New evidence that chronic stress predisposes brain to mental illness

By Robert Sanders, Media Relations | February 11, 2014 BERKELEY — University of California, Berkeley, researchers have shown that chronic stress generates long-term changes in the brain that may explain why people suffering chronic stress are prone to mental problems such as anxiety and mood disorders later in life. myelin stained blue Myelin is stained blue in this cross section of a rat hippocampus. Myelin, which speeds electrical signals flowing through axons, is produced by oligodendrocytes, which increase in number as a result of chronic stress. New oligodendrocytes are shown in yellow. Image by Aaron Friedman and Daniela Kaufer. Their findings could lead to new therapies to reduce the risk of developing mental illness after stressful events. Doctors know that people with stress-related illnesses, such as post-traumatic stress disorder (PTSD), have abnormalities in the brain, including differences in the amount of gray matter versus white matter. Gray matter consists mostly of cells – neurons, which store and process information, and support cells called glia – while white matter is comprised of axons, which create a network of fibers that interconnect neurons. White matter gets its name from the white, fatty myelin sheath that surrounds the axons and speeds the flow of electrical signals from cell to cell. How chronic stress creates these long-lasting changes in brain structure is a mystery that researchers are only now beginning to unravel. In a series of experiments, Daniela Kaufer, UC Berkeley associate professor of integrative biology, and her colleagues, including graduate students Sundari Chetty and Aaron Freidman, discovered that chronic stress generates more myelin-producing cells and fewer neurons than normal. This results in an excess of myelin – and thus, white matter – in some areas of the brain, which disrupts the delicate balance and timing of communication within the brain. “We studied only one part of the brain, the hippocampus, but our findings could provide insight into how white matter is changing in conditions such as schizophrenia, autism, depression, suicide, ADHD and PTSD,” she said. The hippocampus regulates memory and emotions, and plays a role in various emotional disorders. Kaufer and her colleagues published their findings in the Feb. 11 issue of the journal Molecular Psychiatry. Does stress affect brain connectivity? Kaufer’s findings suggest a mechanism that may explain some changes in brain connectivity in people with PTSD, for example. One can imagine, she said, that PTSD patients could develop a stronger connectivity between the hippocampus and the amygdala – the seat of the brain’s fight or flight response – and lower than normal connectivity between the hippocampus and prefrontal cortex, which moderates our responses. “You can imagine that if your amygdala and hippocampus are better connected, that could mean that your fear responses are much quicker, which is something you see in stress survivors,” she said. “On the other hand, if your connections are not so good to the prefrontal cortex, your ability to shut down responses is impaired. So, when you are in a stressful situation, the inhibitory pathways from the prefrontal cortex telling you not to get stressed don’t work as well as the amygdala shouting to the hippocampus, ‘This is terrible!’ You have a much bigger response than you should.” white matter fibers in human brain White matter fiber architecture of the brain. Human Connectome Project. She is involved in a study to test this hypothesis in PTSD patients, and continues to study brain changes in rodents subjected to chronic stress or to adverse environments in early life. Stress tweaks stem cells Kaufer’s lab, which conducts research on the molecular and cellular effects of acute and chronic stress, focused in this study on neural stem cells in the hippocampus of the brains of adult rats. These stem cells were previously thought to mature only into neurons or a type of glial cell called an astrocyte. The researchers found, however, that chronic stress also made stem cells in the hippocampus mature into another type of glial cell called an oligodendrocyte, which produces the myelin that sheaths nerve cells. The finding, which they demonstrated in rats and cultured rat brain cells, suggests a key role for oligodendrocytes in long-term and perhaps permanent changes in the brain that could set the stage for later mental problems. Oligodendrocytes also help form synapses – sites where one cell talks to another – and help control the growth pathway of axons, which make those synapse connections. The fact that chronic stress also decreases the number of stem cells that mature into neurons could provide an explanation for how chronic stress also affects learning and memory, she said. Kaufer is now conducting experiments to determine how stress in infancy affects the brain’s white matter, and whether chronic early-life stress decreases resilience later in life. She also is looking at the effects of therapies, ranging from exercise to antidepressant drugs, that reduce the impact of stress and stress hormones. Kaufer’s coauthors include Chetty, formerly from UC Berkeley’s Helen Wills Neuroscience Institute and now at Harvard University; Friedman and K. Taravosh-Lahn at UC Berkeley’s Department of Integrative Biology; additional colleagues from UC Berkeley and others from Stanford University and UC Davis. The work was supported by a BRAINS (Biobehavioral Research Awards for Innovative New Scientists) award from the National Institute of Mental Health of the National Institutes of Health (R01 MH087495), a Berkeley Stem Cell Center Seed Grant, the Hellman Family Foundation and the National Alliance for Research on Schizophrenia and Depression. RELATED INFORMATION •Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus (2/11/14 Molecular Psychiatry) •Daniela Kaufer’s web site •Researchers find out why some stress is good for you (4/16/13 press release) For more information on this and other mental health topics, please visit Counselor CEUs

Gene found to foster synapse formation in the brain

Implications for language development, autism, epilepsy Researchers at Johns Hopkins say they have found that a gene already implicated in human speech disorders and epilepsy is also needed for vocalizations and synapse formation in mice. The finding, they say, adds to scientific understanding of how language develops, as well as the way synapses — the connections among brain cells that enable us to think — are formed. A description of their experiments appears in Science Express on Oct. 31. A group led by Richard Huganir, Ph.D., director of the Solomon H. Snyder Department of Neuroscience and a Howard Hughes Medical Institute investigator, set out to investigate genes involved in synapse formation. Gek-Ming Sia, Ph.D., a research associate in Huganir's laboratory, first screened hundreds of human genes for their effects on lab-grown mouse brain cells. When one gene, SRPX2, was turned up higher than normal, it caused the brain cells to erupt with new synapses, Sia found. When Huganir's team injected fetal mice with an SRPX2-blocking compound, the mice showed fewer synapses than normal mice even as adults, the researchers found. In addition, when SRPX2-deficient mouse pups were separated from their mothers, they did not emit high-pitched distress calls as other pups do, indicating they lacked the rodent equivalent of early language ability. Other researchers' analyses of the human genome have found that mutations in SRPX2 are associated with language disorders and epilepsy, and when Huganir's team injected the human SRPX2 with the same mutations into the fetal mice, they also had deficits in their vocalization as young pups. Another research group at Institut de Neurobiologie de la Méditerranée in France had previously shown that SRPX2 interacts with FoxP2, a gene that has gained wide attention for its apparently crucial role in language ability. Huganir's team confirmed this, showing that FoxP2 controls how much protein the SRPX2 gene makes and may affect language in this way. "FoxP2 is famous for its role in language, but it's actually involved in other functions as well," Huganir comments. "SRPX2 appears to be more specialized to language ability." Huganir suspects that the gene may also be involved in autism, since autistic patients often have language impairments, and the condition has been linked to defects in synapse formation. This study is only the beginning of teasing out how SRPX2 acts on the brain, Sia says. "We'd like to find out what other proteins it acts on, and how exactly it regulates synapses and enables language development." Roger Clem of the Mount Sinai School of Medicine also participated in the study CADC I & II Continuing Education ### This study was supported by the National Institute of Mental Health (grant number P50MH084020) and the National Institute of Neurological Disorders and Stroke (grant number NS050274). Related stories: Study Refutes Accepted Model of Memory Formation Johns Hopkins Scientists Reveal Molecular Sculptor of Memories Johns Hopkins Researchers Discover How to Erase Memory

Research uncovers new details about brain anatomy and language in young children

PROVIDENCE, R.I. [Brown University] — Researchers from Brown University and King's College London have gained surprising new insights into how brain anatomy influences language acquisition in young children. Their study, published in the Journal of Neuroscience, found that the explosion of language acquisition that typically occurs in children between 2 and 4 years old is not reflected in substantial changes in brain asymmetry. Structures that support language ability tend to be localized on the left side of the brain. For that reason, the researchers expected to see more myelin — the fatty material that insulates nerve fibers and helps electrical signals zip around the brain — developing on the left side in children entering the critical period of language acquisition. But that is not what the research showed. "What we actually saw was that the asymmetry of myelin was there right from the beginning, even in the youngest children in the study, around the age of 1," said the study's lead author, Jonathan O'Muircheartaigh, the Sir Henry Wellcome Postdoctoral Fellow at King's College London. "Rather than increasing, those asymmetries remained pretty constant over time." That finding, the researchers say, underscores the importance of environment during this critical period for language. O'Muircheartaigh is currently working in Brown University's Advanced Baby Imaging Lab. The lab uses a specialized MRI technique to look at the formation of myelin in babies and toddlers. Babies are born with little myelin, but its growth accelerates rapidly in the first few years of life. The researchers imaged the brains of 108 children between ages 1 and 6, looking for myelin growth in and around areas of the brain known to support language. While asymmetry in myelin remained constant over time, the relationship between specific asymmetries and language ability did change, the study found. To investigate that relationship, the researchers compared the brain scans to a battery of language tests given to each child in the study. The comparison showed that asymmetries in different parts of the brain appear to predict language ability at different ages. "Regions of the brain that weren't important to successful language in toddlers became more important in older children, about the time they start school," O'Muircheartaigh said. "As language becomes more complex and children become more proficient, it seems as if they use different regions of the brain to support it." Interestingly, the association between asymmetry and language was generally weakest during the critical language period. "We found that between the ages of 2 and 4, myelin asymmetry doesn't predict language very well," O'Muircheartaigh said. "So if it's not a child's brain anatomy predicting their language skills, it suggests their environment might be more influential." The researchers hope this study will provide a helpful baseline for future research aimed at pinpointing brain structures that might predict developmental disorders. "Disorders like autism, dyslexia, and ADHD all have specific deficits in language ability," O'Muircheartaigh said. "Before we do studies looking at abnormalities we need to know how typical children develop. That's what this study is about." "This work is important, as it is the first to investigate the relationship between brain structure and language across early childhood and demonstrate how this relationship changes with age," said Sean Deoni, assistant professor of engineering, who oversees the Advanced Baby Imaging Lab. "The study highlights the advantage of collaborative work, combining expertise in pediatric imaging at Brown and neuropsychology from the King's College London Institute of Psychiatry, making this work possible." ### Other authors on the paper include Douglas Dean, Holly Dirks, Nicole Waskiewicz, and Katie Lehman from Brown's Baby Imaging Lab, and Beth Jerskey from Brown's Alpert Medical School. The work was funded by the National Institutes of Mental Health and the Wellcome Trust. Editors: Brown University has a fiber link television studio available for domestic and international live and taped interviews, and maintains an ISDN line for radio interviews. For more information, call (401) 863-2476 ASW Continuing Education -------------------------------------------------------------------------------- [ Back to EurekAlert! ] [ Print | E-mail Share Share ] [ Close Window ] AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system. HOME DISCLAIMER PRIVACY POLICY TERMS & CONDITIONS CONTACT US TOP Copyright ©2013 by AAAS, the science society.

NIMH Grantee Receives 2013 Nobel Prize

Congratulations to current NIMH grantee Thomas C. Südhof, M.D., at Stanford University School of Medicine, for winning the Nobel Prize in Physiology or Medicine for his work on how the brain sends and receives chemical messages. Thomas C. Südhof, M.D. Thomas C. Südhof, M.D. Stanford University School of Medicine “We are extremely proud of Dr. Südhof,” said National Institute of Mental Health (NIMH) Director Thomas Insel, M.D. “NIMH has supported Dr. Südhof's ground-breaking research for more than two decades as part of our commitment to understanding the fundamental mechanisms of brain function." The human brain houses about 100 billion neurons—about half the number of stars in the Milky Way. Each of these neurons “converses” with, on average, thousands of other neurons, sending molecular messages in a matter of milliseconds, about the same timeframe as a camera flash. How these messages are sent in such a rapid and precise manner has long been a mystery to neuroscientists. When these messages go awry, mental disorders such as schizophrenia, autism, and depression may arise. Specifically, Dr. Südhof parsed the proteins that are used in a synapse—the gap between neurons where one neuron reaches out to talk to another via chemical messengers known as neurotransmitters. These specialized spaces are comprised of three components: the messenger or presynaptic neuron, the recipient or postsynaptic neuron, and the cleft or space between these two neurons. Dr. Südhof’s work identified key molecules involved in the rapid release of neurotransmitters from the terminals of presynaptic neurons and revealed how electrical signals in the form of calcium ions instruct a protein called synaptotagmin. Once calcium binds to synaptotagmin, the protein serves as a switch for neurotransmitter-carrying cellular shuttles called vesicles to fuse with the outer surface of the presynaptic neuron and release these chemical messengers into the synaptic cleft. Upon release, the neurotransmitters cross the synaptic cleft and bind to docking sites or receptors on the postsynaptic neuron, triggering an electrical signal to pulse through it. Südhof’s work revealed that synaptotagmins also act as universal calcium sensors in non-neuronal cells, functioning, for example, in the release of hormones such as insulin from pancreatic beta cells. Dr. Südhof shares the world’s most prestigious science award with James E. Rothman, Ph.D., at Yale University, and Randy W. Schekman, Ph.D., at the University of California, Berkeley. Dr. Rothman unraveled protein machinery that allows vesicles to fuse with their targets to permit transfer of cargo. Dr. Schekman discovered a set of genes that were required for vesicle traffic. The researchers will share a prize that totals roughly $1.2 million USD. Previously, Dr. Südhof and Richard H. Scheller, Ph.D., at Genentech, collected the 2013 Albert Lasker Basic Medical Research Award for their work. Known as “America’s Nobels,” the Lasker Awards often predict future Nobel Prize recipients. The National Institutes of Health (NIH) has supported Dr. Südhof’s research over the past 22 years. In turn, Dr. Südhof has served on several study sections at the NIH Center for Scientific Review, in addition to the Molecular, Cellular, and Developmental Neuroscience study section at NIMH. Over the years, Dr. Südhof’s work on the neurotransmitter release machinery has been supported with research program grants as well as center grants from NIMH. He is also the recipient of an NIMH MERIT (Method to Extend Research in Time) award, which along with an additional NIMH grant and funding from the Howard Hughes Medical Institute helped support his Nobel work. MERIT awards provide up to 10 years of stable research support for highly productive outstanding investigators working on projects well aligned with the mission of NIMH Social Worker Continuing Education Dr. Südof also holds an NIH TR01 award for work to facilitate the creation of neurons from non-neuronal cells (skin fibroblasts of human patients). This work is anticipated to provide a novel way for scientists to study the biological effects of gene mutations associated with neuropsychiatric diseases

National Institute of Mental Health (NIMH) Grantees To Receive 2013 Lasker Award

A current and a former National Institute of Mental Health (NIMH) grantee recently collected the prestigious 2013 Albert Lasker Basic Medical Research Award for their meticulous mapping of the molecular mechanisms involved in neurotransmitter release, the process by which the brain sends and receives chemical messages. Richard H. Scheller, Ph.D. Richard H. Scheller, Ph.D Genentech Thomas C. Südhof, M.D., at Stanford University School of Medicine, and Richard H. Scheller, Ph.D., at Genentech, parsed the proteins that enable one neuron to speak to another. This communication occurs across the synapse, a gap that separates the two neurons. Collectively called the “SNARE complex,” these proteins include vesicle-associated membrane protein (VAMP/synaptobrevin), synaptogamin, syntaxin, and SNAP-25. The complex allows for the preparation and release of the neurotransmitters into the synapse. Defects in this process contribute to mental disorders such as schizophrenia, depression, bipolar disorder, epilepsy, and many other pathological conditions. Thomas C. Südhof, M.D. Thomas C. Südhof, M.D. Stanford University School of Medicine Dr. Südhof is a current NIMH grantee and has served on several study sections at the NIH Center for Scientific Review, in addition to the Molecular, Cellular, and Developmental Neuroscience study section at NIMH. Dr. Scheller received research support from NIMH, and served on both the NIMH Molecular, Cellular, and Developmental Neuroscience study section, and the National Advisory Mental Health Council. Both have received the NIMH MERIT Award. Known as “America’s Nobels” because many recipients go on to win the Nobel Prize, the Lasker Awards are among the most respected science prizes in the world. Congratulations, Drs. Südof and Scheller Aspira Continuing Education Online Courses

Astrocytes identified as target for new depression therapy

Tufts neuroscientists find that starry brain cells can be used to mimic sleep deprivation BOSTON (January 23, 2013) — Neuroscience researchers from Tufts University have found that our star-shaped brain cells, called astrocytes, may be responsible for the rapid improvement in mood in depressed patients after acute sleep deprivation. This in vivo study, published in the current issue of Translational Psychiatry, identified how astrocytes regulate a neurotransmitter involved in sleep. The researchers report that the findings may help lead to the development of effective and fast-acting drugs to treat depression, particularly in psychiatric emergencies. Drugs are widely used to treat depression, but often take weeks to work effectively. Sleep deprivation, however, has been shown to be effective immediately in approximately 60% of patients with major depressive disorders. Although widely-recognized as helpful, it is not always ideal because it can be uncomfortable for patients, and the effects are not long-lasting Marriage and Family Therapist Continuing Education During the 1970s, research verified the effectiveness of acute sleep deprivation for treating depression, particularly deprivation of rapid eye movement sleep, but the underlying brain mechanisms were not known. Most of what we understand of the brain has come from research on neurons, but another type of largely-ignored cell, called glia, are their partners. Although historically thought of as a support cell for neurons, the Phil Haydon group at Tufts University School of Medicine has shown in animal models that a type of glia, called astrocytes, affect behavior. Haydon's team had established previously that astrocytes regulate responses to sleep deprivation by releasing neurotransmitters that regulate neurons. This regulation of neuronal activity affects the sleep-wake cycle. Specifically, astrocytes act on adenosine receptors on neurons. Adenosine is a chemical known to have sleep-inducing effects. During our waking hours, adenosine accumulates and increases the urge to sleep, known as sleep pressure. Chemicals, such as caffeine, are adenosine receptor antagonists and promote wakefulness. In contrast, an adenosine receptor agonist creates sleepiness. "In this study, we administered three doses of an adenosine receptor agonist to mice over the course of a night that caused the equivalent of sleep deprivation. The mice slept as normal, but the sleep did not reduce adenosine levels sufficiently, mimicking the effects of sleep deprivation. After only 12 hours, we observed that mice had decreased depressive-like symptoms and increased levels of adenosine in the brain, and these results were sustained for 48 hours," said first author Dustin Hines, Ph.D., a post-doctoral fellow in the department of neuroscience at Tufts University School of Medicine (TUSM). "By manipulating astrocytes we were able to mimic the effects of sleep deprivation on depressive-like symptoms, causing a rapid and sustained improvement in behavior," continued Hines. "Further understanding of astrocytic signaling and the role of adenosine is important for research and development of anti-depressant drugs. Potentially, new drugs that target this mechanism may provide rapid relief for psychiatric emergencies, as well as long-term alleviation of chronic depressive symptoms," said Naomi Rosenberg, Ph.D., dean of the Sackler School of Graduate Biomedical Sciences and vice dean for research at Tufts University School of Medicine. "The team's next step is to further understand the other receptors in this system and see if they, too, can be affected." ### Senior author, Phillip G. Haydon, Ph.D., is the Annetta and Gustav Grisard professor and chair of the department of neuroscience at Tufts University School of Medicine (TUSM). Haydon is also a member of the neuroscience program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts. Additional authors are Luke I. Schmitt, B.S., a Ph.D. candidate in neuroscience at the Sackler School; Rochelle M. Hines, Ph.D., a post-doctoral fellow in the department of neuroscience at TUSM; and Stephen J. Moss, Ph.D., a professor of neuroscience at Tufts University School of Medicine and a member of the neuroscience program faculty at the Sackler School. Hines DJ, Schmitt LI, Hines RM, Moss SJ, Haydon PG. Translational Psychiatry. "Antidepressant effects of sleep deprivation require astrocyte-dependent adenosine mediated signaling." (2013) 3, e212; doi:10.1038/tp.2012.136. Published online 15 January 2013. This research was supported by award number R01MH095385 from the National Institute of Mental Health, part of the National Institutes of Health, as well as by award number R01NS037585 from the National Institute of Neurological Disorders and Stroke, both of the National Institutes of Health. Dustin Hines was partially funded by the Heart and Stroke Foundation of Canada. Haydon is co-founder and president of GliaCure Inc., which has licensed a pending patent application filed by Tufts University claiming compounds that modulate the signaling cascades, and related methods of use, described in this paper. About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, biomedical sciences, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. Tufts University School of Medicine and the Sackler School undertake research that is consistently rated among the highest in the nation for its effect on the advancement of medical science. If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Tufts University School of Medicine or another Tufts health sciences researcher, please contact Siobhan Gallagher.