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 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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Study identifies distinct brain organization patterns in women and men

A new study by Stanford Medicine investigators unveils a new artificial intelligence model that was more than 90% successful at determining whether scans of brain activity came from a woman or a man.

The findings, to be published Feb. 19 in the Proceedings of the National Academy of Sciences, help resolve a long-term controversy about whether reliable sex differences exist in the human brain and suggest that understanding these differences may be critical to addressing neuropsychiatric conditions that affect women and men differently.

"A key motivation for this study is that sex plays a crucial role in human brain development, in aging, and in the manifestation of psychiatric and neurological disorders," said Vinod Menon, PhD, professor of psychiatry and behavioral sciences and director of the Stanford Cognitive and Systems Neuroscience Laboratory. "Identifying consistent and replicable sex differences in the healthy adult brain is a critical step toward a deeper understanding of sex-specific vulnerabilities in psychiatric and neurological disorders."

Menon is the study's senior author. The lead authors are senior research scientist Srikanth Ryali, PhD, and academic staff researcher Yuan Zhang, PhD.

"Hotspots" that most helped the model distinguish male brains from female ones include the default mode network, a brain system that helps us process self-referential information, and the striatum and limbic network, which are involved in learning and how we respond to rewards.

The investigators noted that this work does notweigh in on whether sex-related differences arise early in life or may be driven by hormonal differences or the different societal circumstances that men and women may be more likely to encounter.

Uncovering brain differences

The extent to which a person's sex affects how their brain is organized and operates has long been a point of dispute among scientists. While we know the sex chromosomes we are born with help determine the cocktail of hormones our brains are exposed to -- particularly during early development, puberty and aging -- researchers have long struggled to connect sex to concrete differences in the human brain. Brain structures tend to look much the same in men and women, and previous research examining how brain regions work together has also largely failed to turn up consistent brain indicators of sex.

In their current study, Menon and his team took advantage of recent advances in artificial intelligence, as well as access to multiple large datasets, to pursue a more powerful analysis than has previously been employed. First, they created a deep neural network model, which learns to classify brain imaging data: As the researchers showed brain scans to the model and told it that it was looking at a male or female brain, the model started to "notice" what subtle patterns could help it tell the difference.

This model demonstrated superior performance compared with those in previous studies, in part because it used a deep neural network that analyzes dynamic MRI scans. This approach captures the intricate interplay among different brain regions. When the researchers tested the model on around 1,500 brain scans, it could almost always tell if the scan came from a woman or a man.

The model's success suggests that detectable sex differences do exist in the brain but just haven't been picked up reliably before. The fact that it worked so well in different datasets, including brain scans from multiple sites in the U.S. and Europe, make the findings especially convincing as it controls for many confounds that can plague studies of this kind.

"This is a very strong piece of evidence that sex is a robust determinant of human brain organization," Menon said.

Making predictions

Until recently, a model like the one Menon's team employed would help researchers sort brains into different groups but wouldn't provide information about how the sorting happened. Today, however, researchers have access to a tool called "explainable AI," which can sift through vast amounts of data to explain how a model's decisions are made.

Using explainable AI, Menon and his team identified the brain networks that were most important to the model's judgment of whether a brain scan came from a man or a woman. They found the model was most often looking to the default mode network, striatum, and the limbic network to make the call.

The team then wondered if they could create another model that could predict how well participants would do on certain cognitive tasks based on functional brain features that differ between women and men. They developed sex-specific models of cognitive abilities: One model effectively predicted cognitive performance in men but not women, and another in women but not men. The findings indicate that functional brain characteristics varying between sexes have significant behavioral implications.

"These models worked really well because we successfully separated brain patterns between sexes," Menon said. "That tells me that overlooking sex differences in brain organization could lead us to miss key factors underlying neuropsychiatric disorders."

While the team applied their deep neural network model to questions about sex differences, Menon says the model can be applied to answer questions regarding how just about any aspect of brain connectivity might relate to any kind of cognitive ability or behavior. He and his team plan to make their model publicly available for any researcher to use.

"Our AI models have very broad applicability," Menon said. "A researcher could use our models to look for brain differences linked to learning impairments or social functioning differences, for instance -- aspects we are keen to understand better to aid individuals in adapting to and surmounting these challenges."

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Human behavior guided by fast changes in dopamine levels

What happens in the human brain when we learn from positive and negative experiences? To help answer that question and better understand decision-making and human behavior, scientists are studying dopamine.

Dopamine is a neurotransmitter produced in the brain that serves as a chemical messenger, facilitating communication between nerve cells in the brain and the body. It is involved in functions such as movement, cognition and learning. While dopamine is most known for its association with positive emotions, scientists are also exploring its role in negative experiences.

Now, a new study from researchers at Wake Forest University School of Medicine shows that dopamine release in the human brain plays a crucial role in encoding both reward and punishment prediction errors. This means that dopamine is involved in the process of learning from both positive and negative experiences, allowing the brain to adjust and adapt its behavior based on the outcomes of these experiences.

The study was published today in Science Advances.

"Previously, research has shown that dopamine plays an important role in how animals learn from 'rewarding' (and possibly 'punishing') experiences. But, little work has been done to directly assess what dopamine does on fast timescales in the human brain," said Kenneth T. Kishida, Ph.D., associate professor of physiology and pharmacology and neurosurgery at Wake Forest University School of Medicine. "This is the first study in humans to examine how dopamine encodes rewards and punishments and whether dopamine reflects an 'optimal' teaching signal that is used in today's most advanced artificial intelligence research."

For the study, researchers on Kishida's team utilized fast-scan cyclic voltammetry, an electrochemical technique, paired with machine learning, to detect and measure dopamine levels in real-time (i.e., 10 measurements per second). However, this method is challenging and can only be performed during invasive procedures such as deep-brain stimulation (DBS) brain surgery. DBS is commonly employed to treat conditions such as Parkinson's disease, essential tremor, obsessive-compulsive disorder and epilepsy.

Kishida's team collaborated with Atrium Health Wake Forest Baptist neurosurgeons Stephen B. Tatter, M.D., and Adrian W. Laxton, M.D., who are also both faculty members in the Department of Neurosurgery at Wake Forest University School of Medicine, to insert a carbon fiber microelectrode deep into the brain of three participants at Atrium Health Wake Forest Baptist Medical Center who were scheduled to receive DBS to treat essential tremor.

While the participants were awake in the operating room, they played a simple computer game. As they played the game, dopamine measurements were taken in the striatum, a part of the brain that is important for cognition, decision-making, and coordinated movements.

During the game, participants' choices were either rewarded or punished with real monetary gains or losses. The game was divided into three stages in which participants learned from positive or negative feedback to make choices that maximized rewards and minimized penalties. Dopamine levels were measured continuously, once every 100 milliseconds, throughout each of the three stages of the game.

"We found that dopamine not only plays a role in signaling both positive and negative experiences in the brain, but it seems to do so in a way that is optimal when trying to learn from those outcomes. What was also interesting, is that it seems like there may be independent pathways in the brain that separately engage the dopamine system for rewarding versus punishing experiences. Our results reveal a surprising result that these two pathways may encode rewarding and punishing experiences on slightly shifted timescales separated by only 200 to 400 milliseconds in time," Kishida said.

Kishida believes that this level of understanding may lead to a better understanding of how the dopamine system is affected in humans with psychiatric and neurological disorders. Kishida said additional research is needed to understand how dopamine signaling is altered in psychiatric and neurological disorders.

"Traditionally, dopamine is often referred to as 'the pleasure neurotransmitter,"' Kishida said. "However, our work provides evidence that this is not the way to think about dopamine. Instead, dopamine is a crucial part of a sophisticated system that teaches our brain and guides our behavior. That dopamine is also involved in teaching our brain about punishing experiences is an important discovery and may provide new directions in research to help us better understand the mechanisms underlying depression, addiction, and related psychiatric and neurological disorders."

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How climate change could be affecting your brain

A new element of the catastrophic impacts of climate change is emerging -- how global warming is impacting the human brain.

In a paper published today in Nature Climate Change, an international team of academics explore the ways in which research has shown that a changing environment affects how our brains work, and how climate change could impact our brain function in the future. The paper is led by the University of Vienna with input from the universities of Geneva, New York, Chicago, Washington, Stanford, Exeter in the UK and the Max Plank Institute in Berlin. It also explores the role that neuroscientists can play in further understanding and addressing these challenges.

Lead author Dr Kimberly C. Doell, of the University of Vienna, said: "We've long known that factors in our environment can lead to changes in the brain. Yet we're only just beginning to look at how climate change, the greatest global threat of our time, might change our brains. Given the increasingly frequent extreme weather events we're already experiencing, alongside factors such as air pollution, the way we access nature and the stress and anxiety people experience around climate change, it's crucial that we understand the impact this could all have on our brains. Only then can we start to find ways to mitigate these changes."

Since the 1940s, scientists have known from mouse studies that changing environmental factors can profoundly change the development and plasticity of the brain. This effect as also been seen in humans in research looking at the effects of growing up in poverty, which found disturbances to brain systems, including lack of cognitive stimulation, exposure to toxins, poor nutrition, and heightened childhood stress. While not entirely surprising, this research highlights the profound impact that one's environment can have on their brain.

Now, the authors are calling for research to explore the impact on the human brain of being exposed to more extreme weather events, such as heatwaves, droughts, and hurricanes, and associated forest fires and floods. They believe such events may change brain structure, function, and overall health, and also call for more research to evaluate how this may explain changes in well-being and behaviour.

The paper also explores the role that neuroscience can play in influencing the way we think about climate change, our judgments and how we respond.

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Scientists unveil detailed cell maps of the human brain and the nonhuman primate brain

A group of international scientists have mapped the genetic, cellular, and structural makeup of the human brain and the nonhuman primate brain. This understanding of brain structure, achieved by funding through the National Institutes of Health's Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative®, allows for a deeper knowledge of the cellular basis of brain function and dysfunction, helping pave the way for a new generation of precision therapeutics for people with mental disorders and other disorders of the brain. The findings appear in a compendium of 24 papers across Science, Science Advances, and Science Translational Medicine.

"Mapping the brain's cellular landscape is a critical step toward understanding how this vital organ works in health and disease," said Joshua A. Gordon, M.D., Ph.D., director of the National Institute of Mental Health. "These new detailed cell atlases of the human brain and the nonhuman primate brain offer a foundation for designing new therapies that can target the specific brain cells and circuits involved in brain disorders."

The 24 papers in this latest BRAIN Initiative Cell Census Network (BICCN) collection detail the exceptionally complex diversity of cells in the human brain and the nonhuman primate brain. The studies identify similarities and differences in how cells are organized and how genes are regulated in the human brain and the nonhuman primate brain. For example:

• Three papers in the collection present the first atlas of cells in the adult human brain, mapping the transcriptional and epigenomic landscape of the brain. The transcriptome is the complete set of gene readouts in a cell, which contains instructions for making proteins and other cellular products. The epigenome refers to chemical modifications to a cell's DNA and chromosomes that alter the way the cell's genetic information is expressed.
• In another paper, a comparison of the cellular and molecular properties of the human brain and several nonhuman primate brains (chimpanzee, gorilla, macaque, and marmoset brains) revealed clear similarities in the types, proportions, and spatial organization of cells in the cerebral cortex of humans and nonhuman primates. Examination of the genetic expression of cortical cells across species suggests that relatively small changes in gene expression in the human lineage led to changes in neuronal wiring and synaptic function that likely allowed for greater brain plasticity in humans, supporting the human brain's ability to adapt, learn, and change.
• A study exploring how cells vary in different brain regions in marmosets found a link between the properties of cells in the adult brain and the properties of those cells during development. The link suggests that developmental programming is embedded in cells when they are formed and maintained into adulthood and that some observable cellular properties in an adult may have their origins very early in life. This finding could lead to new insights into brain development and function across the lifespan.
• An exploration of the anatomy and physiology of neurons in the outermost layer of the neocortex -- part of the brain involved in higher-order functions such as cognition, motor commands, and language -- revealed differences in the human brain and the mouse brain that suggest this region may be an evolutionary hotspot, with changes in humans reflecting the higher demands of regulating humans' more complex brain circuits.

The core aim of the BICCN, a groundbreaking effort to understand the brain's cellular makeup, is to develop a comprehensive inventory of the cells in the brain -- where they are, how they develop, how they work together, and how they regulate their activity -- to better understand how brain disorders develop, progress, and are best treated.

"This suite of studies represents a landmark achievement in illuminating the complexity of the human brain at the cellular level," said John Ngai, Ph.D., director of the NIH BRAIN Initiative. "The scientific collaborations forged through BICCN are propelling the field forward at an exponential pace; the progress -- and possibilities -- have been simply breathtaking."

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Researchers identify the link between memory and appetite in the human brain to explain obesity

Disrupted connections between memory and appetite regulating brain circuits are directly proportional to body mass index (BMI), notably in patients who suffer from disordered or overeating that can lead to obesity, such as binge eating disorder (BED), according to new research from the Perelman School of Medicine at the University of Pennsylvania. Published today in Nature, the research notes that individuals who are obese have impaired connections between the dorsolateral hippocampus (dlHPC) and the lateral hypothalamus (LH), which may impact their ability to control or regulate emotional responses when anticipating rewarding meals or treats.

"These findings underscore that some individual's brains can be fundamentally different in regions that increase the risk for obesity," senior author, Casey Halpern, MD, an associate professor of Neurosurgery and Chief of Stereotactic and Functional Neurosurgery at Penn Medicine and the Corporal Michael J. Crescenz Veterans Affairs Medical Center. "Conditions like disordered eating and obesity are a lot more complicated than simply managing self-control and eating healthier. What these individuals need is not more willpower, but the therapeutic equivalent of an electrician that can make right these connections inside their brain."

The dlHPC is located in the region of the brain that processes memory, and the LH is in the region of the brain that is responsible for keeping the body in a stable state, called homeostasis. Previous research has found an association with loss of function in the human hippocampus in individuals with obesity and related disordered eating, like BED. However, outside of imaging techniques such as magnetic resonance imaging (MRI), the role of the hippocampus has been difficult to study in humans with obesity and related eating disorders.

In this study, researchers were able to evaluate patients whose brains were already being monitored electrically in the Epilepsy Monitoring Unit. Researchers monitored brain activity as patients anticipated and then received a sweet treat (a chocolate milkshake). They found that both the dlHPC and the LH activated simultaneously when participants anticipated receiving the rewarding meal. These researchers confirmed using stimulation techniques pioneered by coauthors, Kai Miller, MD, PhD, and Dora Hermes Miller, PhD, from Mayo Clinic, that this specific zone of the hippocampus, the dlHPC, and LH exhibited extremely strong connectivity, as well.

In individuals with obesity, researchers found that the impairment of this hypothalamus-hippocampus circuit was directly proportional to their BMI. That is, in participants with a high BMI, the connection was even more disturbed.

To further validate the connection, Halpern's team used a technique called "brain clearing," to analyze brain tissue. The technique revealed melanin-concentrating hormone, a hormone known to regulate feeding behavior that is produced in the LH. They found the presence of MCH in the dlHPC, and nowhere else, confirming a link between the two regions.

"The hippocampus has never been targeted to treat obesity, or the disordered eating that can sometimes cause obesity," said Halpern. "We hope to be able to use this research to both identify which individuals who are likely to develop obesity later in life, and to develop novel therapies -- both invasive and not -- to help improve function of this critical circuit that seems to go awry in patients who are obese."

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Space travel influences the way the brain works

Scientists of the University of Antwerp and University of Liège have found how the human brain changes and adapts to weightlessness, after being in space for 6 months. Some of the changes turned out to be lasting -- even after 8 months back on Earth. Raphaël Liégeois, soon to be the third Belgian in space, acknowledges the importance of the research, "to prepare the new generation of astronauts for longer missions."

A child who learns not to drop a glass on the floor, or a tennis player predicting the course of an incoming ball to hit it accurately are examples of how the brain incorporates the physical laws of gravity to optimally function on Earth. Astronauts who go to space reside in a weightless environment, where the brain's rules about gravity are no longer applicable. A new study on brain function in cosmonauts has revealed how the brain's organization is changed after a six-month mission to the International Space Station (ISS), demonstrating the adaptation that is required to live in weightlessness.

The University of Antwerp has been leading this BRAIN-DTI scientific project through the European Space Agency. Magnetic resonance imaging (MRI) data were taken from 14 astronaut brains before and several times after their mission to space. Using a special MRI technique, the researchers collected the astronauts' brain data in a resting condition, hence without having them engage in a specific task. This resting-state functional MRI technique enabled the researchers to investigate the brain's default state and to find out whether this changes or not after long-duration spaceflight.

Learning effect

In collaboration with the University of Liège, recent analyses of the brain's activity at rest revealed how functional connectivity, a marker of how activity in some brain areas is correlated with the activity in others, changes in specific regions.

"We found that connectivity was altered after spaceflight in regions which support the integration of different types of information, rather than dealing with only one type each time, such as visual, auditory, or movement information', say Steven Jillings and Floris Wuyts (University of Antwerp). "Moreover, we found that some of these altered communication patterns were retained throughout 8 months of being back on Earth. At the same time, some brain changes returned to the level of how the areas were functioning before the space mission."

Both scenarios of changes are plausible: retained changes in brain communication may indicate a learning effect, while transient changes may indicate more acute adaptation to changed gravity levels.

"This dataset is so special as their participants themselves. Back in 2016, we were historically the first to show how spaceflight may affect brain function on a single cosmonaut. Some years later we are now in a unique position to investigate the brains of more astronauts, several times. Therefore, we are deciphering the potential of the human brain all the more in confidence," says Dr. Athena Demertzi (GIGA Institute, University of Liège), co-supervisor of this this work.

New generation of astronauts

"Understanding physiological and behavioral changes triggered by weightlessness is key to plan human space exploration. Therefore, mapping changes of brain function using neuroimaging techniques as done in this work is an important step to prepare the new generation of astronauts for longer missions," comments Raphaël Liégeois, Doctor of Engineering Science (ULiège) with a Thesis in the field of Neuroscience, future ESA Astronaut.

Read more at Science Daily

Traffic pollution impairs brain function

A new study by researchers at the University of British Columbia and the University of Victoria has shown that common levels of traffic pollution can impair human brain function in only a matter of hours.

The peer-reviewed findings, published in the journal Environmental Health, show that just two hours of exposure to diesel exhaust causes a decrease in the brain's functional connectivity -- a measure of how The study provides the first evidence in humans, from a controlled experiment, of altered brain network connectivity induced by air pollution.

"For many decades, scientists thought the brain may be protected from the harmful effects of air pollution," said senior study author Dr. Chris Carlsten, professor and head of respiratory medicine and the Canada Research Chair in occupational and environmental lung disease at UBC. "This study, which is the first of its kind in the world, provides fresh evidence supporting a connection between air pollution and cognition."

For the study, the researchers briefly exposed 25 healthy adults to diesel exhaust and filtered air at different times in a laboratory setting. Brain activity was measured before and after each exposure using functional magnetic resonance imaging (fMRI).

The researchers analyzed changes in the brain's default mode network (DMN), a set of inter-connected brain regions that play an important role in memory and internal thought. The fMRI revealed that participants had decreased functional connectivity in widespread regions of the DMN after exposure to diesel exhaust, compared to filtered air.

"We know that altered functional connectivity in the DMN has been associated with reduced cognitive performance and symptoms of depression, so it's concerning to see traffic pollution interrupting these same networks," said Dr. Jodie Gawryluk, a psychology professor at the University of Victoria and the study's first author. "While more research is needed to fully understand the functional impacts of these changes, it's possible that they may impair people's thinking or ability to work."

Taking steps to protect yourself

Notably, the changes in the brain were temporary and participants' connectivity returned to normal after the exposure. Dr. Carlsten speculated that the effects could be long lasting where exposure is continuous. He said that people should be mindful of the air they're breathing and take appropriate steps to minimize their exposure to potentially harmful air pollutants like car exhaust.

"People may want to think twice the next time they're stuck in traffic with the windows rolled down," said Dr. Carlsten. "It's important to ensure that your car's air filter is in good working order, and if you're walking or biking down a busy street, consider diverting to a less busy route."

While the current study only looked at the cognitive impacts of traffic-derived pollution, Dr. Carlsten said that other products of combustion are likely a concern.

"Air pollution is now recognized as the largest environmental threat to human health and we are increasingly seeing the impacts across all major organ systems," says Dr. Carlsten. "I expect we would see similar impacts on the brain from exposure to other air pollutants, like forest fire smoke. With the increasing incidence of neurocognitive disorders, it's an important consideration for public health officials and policymakers."

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Human brain organoids implanted into mouse cortex respond to visual stimuli for first time

A team of engineers and neuroscientists has demonstrated for the first time that human brain organoids implanted in mice have established functional connectivity to the animals' cortex and responded to external sensory stimuli. The implanted organoids reacted to visual stimuli in the same way as surrounding tissues, an observation that researchers were able to make in real time over several months thanks to an innovative experimental setup that combines transparent graphene microelectrode arrays and two-photon imaging.

The team, led by Duygu Kuzum, a faculty member in the University of California San Diego Department of Electrical and Computer Engineering, details their findings in the Dec. 26 issue of the journal Nature Communications. Kuzum's team collaborated with researchers from Anna Devor's lab at Boston University; Alysson R. Muotri's lab at UC San Diego; and Fred H. Gage's lab at the Salk Institute.

Human cortical organoids are derived from human induced pluripotent stem cells, which are usually derived themselves from skin cells. These brain organoids have recently emerged as promising models to study the development of the human brain, as well as a range of neurological conditions.

But until now, no research team had been able to demonstrate that human brain organoids implanted in the mouse cortex were able to share the same functional properties and react to stimuli in the same way. This is because the technologies used to record brain function are limited, and are generally unable to record activity that lasts just a few milliseconds.

The UC San Diego-led team was able to solve this problem by developing experiments that combine microelectrode arrays made from transparent graphene, and two-photon imaging, a microscopy technique that can image living tissue up to one millimeter in thickness.

"No other study has been able to record optically and electrically at the same time," said Madison Wilson, the paper's first author and a Ph.D. student in Kuzum's research group at UC San Diego. "Our experiments reveal that visual stimuli evoke electrophysiological responses in the organoids, matching the responses from the surrounding cortex."

The researchers hope that this combination of innovative neural recording technologies to study organoids will serve as a unique platform to comprehensively evaluate organoids as models for brain development and disease, and investigate their use as neural prosthetics to restore function to lost, degenerated or damaged brain regions.

"This experimental setup opens up unprecedented opportunities for investigations of human neural network-level dysfunctions underlying developmental brain diseases," said Kuzum.

Kuzum's lab first developed the transparent graphene electrodes in 2014 and has been advancing the technology since then. The researchers used platinum nanoparticles to lower the impedance of graphene electrodes by 100 times while keeping them transparent. The low-impedance graphene electrodes are able to record and image neuronal activity at both the macroscale and single cell levels.

By placing an array of these electrodes on top of the transplanted organoids, researchers were able to record neural activity electrically from both the implanted organoid and the surrounding host cortex in real time. Using two-photon imaging, they also observed that mouse blood vessels grew into the organoid providing necessary nutrients and oxygen to the implant.

Researchers applied a visual stimulus-an optical white light LED-to the mice with implanted organoids, while the mice were under two-photon microscopy. They observed electrical activity in the electrode channels above the organoids showing that the organoids were reacting to the stimulus in the same way as surrounding tissue. The electrical activity propagated from the area closest to the visual cortex in the implanted organoids area through functional connections. In addition, their low noise transparent graphene electrode technology enabled electrical recording of spiking activity from the organoid and the surrounding mouse cortex. Graphene recordings showed increases in the power of gamma oscillations and phase locking of spikes from organoids to slow oscillations from mouse visual cortex. These findings suggest that the organoids had established synaptic connections with surrounding cortex tissue three weeks after implantation, and received functional input from the mouse brain. Researchers continued these chronic multimodal experiments for eleven weeks and showed functional and morphological integration of implanted human brain organoids with the host mice cortex.

Next steps include longer experiments involving neurological disease models, as well as incorporating calcium imaging in the experimental set up to visualize spiking activity in organoid neurons. Other methods could also be used to trace axonal projections between organoid and mouse cortex.

"We envision that, further along the road, this combination of stem cells and neurorecording technologies will be used for modeling disease under physiological conditions; examining candidate treatments on patient-specific organoids; and evaluating organoids' potential to restore specific lost, degenerated or damaged brain regions," Kuzum said.

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Artificial neural networks learn better when they spend time not learning at all

Depending on age, humans need 7 to 13 hours of sleep per 24 hours. During this time, a lot happens: Heart rate, breathing and metabolism ebb and flow; hormone levels adjust; the body relaxes. Not so much in the brain.

"The brain is very busy when we sleep, repeating what we have learned during the day," said Maxim Bazhenov, PhD, professor of medicine and a sleep researcher at University of California San Diego School of Medicine. "Sleep helps reorganize memories and presents them in the most efficient way."

In previous published work, Bazhenov and colleagues have reported how sleep builds rational memory, the ability to remember arbitrary or indirect associations between objects, people or events, and protects against forgetting old memories.

Artificial neural networks leverage the architecture of the human brain to improve numerous technologies and systems, from basic science and medicine to finance and social media. In some ways, they have achieved superhuman performance, such as computational speed, but they fail in one key aspect: When artificial neural networks learn sequentially, new information overwrites previous information, a phenomenon called catastrophic forgetting.

"In contrast, the human brain learns continuously and incorporates new data into existing knowledge," said Bazhenov, "and it typically learns best when new training is interleaved with periods of sleep for memory consolidation."

Writing in the November 18, 2022 issue of PLOS Computational Biology, senior author Bazhenov and colleagues discuss how biological models may help mitigate the threat of catastrophic forgetting in artificial neural networks, boosting their utility across a spectrum of research interests.

The scientists used spiking neural networks that artificially mimic natural neural systems: Instead of information being communicated continuously, it is transmitted as discrete events (spikes) at certain time points.

They found that when the spiking networks were trained on a new task, but with occasional off-line periods that mimicked sleep, catastrophic forgetting was mitigated. Like the human brain, said the study authors, "sleep" for the networks allowed them to replay old memories without explicitly using old training data.

Memories are represented in the human brain by patterns of synaptic weight -- the strength or amplitude of a connection between two neurons.

"When we learn new information," said Bazhenov, "neurons fire in specific order and this increases synapses between them. During sleep, the spiking patterns learned during our awake state are repeated spontaneously. It's called reactivation or replay.

"Synaptic plasticity, the capacity to be altered or molded, is still in place during sleep and it can further enhance synaptic weight patterns that represent the memory, helping to prevent forgetting or to enable transfer of knowledge from old to new tasks."

When Bazhenov and colleagues applied this approach to artificial neural networks, they found that it helped the networks avoid catastrophic forgetting.

"It meant that these networks could learn continuously, like humans or animals. Understanding how human brain processes information during sleep can help to augment memory in human subjects. Augmenting sleep rhythms can lead to better memory.

"In other projects, we use computer models to develop optimal strategies to apply stimulation during sleep, such as auditory tones, that enhance sleep rhythms and improve learning. This may be particularly important when memory is non-optimal, such as when memory declines in aging or in some conditions like Alzheimer's disease."

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Even smartest AI models don't match human visual processing

Deep convolutional neural networks (DCNNs) don't see objects the way humans do -- using configural shape perception -- and that could be dangerous in real-world AI applications, says Professor James Elder, co-author of a York University study published today.

Published in the Cell Press journal iScience, Deep learning models fail to capture the configural nature of human shape perception is a collaborative study by Elder, who holds the York Research Chair in Human and Computer Vision and is Co-Director of York's Centre for AI & Society, and Assistant Psychology Professor Nicholas Baker at Loyola College in Chicago, a former VISTA postdoctoral fellow at York.

The study employed novel visual stimuli called "Frankensteins" to explore how the human brain and DCNNs process holistic, configural object properties.

"Frankensteins are simply objects that have been taken apart and put back together the wrong way around," says Elder. "As a result, they have all the right local features, but in the wrong places."

The investigators found that while the human visual system is confused by Frankensteins, DCNNs are not -- revealing an insensitivity to configural object properties.

"Our results explain why deep AI models fail under certain conditions and point to the need to consider tasks beyond object recognition in order to understand visual processing in the brain," Elder says. "These deep models tend to take 'shortcuts' when solving complex recognition tasks. While these shortcuts may work in many cases, they can be dangerous in some of the real-world AI applications we are currently working on with our industry and government partners," Elder points out.

One such application is traffic video safety systems: "The objects in a busy traffic scene -- the vehicles, bicycles and pedestrians -- obstruct each other and arrive at the eye of a driver as a jumble of disconnected fragments," explains Elder. "The brain needs to correctly group those fragments to identify the correct categories and locations of the objects. An AI system for traffic safety monitoring that is only able to perceive the fragments individually will fail at this task, potentially misunderstanding risks to vulnerable road users."

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What you know changes how you see things

Researchers at the George Washington University have gained important insight into how the human brain processes an object in the visual system and where in the brain this processing takes place. Their study, "Mugs and Plants: Object Semantic Knowledge Alters Perceptual Processing with Behavioral Ramifications," shows people perceive objects differently depending on their prior knowledge and experience with that object.

The findings could have important implications in applied settings such as medical displays, cognitive assistants, and product and environmental design, according to the researchers.

"Since the way we perceive objects determines how we interact with them, it is important to visually process them quickly and with high detail" Sarah Shomstein, a professor of cognitive neuroscience at GW said. "However, the way our eyes perceive and process an object can be different depending on what we know about this object. Our study shows, for the first time, that if we recognize an object as a tool, we perceive it faster but with less detail. If we recognize an object as a non-tool, we perceive it slower but with higher detail."

To determine how the human brain processes an object visually, Shomstein and Dick Dubbelde, a recent PhD graduate at GW and co-author on the study, showed participants several images of objects that can be easily manipulated by hand such as a coffee mug, snow shovel or screwdriver, and several images of objects that are infrequently manipulated by hand, such as a potted plant, a picture frame or a fire hydrant. For half of the experiment, a small gap could be cut out of the bottom of each object. For the other half of the experiment, the objects could flicker on the screen. The team asked participants to report the presence or absence of a gap or the flicker, which helped the researchers figure out the speed and detail of object processing, and also which regions of the brain were being used to process the object.

Researchers found that objects usually manipulated by your hands are perceived faster than non-manipulable objects, making it easier to see the flickering. Alternatively, objects that we usually do not manipulate are perceived with greater detail than manipulable objects, making it easier to see the small gaps.

"The differences in perception between 'mugs' and 'plants' in both speed and detail of perception means that these objects are sorted by the visual system for processing in different brain regions," Dubbelde said. "In other words, your knowledge of the object's purpose actually determines where in the brain object processing will occur and how well you will perceive it."

The study also showed that if you interfere with object recognition by making it harder to recognize an object as either manipulable or not manipulable -- for example, by turning it upside down -- then the differences in the speed and detail perception of the objects disappear.

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What makes the human brain different? Study reveals clues

What makes the human brain distinct from that of all other animals -- including even our closest primate relatives? In an analysis of cell types in the prefrontal cortex of four primate species, Yale researchers identified species-specific -- particularly human-specific -- features, they report Aug. 25 in the journal Science.

And they found that what makes us human may also makes us susceptible to neuropsychiatric diseases.

For the study, the researchers looked specifically at the dorsolateral prefrontal cortex (dlPFC), a brain region that is unique to primates and essential for higher-order cognition. Using a single cell RNA-sequencing technique, they profiled expression levels of genes in hundreds of thousands of cells collected from the dlPFC of adult humans, chimpanzees, macaque, and marmoset monkeys.

"Today, we view the dorsolateral prefrontal cortex as the core component of human identity, but still we don't know what makes this unique in humans and distinguishes us from other primate species." said Nenad Sestan, the Harvey and Kate Cushing Professor of Neuroscience at Yale, professor of comparative medicine, of genetics. and of psychiatry, and the lead senior author of the paper. "Now we have more clues."

To answer this, the researchers first asked whether there are there any cell types uniquely present in humans or other analyzed non-human primate species. After grouping cells with similar expression profiles they revealed 109 shared primate cell types but also five that were not common to all species. These included a type of microglia, or brain-specific immune cell, that was present only in humans and a second type shared by only humans and chimpanzees.

The human-specific microglia type exists throughout development and adulthood, the researchers found, suggesting the cells play a role in maintenance of the brain upkeep rather than combatting disease.

"We humans live in a very different environment with a unique lifestyle compared to other primate species; and glia cells, including microglia, are very sensitive to these differences," Sestan said. "The type of microglia found in the human brain might represent an immune response to the environment."

An analysis of gene expression in the microglia revealed another human-specific surprise -- the presence of the gene FOXP2. This discovery raised great interest because variants of FOXP2 have been linked to verbal dyspraxia, a condition in which patients have difficulty producing language or speech. Other studies have also shown that FOXP2 is associated with other neuropsychiatric diseases, such as autism, schizophrenia, and epilepsy.

Sestan and colleagues found that this gene exhibits primate-specific expression in a subset of excitatory neurons and human-specific expression in microglia.

"FOXP2 has intrigued many scientists for decades, but still we had no idea of what makes it unique in humans versus other primate species," said Shaojie Ma, a postdoctoral associate in Sestan's lab and co-lead author. We are extremely excited about the FOXP2 findings because they open new directions in the study of language and diseases."

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No, the human brain did not shrink 3,000 years ago

Did the 12th century B.C.E. -- a time when humans were forging great empires and developing new forms of written text -- coincide with an evolutionary reduction in brain size? Think again, says a UNLV-led team of researchers who refute a hypothesis that's growing increasingly popular among the science community.

Last year, a group of scientists made headlines when they concluded that the human brain shrank during the transition to modern urban societies about 3,000 years ago because, they said, our ancestors' ability to store information externally in social groups decreased our need to maintain large brains. Their hypothesis, which explored decades-old ideas on the evolutionary reduction of modern human brain size, was based on a comparison to evolutionary patterns seen in ant colonies.

Not so fast, said UNLV anthropologist Brian Villmoare and Liverpool John Moores University scientist Mark Grabowski.

In a new paper published last week in Frontiers in Ecology and Evolution, the UNLV-led team analyzed the dataset that the research group from last year's study used and dismissed their findings.

"We were struck by the implications of a substantial reduction in modern human brain size at roughly 3,000 years ago, during an era of many important innovations and historical events -- the appearance of Egypt's New Kingdom, the development of Chinese script, the Trojan War, and the emergence of the Olmec civilization, among many others," Villmoare said.

"We re-examined the dataset from DeSilva et al. and found that human brain size has not changed in 30,000 years, and probably not in 300,000 years," Villmoare said. "In fact, based on this dataset, we can identify no reduction in brain size in modern humans over any time-period since the origins of our species."

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Microglial methylation 'landscape' in human brain

In the central nervous system, microglial cells play critical roles in development, aging, brain homeostasis, and pathology. Recent studies have shown variation in the gene-expression profile and phenotype of microglia across brain regions and between different age and disease states. But the molecular mechanisms that contribute to these transcriptomic changes in the human brain are not well understood. Now, a new study targets the methylation profile of microglia from human brain.

The study appears in Biological Psychiatry, published by Elsevier.

Microglia, the brain's own immune cells, were once thought of as a homogenous population that was either "activated" or "inactivated," with either pro-inflammatory or neuroprotective effects. But the cells are now recognized to have a vast array of phenotypes depending on environmental conditions with myriad functional consequences. Microglia are increasingly appreciated as critical players in neurologic and psychiatric disorders.

Fatemeh Haghighi, PhD, senior author of the new work, said: "To address this gap in knowledge, we set out to characterize the DNA methylation landscape of human primary microglia cells and factors that contribute to variations in the microglia methylome."

DNA methylation is the main form of epigenetic regulation, which determines the pattern of which genes are being turned "on" or "off" in various circumstances over time.

The researchers studied isolated microglia cells from post-mortem human brain tissue from 22 donors of various age, including 1 patient with schizophrenia, 13 with mood disorder, and 8 controls with no psychiatric disorder, taken from 4 brain regions. They analyzed the microglia using genome-scale methylation microarrays.

Unsurprisingly, microglia showed DNA methylation profiles that were distinct from other cells in the central nervous system. But less expected, said Haghighi, "we found that interindividual differences rather than brain region differences had a much larger effect on the DNA methylation variability." In addition, an exploratory analysis showed differences in the methylation profile of microglia from brains of subjects with psychiatric disorders compared to controls.

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Scientists key in on brain’s mechanism for singing, learning

New research reveals that specialized cells within neural circuitry that triggers complex learning in songbirds bears a striking resemblance to a type of neural cell associated with the development of fine motor skills in the cortex of the human brain.

The study by scientists at Oregon Health & Science University published today in the journal Nature Communications.

"These are the properties you need if you want to have a male song that's precise and distinct so the female can choose which bird she wants to mate with," said co-senior author Henrique von Gersdorff, Ph.D., senior scientist the OHSU Vollum Institute. "You need a highly specialized brain to produce this."

Benjamin Zemel, Ph.D., a postdoctoral fellow at OHSU, is lead author and conducted most of the challenging electrophysiology work involved in using thin brain slices and single cell recording.

The study reveals that a particular group of neurons express a set of genes that modulate sodium ion channel proteins. These ion channels generate electrical signals used for communication between cells in the nervous system. In this case, the assemblage enables neurons to fire repetitive spikes - known as action potentials - at extremely high speeds and frequencies as the bird sings.

The study describes "ultrafast spikes" that only last 0.2 milliseconds - compared with most action potential spikes that last a millisecond or more. A millisecond is itself mind-bendingly fast, a thousandth of a second.

Further, the findings suggest new avenues for understanding the mechanism in various aspects of human behavior and development that involves fine motor control.

Researchers say the assemblage of neurons and ion channels involved in the male zebra finch's singing closely resembles a similar assemblage of neurons known as Betz cells in the primary motor cortex of the human brain.

Among the largest known brain cells in humans, Betz cells have long and thick axons that can propagate spikes at very high velocities and frequencies. As such, they are thought to be important for fine motor skills involving hands, feet, fingers and wrists.

"Think of a piano player," said co-senior author Claudio Mello, M.D., Ph.D., professor of behavioral neuroscience in the OHSU School of Medicine. "They're thinking so fast, they have to rely on memories and actions that are learned and stored. Playing the guitar is the same thing."

The study published today is a result of an informal conversation that initially occurred over lunch in the Mackenzie Hall Café on OHSU's Marquam Hill campus.

Mello, a behavioral neuroscientist who has relied on the zebra finch as an animal model, has known Von Gersdorff socially for 20 years. Over lunch one day in the cafeteria, Mello popped open his laptop and showed a brain image of a young male zebra finch at an age just before he could sing, followed by a second image revealing a telltale subunit of proteins that had materialized after the bird was old enough to begin singing.

"Something remarkable was happening in a period of just a few days," said von Gersdorff, an expert in electrophysiology and the biophysics of neurons. "I said, this is exactly the protein we've been studying in the rodent auditory system. It promotes high frequency spiking."

Mello said the new study deepens scientific understanding of the mechanism involved in learning fine motor skills.

"This is a very important model, and we think this new study has broad potential," he said.

The fact that these same motor circuit properties are shared by species that diverged more than 300 million years ago speaks to the strength of the discovery, von Gersdorff and Mello said. Researchers say the neuronal properties they discovered in the male zebra finch may become optimized for speed and precision through convergent evolution.

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