Exercise reorganizes the brain to be more resilient to stress

Physical activity reorganizes the brain so that its response to stress is reduced and anxiety is less likely to interfere with normal brain function, according to a research team based at Princeton University.

The researchers report in the Journal of Neuroscience that when mice allowed to exercise regularly experienced a stressor — exposure to cold water — their brains exhibited a spike in the activity of neurons that shut off excitement in the ventral hippocampus, a brain region shown to regulate anxiety.

These findings potentially resolve a discrepancy in research related to the effect of exercise on the brain — namely that exercise reduces anxiety while also promoting the growth of new neurons in the ventral hippocampus. Because these young neurons are typically more excitable than their more mature counterparts, exercise should result in more anxiety, not less. The Princeton-led researchers, however, found that exercise also strengthens the mechanisms that prevent these brain cells from firing.

The impact of physical activity on the ventral hippocampus specifically has not been deeply explored, said senior author Elizabeth Gould, Princeton’s Dorman T. Warren Professor of Psychology. By doing so, members of Gould’s laboratory pinpointed brain cells and regions important to anxiety regulation that may help scientists better understand and treat human anxiety disorders, she said.

From an evolutionary standpoint, the research also shows that the brain can be extremely adaptive and tailor its own processes to an organism’s lifestyle or surroundings, Gould said. A higher likelihood of anxious behavior may have an adaptive advantage for less physically fit creatures. Anxiety often manifests itself in avoidant behavior and avoiding potentially dangerous situations would increase the likelihood of survival, particularly for those less capable of responding with a “fight or flight” reaction, she said.

"Understanding how the brain regulates anxious behavior gives us potential clues about helping people with anxiety disorders. It also tells us something about how the brain modifies itself to respond optimally to its own environment," said Gould, who also is a professor in the Princeton Neuroscience Institute.

The research was part of the graduate dissertation for first author Timothy Schoenfeld, now a postdoctoral fellow at the National Institute of Mental Health, as well as part of the senior thesis project of co-author Brian Hsueh, now an MD/Ph.D. student at Stanford University. The project also included co-authors Pedro Rada and Pedro Pieruzzini, both from the University of Los Andes in Venezuela.

For the experiments, one group of mice was given unlimited access to a running wheel and a second group had no running wheel. Natural runners, mice will dash up to 4 kilometers (about 2.5 miles) a night when given access to a running wheel, Gould said. After six weeks, the mice were exposed to cold water for a brief period of time.

The brains of active and sedentary mice behaved differently almost as soon as the stressor occurred, an analysis showed. In the neurons of sedentary mice only, the cold water spurred an increase in “immediate early genes,” or short-lived genes that are rapidly turned on when a neuron fires. The lack of these genes in the neurons of active mice suggested that their brain cells did not immediately leap into an excited state in response to the stressor.

Instead, the brain in a runner mouse showed every sign of controlling its reaction to an extent not observed in the brain of a sedentary mouse. There was a boost of activity in inhibitory neurons that are known to keep excitable neurons in check. At the same time, neurons in these mice released more of the neurotransmitter gamma-aminobutyric acid, or GABA, which tamps down neural excitement. The protein that packages GABA into little travel pods known as vesicles for release into the synapse also was present in higher amounts in runners.

The anxiety-reducing effect of exercise was canceled out when the researchers blocked the GABA receptor that calms neuron activity in the ventral hippocampus. The researchers used the chemical bicuculine, which is used in medical research to block GABA receptors and simulate the cellular activity underlying epilepsy. In this case, when applied to the ventral hippocampus, the chemical blocked the mollifying effects of GABA in active mice.

Researchers find new clue to cause of human narcolepsy

In 2000, researchers at the UCLA Center for Sleep Research published findings showing that people suffering from narcolepsy, a disorder characterized by uncontrollable periods of deep sleep, had 90 percent fewer neurons containing the neuropeptide hypocretin in their brains than healthy people. The study was the first to show a possible biological cause of the disorder.

Subsequent work by this group and others demonstrated that hypocretin is an arousing chemical that keeps us awake and elevates both mood and alertness; the death of hypocretin cells, the researchers said, helps explain the sleepiness of narcolepsy. But it has remained unclear what kills these cells.

Now the same UCLA team reports that an excess of another brain cell type — this one containing histamine — may be the cause of the loss of hypocretin cells in human narcoleptics.

UCLA professor of psychiatry Jerome Siegel and colleagues report in the current online edition of the journal Annals of Neurology that people with the disorder have nearly 65 percent more brain cells containing the chemical histamine. Their research suggests that this excess of histamine cells causes the loss of hypocretin cells in human narcoleptics.

Narcolepsy is a chronic disorder of the central nervous system characterized by the brain’s inability to control sleep–wake cycles. It causes sudden bouts of sleep and is often accompanied by cataplexy, an abrupt loss of voluntary muscle tone that can cause person to collapse. According to the National Institutes of Health, narcolepsy is thought to affect roughly one in every 3,000 Americans. Currently, there is no cure.

Histamine is a body chemical that works as part of the immune system to kill invading cells. When the immune system goes awry, histamine can act on a person’s eyes, nose, throat, lungs, skin or gastrointestinal tract, causing the symptoms of allergy that many people are familiar with. But histamine is also present in a type of brain cell.

For the study, researchers examined five narcoleptic brains and seven control brains from human cadavers. Prior to death, all the narcoleptics had been diagnosed by a sleep disorder center as having narcolepsy with cataplexy. These brains were also compared with the brains of three narcoleptic mouse models and to the brains of narcoleptic dogs.

The researchers found that the humans with narcolepsy had an average of 64 percent more histamine neurons. Interestingly, the team did not see an increased number of these cells in any of the animal models of narcolepsy.

"Humans and animals with narcolepsy share the same symptoms, but we did not see the histamine cell changes we saw in humans in the animal models we examined," said Siegel, who directs the Center for Sleep Research at the UCLA Semel Institute for Neuroscience and Human Behavior and is the senior author of the research. "We know that narcolepsy in the animal models is caused by engineered genetic changes that block hypocretin function. However, in humans, we did not know why the hypocretin cells die.

"Our current findings indicate that the increase of histamine cells that we see in human narcolepsy may cause the loss of hypocretin cells," he said.

The study results may also further our understanding of brain plasticity, Siegel noted. While scientists have known of the existence neurogenesis — the process by which the brain is populated with new neurons — it was thought to function mainly to replace existing cells that had died.

"This paper shows for the first time that neuronal numbers can increase greatly and not just serve as replacement cells," he said. "In the current example, this appears to be pathological with the destruction of hypocretin, but in other circumstances, it may underlie recovery and learning and open new routes to treatment of a number of neurological disorders."

Brain Sets Prices With Emotional Value

You might be falling in love with that new car, but you probably wouldn’t pay as much for it if you could resist the feeling.

Researchers at Duke University who study how the brain values things — a field called neuroeconomics — have found that your feelings about something and the value you put on it are calculated similarly in a specific area of the brain. 

The region is small area right between the eyes at the front of the brain. It’s called the ventromedial prefrontal cortex, or vmPFC for short. Scott Huettel, director of Duke’s Center for Interdisciplinary Decision Science, said scientists studying emotion and neuroeconomics had independently singled out this area of the brain in their research but neither group recognized that the other’s research was focused on it too.

Now, after a series of experiments in which subjects were asked to modify how they felt about something either positively or negatively, the Duke group is arguing that emotional and economic calculations are more closely related than brain scientists had realized. The study appears July 3 in the Journal of Neuroscience.

Earlier research by other groups had shown the vmPFC participates in calculating the value of rewards and that it is engaged by positive stimuli that aren’t really rewards, like a happy memory or a picture of a happy face. A separate line of studies had shown that this brain region also set values on little things like snacks. 

The vmPFC handles value tradeoffs such as ‘is that product worth parting with my hard-earned money?’ “This says that your emotions would enter into that tradeoff,” Huettel said. 

"The neuroscience fits with your intuitive understanding," said Amy Winecoff, a graduate student in psychology and neuroscience who led the research. "Emotions appear to be relying on the same value system."

In the Duke study, experimental subjects were first trained to do “reappraisal,” in which they could change their emotional response to a situation. “In reappraisal you reassess the meaning of an emotional stimulus, rather than trying to avoid the emotional stimulus or suppress your reaction to it,” Winecoff said. 

While the subjects’ brains were being scanned using functional MRI, they were shown images of evocative scenes and faces. After each image the subjects were told to either let their feelings flow or to practice reappraisal to change their thoughts. Then they were asked to rate how positive or negative they felt.

In the case of “an unregulated positive affect” — letting the good feelings flow — the vmPFC was shown to be working harder, which the researchers say could be used to predict how much value a person is putting on something. But when the subjects dampened their emotion responses to positive images, the vmPFC activation diminished, as if the images were less valuable to the subjects.  

"This changes our frame of reference for thinking about these things," Huettel said. He said advertisers have long been using emotional appeals to get people to value their products, "but they didn’t know why it worked."

Previous studies had focused only on reappraisal of negative emotions, but this time around the Duke scientists wanted to watch people reappraise both negative and positive responses. “We have kind of a skewed picture because this has only been done on the negative,” Winecoff said.

"It’s not the case that you never want to reappraise a positive emotion," said Huettel. But when buying a house or a car, it’s a good idea to dampen your infatuation down a bit, he added.

Teens’ Self-Consciousness Linked With Specific Brain, Physiological Responses

Teenagers are famously self-conscious, acutely aware and concerned about what their peers think of them. A new study reveals that this self-consciousness is linked with specific physiological and brain responses that seem to emerge in adolescence.

“Our study identifies adolescence as a unique period of the lifespan in which self-conscious emotion, physiological reactivity, and activity in specific brain areas converge and peak in response to being evaluated by others,” says psychological scientist and lead researcher Leah Somerville of Harvard University.

The findings, published in Psychological Science, a journal of the Association for Psychological Science, suggest that teens’ sensitivity to social evaluation might be explained by shifts in physiological and brain function during adolescence, in addition to the numerous sociocultural changes that take place during the teen years.

Somerville and colleagues wanted to investigate whether just being looked at — a minimal social-evaluation situation — might register with greater importance, arousal, and intensity for adolescents than for either children or adults. The researchers hypothesized that late-developing regions of the brain, such as the medial prefrontal cortex (MPFC), could play a unique role in the way teens monitor these types of social evaluative contexts.

The researchers had 69 participants, ranging in age from 8 to almost 23 years old, come to the lab and complete measures that gauged emotional, physiological, and neural responses to social evaluation.

They told the participants that they would be testing a new video camera embedded in the head coil of a functional MRI scanner. The participants watched a screen indicating whether the camera was “off,” “warming up,” or “on”, and were told that a same-sex peer of about the same age would be watching the video feed and would be able to see them when the camera was on. In reality, there was no camera in the MRI machine.

The consistency and strength of the resulting data took the researchers by surprise:

“We were concerned about whether simply being looked at was a strong enough ‘social evaluation’ to evoke emotional, physiological and neural responses,” says Somerville. “Our findings suggest that being watched, and to some extent anticipating being watched, were sufficient to elicit self-conscious emotional responses at each level of measurement.”

Specifically, participants’ self-reported embarrassment, physiological arousal, and MPFC activation showed reactivity to social evaluation that seemed to converge and peak during adolescence.

Adolescent participants also showed increased functional connectivity between the MPFC and striatum, an area of the brain that mediates motivated behaviors and actions. Somerville and colleagues speculate that the MPFC-striatum pathway may be a route by which social evaluative contexts influence behavior. The link may provide an initial clue as to why teens often engage in riskier behaviors when they’re with their peers.

Scientists Help Explain Visual System’s Remarkable Ability to Recognize Complex Objects

How is it possible for a human eye to figure out letters that are twisted and looped in crazy directions, like those in the little security test internet users are often given on websites?

It seems easy to us——the human brain just does it. But the apparent simplicity of this task is an illusion. The task is actually so complex, no one has been able to write computer code that translates these distorted letters the same way that neural networks can. That’s why this test, called a CAPTCHA, is used to distinguish a human response from computer bots that try to steal sensitive information.

Now, a team of neuroscientists at the Salk Institute for Biological Studies has taken on the challenge of exploring how the brain accomplishes this remarkable task. Two studies published within days of each other demonstrate how complex a visual task decoding a CAPTCHA, or any image made of simple and intricate elements, actually is to the brain.

The findings of the two studies, published June 19 in Neuron and June 24 in the Proceedings of the National Academy of Sciences (PNAS), take two important steps forward in understanding vision, and rewrite what was believed to be established science. The results show that what neuroscientists thought they knew about one piece of the puzzle was too simple to be true.

Their deep and detailed research——involving recordings from hundreds of neurons——may also have future clinical and practical implications, says the study’s senior co-authors, Salk neuroscientists Tatyana Sharpee and John Reynolds.

"Understanding how the brain creates a visual image can help humans whose brains are malfunctioning in various different ways——such as people who have lost the ability to see," says Sharpee, an associate professor in the Computational Neurobiology Laboratory. "One way of solving that problem is to figure out how the brain——not the eye, but the cortex—— processes information about the world. If you have that code then you can directly stimulate neurons in the cortex and allow people to see."

Reynolds, a professor in the Systems Neurobiology Laboratory, says an indirect benefit of understanding the way the brain works is the possibility of building computer systems that can act like humans.

"The reason that machines are limited in their capacity to recognize things in the world around us is that we don’t really understand how the brain does it as well as it does," he says.

The scientists emphasize that these are long-term goals that they are striving to reach, a step at a time.

Integrating parts into wholes

In these studies, Salk neurobiologists sought to figure out how a part of the visual cortex known as area V4 is able to distinguish between different visual stimuli even as the stimuli move around in space. V4 is responsible for an intermediate step in neural processing of images.

"Neurons in the visual system are sensitive to regions of space—— they are like little windows into the world," says Reynolds. "In the earliest stages of processing, these windows ——known as receptive fields——are small. They only have access to information within a restricted region of space. Each of these neurons sends brain signals that encode the contents of a little region of space——they respond to tiny, simple elements of an object such as edge oriented in space, or a little patch of color."

Neurons in V4 have a larger receptive field that can also compute more complex shapes such as contours. They accomplishes this by integrating inputs from earlier visual areas in the cortex——that is, areas nearer the retina, which provides the input to the visual system, which have small receptive fields, and sends on that information for higher level processing that allow us to see complex images, such as faces, he says.

Both new studies investigated the issue of translation invariance—— the ability of a neuron to recognize the same stimulus within its receptive field no matter where it is in space, where it happens to fall within the receptive field.

The Neuron paper looked at translation invariance by analyzing the response of 93 individual neurons in V4 to images of lines and shapes like curves, while the PNAS study looked at responses of V4 neurons to natural scenes full of complex contours.

Dogma in the field is that V4 neurons all exhibit translation invariance.

"The accepted understanding is that individuals neurons are tuned to recognize the same stimulus no matter where it was in their receptive field," says Sharpee.

For example, a neuron might respond to a bit of the curve in the number 5 in a CAPTCHA image, no matter how the 5 is situated within its receptive field. Researchers believed that neuronal translation invariance——the ability to recognize any stimulus, no matter where it is in space——increases as an image moves up through the visual processing hierarchy.

"But what both studies show is that there is more to the story," she says. "There is a trade off between the complexity of the stimulus and the degree to which the cell can recognize it as it moves from place to place."

A deeper mystery to be solved

The Salk researchers found that neurons that respond to more complicated shapes——like the curve in 5 or in a rock—— demonstrated decreased translation invariance. “They need that complicated curve to be in a more restricted range for them to detect it and understand its meaning,” Reynolds says. “Cells that prefer that complex shape don’t yet have the capacity to recognize that shape everywhere.”

On the other hand, neurons in V4 tuned to recognize simpler shapes, like a straight line in the number 5, have increased translation invariance. “They don’t care where the stimuli they are tuned to is, as long as it is within their receptive field,” Sharpee says.

"Previous studies of object recognition have assumed that neuronal responses at later stages in visual processing remain the same regardless of basic visual transformations to the object’s image. Our study highlights where this assumption breaks down, and suggests simple mechanisms that could give rise to object selectivity," says Jude Mitchell, a Salk research scientist who was the senior author on the Neuron paper.

"It is important that results from the two studies are quite compatible with one another, that what we find studying just lines and curves in one first experiment matches what we see when the brain experiences the real world," says Sharpee, who is well known for developing a computational method to extract neural responses from natural images.

"What this tells us is that there is a deeper mystery here to be solved," Reynolds says. "We have not figured out how translation invariance is achieved. What we have done is unpacked part of the machinery for achieving integration of parts into wholes."

Irreversible tissue loss seen within 40 days of spinal cord injury

The rate and extent of damage to the spinal cord and brain following spinal cord injury have long been a mystery. Now, a joint research effort between the University of Zurich, University Hospital Balgrist and colleagues from University College London have found evidence that patients already have irreversible tissue loss in the spinal cord within 40 days of injury. Using a new imaging measurement technique the impact of therapeutic treatments and rehabilitative interventions can be now determined more quickly and directly than before.

A spinal cord injury changes the functional state and structure of the spinal cord and the brain. For example, the patients’ ability to walk or move their hands can become restricted. How quickly such degenerative changes develop, however, has remained a mystery until now. The assumption was that it took years for patients with a spinal cord injury to also display anatomical changes in the spinal cord and brain above the injury site. For the first time, researchers from the University of Zurich and the Uniklinik Balgrist, along with English colleagues from University College London (UCL), now demonstrate that these changes already occur within 40 days of acute spinal cord injury.

Spinal cord depletes rapidly

The scientists studied 13 patients with acute spinal cord injuries every three months for a year using novel MRI (magnetic resonance imaging) protocols. They discovered that the diameter of the spinal cord had rapidly decreased and was already seven percent smaller after twelve months. A lesser volume decline was also evident in the corticospinal tract, a tract indispensable for motor control, and nerve cells in the sensorimotor cortex. The extent of the degenerative changes coincided with the clinical outcome. “Patients with a greater tissue loss above the injury site recovered less effectively than those with less changes,” explains Patrick Freund, the investigator responsible for the study at the Paraplegic Center Balgrist.

Gaining insights into effect of therapies

Treatments targeting the injured spinal cord have entered clinical trials. Gaining insights into mechanisms of repair and recovery within the first year are crucial. Thanks to the use of the new neuroimaging protocols, Freund says, we now have the possibility of displaying the effect of therapeutic treatments on the central nervous system and of rehabilitative measures more quickly. Consequently, the effect of new therapies can also be recorded more rapidly.

“This study is an excellent example of the value of combining the complementary expertise of the two universities,” says UCL’s Dean of Brain Sciences, Professor Alan Thompson, who is one of the senior authors of the study. “It provides exciting new insights into the complications of spinal cord trauma and gives us the possibility of identifying both imaging biomarkers and therapeutic targets.”

The findings are the result of a new three-year neuroscience partnership between the Neuroscience Centre Zurich (ZNZ) and UCL.

Literature:

Patrick Freund, Nikolaus Weiskopf, John Ashburner, Katharina Wolf, Reto Sutter, Daniel R Altmann, Karl Friston, Alan Thompson, Armin Curt. MRI investigation of the sensorimotor cortex and corticospinal tract after acute spinal cord injury: a prospective longitudinal study. The Lancet Neurology. July 2, 2013.

Researchers discover a gene’s key role in building the developing brain’s scaffolding

The gene, Arl13b, is necessary for the proper construction of the cerebral cortex. The finding offers new insights on normal brain development and illuminates some of the factors behind Joubert’s syndrome, a rare neurological disorder.

Researchers have pinpointed the role of a gene known as Arl13b in guiding the formation and proper placement of neurons in the early stages of brain development. Mutations in the gene could help explain brain malformations often seen in neurodevelopmental disorders.

The research, led by a team at the University of North Carolina School of Medicine, was published June 30 in the journal Nature Neuroscience.

“We wanted to get a better sense of how the cerebral cortex is constructed,” said senior study author Eva Anton, PhD, a professor in the Department of Cell Biology and Physiology and a member of the UNC Neuroscience Center. “The cells we studied — radial glial cells — provide a scaffolding for the formation of the brain by making neurons and guiding them to where they have to go. This is the first step in the formation of functional neuronal circuitry in the brain. This study gives us new information about the mechanisms involved in that process.”

The researchers became interested in the Arl13b gene because of its expression in a part of the cell called primary cilium and its association with a rare neurological disorder known as Joubert syndrome. The syndrome is characterized by brain malformations and autism like features.

“In addition to helping us understand an important cellular mechanism involved in normal brain development, this study may offer an explanation for some of the malformations seen in Joubert syndrome patients,” said Anton. Although there is no immediate clinical application for these patients, the study does help illuminate the factors behind the disease. “It shows what may have gone wrong in some of those patients that led to the malformations,” said Anton.

The cerebral cortex, the brain’s “gray matter,” is responsible for higher-order functions such as memory and consciousness. Like the scaffolding builders use to move people and materials during construction, radial glial cells provide an instructive matrix to create the basic structural features of the cerebral cortex. Mistakes in the formation and development of radial glial cells can translate into structural problems in the brain as it develops, said Anton.

Both mice and humans have the Arl13b gene. The researchers generated a series of mice with mutations on the Arl13b gene at different developmental stages to track the mutations’ effects on brain development. They discovered that the gene is crucial to the radial glial cells’ ability to sense signals through an appendage called the primary cilium. Without this signaling capability, the radial glia were unable to organize into an instructive scaffold capable of orchestrating the orderly formation of cerebral cortex. “The cilia in these cells play an important role in the initial setup of this scaffolding,” said Anton. “Without a functioning Arl13b gene, the cells were not able to determine polarity and formed haphazardly. As a result, they formed a malformed cerebral cortex with ectopic clusters of neurons, instead of the orderly layers of neurons with appropriate connectivity that would be expected, in the developing brain.