a lot of ELOVL4 and also depend on the enzyme, Deak says. ELOVL4 was known to be important to the communication between these and other cells, but why remained elusive.

The new studies found mutation of ELOVL4 resulted in significant reduction of the ability of synapses that bring messages to and away from Purkinje cells to strengthen their signaling, which is essential in this case to coordinating movement, so you could speed up your pace if needed or move your hands wildly about on command.

Their findings point to the essential role of ELOVL4 in motor function and synaptic plasticity, Deak says.

They also suggest that patients with SCA34 have an impairment and asynchrony in the communication between key neurons in the cerebellum well before their brain shows clear signs of degeneration.

Deak notes that over time, the impaired responses between these constantly communicating cells may lead to the degeneration of the cerebellum often found in patients when they first go to their doctor with complaints about problems with walking, talking and other movement.

But in their model of SCA34, the structure of the cerebellum looked normal up to six months of age, even though the animal models clearly had the expected motor deficits, the scientists report.

They found the synapses also were intact and functioning at a basic level that enables the rats to, for example, walk normally, but in these knock-in rats the usual plasticity or flexibility was lacking. Rather synapses in the mutant couldn't increase signaling and make that transition.

ELOVL4 can make both saturated and unsaturated very long chain fatty acids -- dubbed "long" because of the large number of carbon atoms they contain -- depending on which tissue the enzyme is in. In the cerebellum, it enables Purkinje and granule cells to make saturated very long chain fatty acids, which were known to be important to synaptic function, Deak says. But exactly how they are important was an unknown.

The scientists think the weakened synaptic responsiveness they found is a quantity problem: the mutated enzyme makes about 70% of the usual amount of very long chain fatty acids, which appears to be the threshold for gait problems. If the cells produced none, it would result in excessive seizures and death as Deak has seen in other models.

Their current research includes finding ways to deliver more saturated very long chain fatty acids to the brain. The scientists have a patent pending on one way to make this maneuver, which is made tougher by the fact that when you produce saturated very long chain fatty acids they have the consistency of candle wax, Deak says, which the rats don't even digest, just poop out.

Very long chain fatty acids are essential to life but their exact roles are mostly elusive, the scientists say.

"What we know from our work is that they are a very important component for certain cell membranes," Deak says, like the membranes of some excitatory and inhibitory neurons as well as skin cells. In fact, the scientists have shown that when ELOVL4 is missing in the skin, body fluids seep through the skin, our largest natural barrier. In generating other ELOVL4 mutant mice models they had to overexpress ELOVL4 specifically in the skin to enable survival, Deak said.

Deak's research has shown that these saturated very long chain fatty acids also like to accumulate and strengthen vesicles, tiny traveling compartments that can move about inside cells, so they are better able to get to their destination before they fuse with a cell membrane. Fusing is necessary for neurotransmission -- one of the things vesicles in the brain transport is chemical messengers called neurotransmitters -- but unregulated fusion is bad.

The scientists documented its impact when they found that mice with two mutant copies of ELOVL4 died of seizures. While they were making these findings in the laboratory, there were reports out of Saudi Arabia about children having the same mutations and issues, he says. In fact, it was Deak's research interest in seizures that prompted his pursuit of better understanding the roles of very long chain fatty acids. He suspects they have a role in his other interest as well: the aging brain and Alzheimer's.

A team led by Dr. Martin-Paul Agbaga created the "knock-in" rat model of the human condition SCA34, which has been identified in one French-Canadian family and three Japanese families. In these individuals, skin problems can surface from shortly after birth to adolescence, and movement problems and typically progressive movement issues start surfacing in their 30s.

Agbaga, co-corresponding author of the new paper and one of Deak's longtime collaborators, is a vision scientist and cell biologist at the University of Oklahoma Health Sciences Center Department of Ophthalmology and Dean McGee Eye Institute.

Dr. Robert E. Anderson, professor of vision research at the Dean McGee Eye Institute, founder of the ELOVL4 research group in Oklahoma, and a worldwide leader of research on lipid pathophysiology in the retina, is a coauthor on the paper. Deak came to MCG from the University of Oklahoma Health Sciences Center last year.

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Study finds brain areas involved in seeking information about bad possibilities

The term "doomscrolling" describes the act of endlessly scrolling through bad news on social media and reading every worrisome tidbit that pops up, a habit that unfortunately seems to have become common during the COVID-19 pandemic.

The biology of our brains may play a role in that. Researchers at Washington University School of Medicine in St. Louis have identified specific areas and cells in the brain that become active when an individual is faced with the choice to learn or hide from information about an unwanted aversive event the individual likely has no power to prevent.

The findings, published June 11 in Neuron, could shed light on the processes underlying psychiatric conditions such as obsessive-compulsive disorder and anxiety -- not to mention how all of us cope with the deluge of information that is a feature of modern life.

"People's brains aren't well equipped to deal with the information age," said senior author Ilya Monosov, PhD, an associate professor of neuroscience, of neurosurgery and of biomedical engineering. "People are constantly checking, checking, checking for news, and some of that checking is totally unhelpful. Our modern lifestyles could be resculpting the circuits in our brain that have evolved over millions of years to help us survive in an uncertain and ever-changing world."

In 2019, studying monkeys, Monosov laboratory members J. Kael White, PhD, then a graduate student, and senior scientist Ethan S. Bromberg-Martin, PhD, identified two brain areas involved in tracking uncertainty about positively anticipated events, such as rewards. Activity in those areas drove the monkeys' motivation to find information about good things that may happen.

But it wasn't clear whether the same circuits were involved in seeking information about negatively anticipated events, like punishments. After all, most people want to know whether, for example, a bet on a horse race is likely to pay off big. Not so for bad news.

"In the clinic, when you give some patients the opportunity to get a genetic test to find out if they have, for example, Huntington's disease, some people will go ahead and get the test as soon as they can, while other people will refuse to be tested until symptoms occur," Monosov said. "Clinicians see information-seeking behavior in some people and dread behavior in others."

To find the neural circuits involved in deciding whether to seek information about unwelcome possibilities, first author Ahmad Jezzini, PhD, and Monosov taught two monkeys to recognize when something unpleasant might be headed their way. They trained the monkeys to recognize symbols that indicated they might be about to get an irritating puff of air to the face. For example, the monkeys first were shown one symbol that told them a puff might be coming but with varying degrees of certainty. A few seconds after the first symbol was shown, a second symbol was shown that resolved the animals' uncertainty. It told the monkeys that the puff was definitely coming, or it wasn't.

The researchers measured whether the animals wanted to know what was going to happen by whether they watched for the second signal or averted their eyes or, in separate experiments, letting the monkeys choose among different symbols and their outcomes.

Much like people, the two monkeys had different attitudes toward bad news: One wanted to know; the other preferred not to. The difference in their attitudes toward bad news was striking because they were of like mind when it came to good news. When they were given the option of finding out whether they were about to receive something they liked -- a drop of juice -- they both consistently chose to find out.

"We found that attitudes toward seeking information about negative events can go both ways, even between animals that have the same attitude about positive rewarding events," said Jezzini, who is an instructor in neuroscience. "To us, that was a sign that the two attitudes may be guided by different neural processes."

By precisely measuring neural activity in the brain while the monkeys were faced with these choices, the researchers identified one brain area, the anterior cingulate cortex, that encodes information about attitudes toward good and bad possibilities separately. They found a second brain area, the ventrolateral prefrontal cortex, that contains individual cells whose activity reflects the monkeys' overall attitudes: yes for info on either good or bad possibilities vs. yes for intel on good possibilities only.

Understanding the neural circuits underlying uncertainty is a step toward better therapies for people with conditions such as anxiety and obsessive-compulsive disorder, which involve an inability to tolerate uncertainty.

"We started this study because we wanted to know how the brain encodes our desire to know what our future has in store for us," Monosov said. "We're living in a world our brains didn't evolve for. The constant availability of information is a new challenge for us to deal with. I think understanding the mechanisms of information seeking is quite important for society and for mental health at a population level."

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Researchers identify a molecule critical to functional brain rejuvenation

Recent studies suggest that new brain cells are being formed every day in response to injury, physical exercise, and mental stimulation. Glial cells, and in particular the ones called oligodendrocyte progenitors, are highly responsive to external signals and injuries. They can detect changes in the nervous system and form new myelin, which wraps around nerves and provides metabolic support and accurate transmission of electrical signals. As we age, however, less myelin is formed in response to external signals, and this progressive decline has been linked to the age-related cognitive and motor deficits detected in older people in the general population. Impaired myelin formation also has been reported in older individuals with neurodegenerative diseases such as Multiple Sclerosis or Alzheimer's and identified as one of the causes of their progressive clinical deterioration.

A new study from the Neuroscience Initiative team at the Advanced Science Research Center at The Graduate Center, CUNY (CUNY ASRC) has identified a molecule called ten-eleven-translocation 1 (TET1) as a necessary component of myelin repair. The research, published today in Nature Communications, shows that TET1 modifies the DNA in specific glial cells in adult brains so they can form new myelin in response to injury.

"We designed experiments to identify molecules that could affect brain rejuvenation," said Sarah Moyon, Ph.D., a research assistant professor with the CUNY ASRC Neuroscience Initiative and the study's lead author. "We found that TET1 levels progressively decline in older mice, and with that, DNA can no longer be properly modified to guarantee the formation of functional myelin."

Combining whole-genome sequencing bioinformatics, the authors showed that the DNA modifications induced by TET1 in young adult mice were essential to promote a healthy dialogue among cells in the central nervous system and for guaranteeing proper function. The authors also demonstrated that young adult mice with a genetic modification of TET1 in the myelin-forming glial cells were not capable of producing functional myelin, and therefore behaved like older mice.

"This newly identified age-related decline in TET1 may account for the inability of older individuals to form new myelin," said Patrizia Casaccia, founding director of the CUNY ASRC Neuroscience Initiative, a professor of Biology and Biochemistry at The Graduate Center, CUNY, and the study's primary investigator. "I believe that studying the effect of aging in glial cells in normal conditions and in individuals with neurodegenerative diseases will ultimately help us design better therapeutic strategies to slow the progression of devastating diseases like multiple sclerosis and Alzheimer's."

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Scientists find evidence of link between diesel exhaust, risk of Parkinson's

A new UCLA study in zebrafish identified the process by which air pollution can damage brain cells, potentially contributing to Parkinson's disease.

Published in the peer-reviewed journal Toxicological Sciences, the findings show that chemicals in diesel exhaust can trigger the toxic buildup of a protein in the brain called alpha-synuclein, which is commonly seen in people with the disease.

Previous studies have revealed that people living in areas with heightened levels of traffic-related air pollution tend to have higher rates of Parkinson's. To understand what the pollutants do to the brain, Dr. Jeff Bronstein, a professor of neurology and director of the UCLA Movement Disorders Program, tested the effect of diesel exhaust on zebrafish in the lab.

"It's really important to be able to demonstrate whether air pollution is actually the thing that's causing the effect or whether it's something else in urban environments," Bronstein said.

Testing the chemicals on zebrafish, he said, lets researchers tease out whether air pollution components affect brain cells in a way that could increase the risk of Parkinson's. The freshwater fish works well for studying molecular changes in the brain because its neurons interact in a way similar to humans. In addition, the fish are transparent, allowing scientists to easily observe and measure biological processes without killing the animals.

"Using zebrafish allowed us to see what was going on inside their brains at various time-points during the study," said Lisa Barnhill, a UCLA postdoctoral fellow and the study's first author.

Barnhill added certain chemicals found in diesel exhaust to the water in which the zebrafish were kept. These chemicals caused a change in the animals' behavior, and the researchers confirmed that neurons were dying off in the exposed fish.

Next, they investigated the activity in several pathways in the brain known to be related to Parkinson's disease to see precisely how the pollutant particles were contributing to cell death.

In humans, Parkinson's disease is associated with the toxic accumulation of alpha-synuclein proteins in the brain. One way these proteins can build up is through the disruption of autophagy -- the process of breaking down old or damaged proteins. A healthy brain continuously makes and disposes of the proteins it needs for communication between neurons, but when this disposal process stops working, the cells continue to make new proteins and the old ones never get cleared away.

In Parkinson's, alpha-synuclein proteins that would normally be disposed of pile up in toxic clumps in and around neurons, eventually killing them and interfering with the proper functioning of the brain. This can result in various symptoms, such as tremors and muscle rigidity.

Before exposing the zebrafish to diesel particles, the researchers examined the fishes' neurons for the tell-tale pouches that carry out old proteins, including alpha-synuclein, as part of the autophagy disposal operation and found that the process was working properly.

"We can actually watch them move along, and appear and disappear," Bronstein said of the pouches.

After diesel exposure, however, they saw far fewer of the garbage-toting pouches than normal. To confirm that this was the reason brain cells were dying, they treated the fish with a drug that boosts the garbage-disposal process and found that it did save the cells from dying after diesel exposure.

To confirm that diesel could have the same effect on human neurons, the researchers replicated the experiment using cultured human cells. Exposure to diesel exhaust had a similar effect on those cells.

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When damaged, the adult brain repairs itself by going back to the beginning

When adult brain cells are injured, they revert to an embryonic state, according to new findings published in the April 15, 2020 issue of Nature by researchers at University of California San Diego School of Medicine, with colleagues elsewhere. The scientists report that in their newly adopted immature state, the cells become capable of re-growing new connections that, under the right conditions, can help to restore lost function.

Repairing damage to the brain and spinal cord may be medical science's most daunting challenge. Until relatively recently, it seemed an impossible task. The new study lays out a "transcriptional roadmap of regeneration in the adult brain."

"Using the incredible tools of modern neuroscience, molecular genetics, virology and computational power, we were able for the first time to identify how the entire set of genes in an adult brain cell resets itself in order to regenerate. This gives us fundamental insight into how, at a transcriptional level, regeneration happens," said senior author Mark Tuszynski, MD, PhD, professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine.

Using a mouse model, Tuszynski and colleagues discovered that after injury, mature neurons in adult brains revert back to an embryonic state. "Who would have thought," said Tuszynski. "Only 20 years ago, we were thinking of the adult brain as static, terminally differentiated, fully established and immutable."

But work by Fred "Rusty" Gage, PhD, president and a professor at the Salk Institute for Biological Studies and an adjunct professor at UC San Diego, and others found that new brain cells are continually produced in the hippocampus and subventricular zone, replenishing these brain regions throughout life.

"Our work further radicalizes this concept," Tuszynski said. "The brain's ability to repair or replace itself is not limited to just two areas. Instead, when an adult brain cell of the cortex is injured, it reverts (at a transcriptional level) to an embryonic cortical neuron. And in this reverted, far less mature state, it can now regrow axons if it is provided an environment to grow into. In my view, this is the most notable feature of the study and is downright shocking."

To provide an "encouraging environment for regrowth," Tuszynski and colleagues investigated how damaged neurons respond after a spinal cord injury. In recent years, researchers have significantly advanced the possibility of using grafted neural stem cells to spur spinal cord injury repairs and restore lost function, essentially by inducing neurons to extend axons through and across an injury site, reconnecting severed nerves.

Last year, for example, a multi-disciplinary team led by Kobi Koffler, PhD, assistant professor of neuroscience, Tuszynski, and Shaochen Chen, PhD, professor of nanoengineering and a faculty member in the Institute of Engineering in Medicine at UC San Diego, described using 3D printed implants to promote nerve cell growth in spinal cord injuries in rats, restoring connections and lost functions.

The latest study produced a second surprise: In promoting neuronal growth and repair, one of the essential genetic pathways involves the gene Huntingtin (HTT), which, when mutated, causes Huntington's disease, a devastating disorder characterized by the progressive breakdown of nerve cells in the brain.

Tuszynski's team found that the "regenerative transcriptome" -- the collection of messenger RNA molecules used by corticospinal neurons -- is sustained by the HTT gene. In mice genetically engineered to lack the HTT gene, spinal cord injuries showed significantly less neuronal sprouting and regeneration.

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Scientists reveal brain tumors impact normally helpful cells

When the brain gets injured, star-shaped brain cells called astrocytes come to the rescue. In the case of glioma -- the most common type of primary brain tumor -- this protective action comes at a price.

A new study published in Neurochemistry International reveals that gliomas alter astrocyte function, which normally prevents the brain from being flooded with excess excitatory chemicals. This could contribute to the seizures experienced by many brain cancer patients.

"Seizures are a serious and debilitating comorbidity that affect most patients with primary brain tumors. Unfortunately, epilepsy dramatically reduces quality of life, and our current anti-epileptic drugs are not effective for all patients," said Stefanie Robel, an assistant professor at the Fralin Biomedical Research Institute at VTC and the study's co-senior author.

"My lab is looking for other cellular and molecular targets that contribute to seizures resulting from gliomas, and so far, what we're finding is that the scar-forming astrocytes that surround the tumor play an important role."

Gliomas are competitive, fast-growing tumors that -- just like all other living cells -- need an energy source to survive. Composed primarily of glia cells, gliomas take over the brain's microvasculature, syphoning off a fresh supply of nutrients from other healthy cells. The tumors also release toxic levels of glutamate, an excitatory neurotransmitter, which can kill off the brain's densely packed healthy neurons, making space for the cancer to grow. An abundance of glutamate can also cause more neurons to become electrically active, which can result in seizures.

Astrocytes swiftly scar the tumor to protect the brain from further damage -- but this comes at a price.

"Under ordinary circumstances, you'd expect astrocytes to buffer any additional glutamate. Part of their job is to maintain balanced, homeostatic conditions for neurons by removing excess glutamate and potassium," said Robel, who is also an assistant professor in Virginia Tech's School of Neuroscience and the Virginia Tech Carilion School of Medicine. "Like micro vacuum cleaners, they tidy up neurotransmitters and ions floating amid brain cells."

But the astrocytes encasing gliomas exhibited different molecular signatures based on their proximity to the cancer. The cells directly touching the tumor were elongated and swollen, mimicking the response to other brain injuries associated with epilepsy, such as stroke or physical trauma.

Electrophysiology and staining experiments revealed the stretched cells also lacked proper localization or function of proteins needed to carry potassium and glutamate inside an astrocyte. The cells had also lost a vital enzymatic process that converts glutamate into glutamine, a molecule that neurons use to suppress activity.

Under these conditions, the brain's delicate balance of excitation and inhibition tips, and problems arise.

Toxic levels of glutamate emitted from the tumor, exacerbated by the astrocytes dysfunctional state, destroy healthy neurons. Previous studies led by Sontheimer showed that the fluid suspended between brain cells reaches harmful levels of excitability -- enough to spark a seizure. After the first seizure, the circuits involved are preferentially strengthened, making future episodes even more likely.

"A tumor is a dynamic, living tissue that sends and receives chemical signals to surrounding glial cells and neurons, influencing their behavior," Robel said. "What we're seeing is that these very fine changes in astrocyte function and morphology in glioma response could have a very big impact for the patient."

As more research about astrocytic response to injury, disease, and cancer is published, Robel hopes that larger patterns will emerge.

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