Neurobiologists find chronic stress in early life causes anxiety, aggression in adulthood

Cold Spring Harbor, NY -- In recent years, behavioral neuroscientists have debated the meaning and significance of a plethora of independently conducted experiments seeking to establish the impact of chronic, early-life stress upon behavior – both at the time that stress is experienced, and upon the same individuals later in life, during adulthood. These experiments, typically conducted in rodents, have on the one hand clearly indicated a link between certain kinds of early stress and dysfunction in the neuroendocrine system, particularly in the so-called HPA axis (hypothalamic-pituitary-adrenal), which regulates the endocrine glands and stress hormones including corticotropin and glucocorticoid. Yet the evidence is by no means unequivocal. Stress studies in rodents have also clearly identified a native capacity, stronger in some individuals than others, and seemingly weak or absent in still others, to bounce back from chronic early-life stress. Some rodents subjected to early life stress have no apparent behavioral consequences in adulthood – they are disposed neither to anxiety nor depression, the classic pathologies understood to be induced by stress in certain individuals. Today, a research team led by Associate Professor Grigori Enikolopov of Cold Spring Harbor Laboratory (CSHL) reports online in the journal PlOS One the results of experiments designed to assess the impacts of social stress upon adolescent mice, both at the time they are experienced and during adulthood. Involving many different kinds of stress tests and means of measuring their impacts, the research indicates that a "hostile environment in adolescence disturbs psychoemotional state and social behaviors of animals in adult life," the team says. The tests began with 1-month-old male mice – the equivalent, in human terms of adolescents -- each placed for 2 weeks in a cage shared with an aggressive adult male. The animals were separated by a transparent perforated partition, but the young males were exposed daily to short attacks by the adult males. This kind of chronic activity produces what neurobiologists call social-defeat stress in the young mice. These mice were then studied in a range of behavioral tests. "The tests assessed levels of anxiety, depression, and capacity to socialize and communicate with an unfamiliar partner," explains Enikolopov. These experiments showed that in young mice chronic social defeat induced high levels of anxiety helplessness, diminished social interaction, and diminished ability to communicate with other young animals. Stressed mice also had less new nerve-cell growth (neurogenesis) in a portion of the hippocampus known to be affected in depression: the subgranular zone of the dentate gyrus. Another group of young mice was also exposed to social stress, but was then placed for several weeks in an unstressful environment. Following this "rest" period, these mice, now old enough to be considered adults, were tested in the same manner as the other cohort. In this second, now-adult group, most of the behaviors impacted by social defeat returned to normal, as did neurogenesis, which retuned to a level seen in healthy controls. "This shows that young mice, exposed to adult aggressors, were largely resilient biologically and behaviorally," says Dr. Enikolopov. However, in these resilient mice, the team measured two latent impacts on behavior. As adults they were abnormally anxious, and were observed to be more aggressive in their social interactions. "The exposure to a hostile environment during their adolescence had profound consequences in terms of emotional state and the ability to interact with peers," Dr. Enikolopov observes. ### The research described in this release was supported by the Russian Foundation for Basic Research and by the National Institute of Mental Health. "Extended Effect of Chronic Social Defeat Stress in Childhood on Behaviors in Adulthood" appears online in PlOS One Tuesday, March 25, 2014. The authors are: Irina L. Kovalenko, Anna G. Galyamina, Dmitry A. Smagin, Tatyana V. Michurina, Natalia N. Kudryavtseva and Grigori Enikolopov. About Cold Spring Harbor Laboratory Founded in 1890, Cold Spring Harbor Laboratory (CSHL) has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. CSHL is ranked number one in the world by Thomson Reuters for the impact of its research in molecular biology and genetics. The Laboratory has been home to eight Nobel Prize winners. Today, CSHL's multidisciplinary scientific community is more than 600 researchers and technicians strong and its Meetings & Courses program hosts more than 12,000 scientists from around the world each year to its Long Island campus and its China center LCSW Continuing Education

Anxiety linked to higher long-term risk of stroke

American Heart Association Rapid Access Journal Report The greater your anxiety level, the higher your risk of having a stroke, according to new research published in the American Heart Association journal Stroke. The study is the first in which researchers linked anxiety and stroke independent of other factors such as depression. Anxiety disorders are one of the most prevalent mental health problems. Symptoms include feeling unusually worried, stressed, nervous or tense. Over a 22 year period, researchers studied a nationally representative group of 6,019 people 25-74 years old in the first National Health and Nutrition Examination Survey (NHANES I). Participants underwent an interview and took blood tests, medical examinations and completed psychological questionnaires to gauge anxiety and depression levels. Researchers tracked strokes through hospital or nursing home reports and death certificates. After accounting for other factors, they found that even modest increases in anxiety were associated with greater stroke risk. People in the highest third of anxiety symptoms had a 33 percent higher stroke risk than those with the lowest levels. "Everyone has some anxiety now and then. But when it's elevated and/or chronic, it may have an effect on your vasculature years down the road," said Maya Lambiase, Ph.D., study author and cardiovascular behavioral medicine researcher in the Department of Psychiatry at the University of Pittsburgh School of Medicine, in Pittsburgh, Penn. People with high anxiety levels are more likely to smoke and be physically inactive, possibly explaining part of the anxiety-stroke link. Higher stress hormone levels, heart rate or blood pressure could also be factors, Lambiase said. In earlier work, researchers found that depression was linked to greater risk of stroke. In contrast to anxiety, depression is a persistent feeling of hopelessness, dejection, and lack of energy, among other symptoms. Stroke is the No. 4 killer and a leading cause of disability in the United States Continuing Education for MFTs ### Co-authors are Laura Kubzansky, Ph.D. and Rebecca Thurston, Ph.D. Author disclosures are on the manuscript. The National Heart, Lung, and Blood Institute and the National Institute of Mental Health funded the study. For the latest heart and stroke news, follow us on Twitter: @HeartNews. For stroke science, follow the Stroke journal at @StrokeAHA_ASA. Statements and conclusions of study authors published in American Heart Association scientific journals are solely those of the study authors and do not necessarily reflect the association's policy or position. The association makes no representation or guarantee as to their accuracy or reliability. The association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific association programs and events. The association has strict policies to prevent these relationships from influencing the science content. Revenues from pharmaceutical and device corporations are available at http://www.heart.org/corporatefunding.

Forced exercise may still protect against anxiety and stress, says CU-Boulder study

Being forced to exercise may still help reduce anxiety and depression just as exercising voluntarily does, according to a new study by researchers at the University of Colorado Boulder. Past studies have shown that people who exercise are more protected against stress-related disorders. And scientists know that the perception of control can benefit a person's mental health. But it has been an open question whether a person who feels forced to exercise, eliminating the perception of control, would still reap the anxiety-fighting benefits of the exercise. People who may feel forced to exercise could include high school, college and professional athletes, members of the military or those who have been prescribed an exercise regimen by their doctors, said Benjamin Greenwood, an assistant research professor in CU-Boulder's Department of Integrative Physiology. "If exercise is forced, will it still produce mental health benefits?" Greenwood asked. "It's obvious that forced exercise will still produce peripheral physiological benefits. But will it produce benefits to anxiety and depression?" To seek an answer to the question Greenwood and his colleagues, including Monika Fleshner, a professor in the same department, designed a lab experiment using rats. During a six-week period, some rats remained sedentary, while others exercised by running on a wheel. The rats that exercised were divided into two groups that ran a roughly equal amount of time. One group ran whenever it chose to, while the other group ran on mechanized wheels that rotated according to a predetermined schedule. For the study, the motorized wheels turned on at speeds and for periods of time that mimicked the average pattern of exercise chosen by the rats that voluntarily exercised. After six weeks, the rats were exposed to a laboratory stressor before testing their anxiety levels the following day. The anxiety was quantified by measuring how long the rats froze, a phenomenon similar to a deer in the headlights, when they were put in an environment they had been conditioned to fear. The longer the freezing time, the greater the residual anxiety from being stressed the previous day. For comparison, some rats were also tested for anxiety without being stressed the day before. "Regardless of whether the rats chose to run or were forced to run they were protected against stress and anxiety," said Greenwood, lead author of the study appearing in the European Journal of Neuroscience in February. The sedentary rats froze for longer periods of time than any of the active rats. "The implications are that humans who perceive exercise as being forced — perhaps including those who feel like they have to exercise for health reasons — are maybe still going to get the benefits in terms of reducing anxiety and depression," he said. Anxiety Disorders CE Course ### Other CU-Boulder authors include Katie Spence, Danielle Crevling, Peter Clark and Wendy Craig. All the authors are members of Monika Fleshner's Stress Physiology Laboratory in the Department of Integrative Physiology. The research was funded by the National Institutes of Mental Health and the Defense Advanced Research Projects Agency.

Male mice exposed to chronic social stress have anxious female offspring

BOSTON (August 22, 2012) —A study in mice conducted by researchers at Tufts University School of Medicine (TUSM) suggests that a woman's risk of anxiety and dysfunctional social behavior may depend on the experiences of her parents, particularly fathers, when they were young. The study, published online in Biological Psychiatry, suggests that stress caused by chronic social instability during youth contributes to epigenetic changes in sperm cells that can lead to psychiatric disorders in female offspring across multiple generations. "The long-term effects of stress can be pernicious. We first found that adolescent mice exposed to chronic social instability, where the cage composition of mice is constantly changing, exhibited anxious behavior and poor social interactions through adulthood. These changes were especially prominent in female mice," said first author Lorena Saavedra-Rodríguez, Ph.D., postdoctoral fellow in the Larry Feig laboratory at Tufts University School of Medicine (TUSM). The researchers then studied the offspring of these previously-stressed mice and observed that again female, but not male, offspring exhibited elevated anxiety and poor social interactions. Notably, even though the stressed males did not express any of these altered behaviors, they passed on these behaviors to their female offspring after being mated to non-stressed females. Moreover, the male offspring passed on these behaviors to yet another generation of female offspring LSW Continuing Education "We are presently searching for biochemical changes in the sperm of stressed fathers that could account for this newly appreciated form of inheritance" said senior author Larry A. Feig, Ph.D., professor of biochemistry at Tufts University School of Medicine and member of the biochemistry and neuroscience program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts University. "Hopefully, this work will stimulate efforts to determine whether similar phenomena occur in humans." ### This research was supported by award numbers AA019317 from the National Institute on Alcohol Abuse and Alcoholism, and MH083324 from the National Institute of Mental Health, both part of the National Institutes of Health (NIH). The research was also supported by award number NS047243 from National Institute of Neurological Disorders and Stroke (NIH) to the Tufts Center for Neuroscience Research. Saavedra-Rodríguez L, Feig LA. Biological Psychiatry. "Chronic Social Instability Induces Anxiety and Defective Social Interactions Across Generations." Available online August 20, 2012. http://dx.doi.org/10.1016/j.biopsych.2012.06.035 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.

Avatars may help children with social anxiety overcome fears

A principal standing in the hallway says, "You are one of my favorite students!" In class, a smart girl says, "You are the nicest person in our class!" Many children would smile and eagerly return those compliments, but some with social anxiety may be too terrified to respond. Researchers at the University of Central Florida's Anxiety Disorders Clinic and the Atlanta-based company Virtually Better want to give more children with social anxiety the practice they need to become comfortable in social situations. They have developed a new, one-of-a-kind computer simulation program that enables children to interact with avatars playing the roles of classmates, teachers and a principal. The simulation, designed for children ages 8 to 12, allows clinicians to play the roles of the avatars while the children sit at a computer in a different room and respond to situations they encounter routinely. The children practice greetings, giving and receiving compliments, being assertive and asking and answering questions. "These kids come in and say, 'I don't know how to make a friend,'" said Deborah Beidel, director of the Anxiety Disorders Clinic and a psychology professor at UCF. "We have to teach them the skills that most people learn from being around other people." The National Institute of Mental Health, part of the National Institutes of Health, provided a $500,000 grant to fund the development of the software and a 12-week study that will begin this summer. The study will involve 30 Central Florida children ages 8 to 12. Many children are nervous and slow to warm up in new social situations, but those with social anxiety disorders have severe distress that doesn't go away, Beidel said. "If a fear is so severe that it prevents a child from doing something he or she should be doing, such as going to school, playing on a sports team, being in a dance recital, going to birthday parties or making friends, then a parent should call a mental health professional," she said. Under Beidel's leadership, the UCF Anxiety Disorders Clinic has treated children with anxiety disorders for five years. The clinic offers what Beidel calls the "gold standard" of treatments. Children with anxiety disorders are paired with socially comfortable peers for outings to places such as bowling alleys, restaurants and miniature golf courses. The new study will give parents multiple treatment options at UCF. But parents in most communities aren't so fortunate. Many clinicians who treat children don't have the time or resources to recruit socially comfortable children and organize regular outings. Guiding clients through a simulation in the office may be the only feasible solution for them continuing education for counselors The simulation features a realistic school setting, designed with the help of elementary school teachers. The pre-programmed responses of the avatar classmates – which include a cool girl, a smart girl and a bully -- were recorded by children to ensure the language reflects how they talk. "The most important thing is that this was designed by clinicians with a very specific intention to help people get better. That's the big difference between this and a game, and there is nothing like this on the market," said Josh Spitalnick, clinical psychologist and director of research and clinical services at Virtually Better, an Atlanta-based company bringing interactive technologies to behavioral healthcare for treatment and training. The six characters and the varying levels of difficulty in the simulation allow clinicians to design scenarios appropriate for their patients. More challenging scenarios include dealing with a bully who is demanding that a child give up some of her lunch money. If the initial trial goes well, researchers hope to conduct a yearlong trial with more children. If that is successful, the simulation could then become available to clinicians. The program eventually could be expanded to include other settings, such as playgrounds, and to serve other children who need help improving social skills. ### For more information about UCF's Anxiety Disorders Clinic, go to http://anxietyclinic.cos.ucf.edu. For more information about Virtually Better Technologies, visit www.virtuallybetter.com.

Runaway Vigilance Hormone Linked to Panic Attacks

Translational Experiments in Rats, Humans Suggest New Medication Target A study has linked panic disorder to a wayward hormone in a brain circuit that regulates vigilance. While too little of the hormone, called orexin, is known to underlie narcolepsy, the new study suggests that too much of it may lead to panic attacks that afflict 6 million American adults. "Targeting the brain's orexin system may hold promise for a new generation of anti-anxiety treatments," said Thomas R. Insel, M.D., Director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health. "This is a good example of how translational experiments in rats and humans can potentially yield clinical benefits." NIMH grantee Anantha Shekhar, M.B., Ph.D., and colleagues at Indiana University and Lund University, report on their findings online Dec. 27, 2009 in the journal Nature Medicine. They showed that blocking orexin gene expression or its receptor prevented panic attack-like responses in rats. The study also revealed that panic disorder patients have excess levels of the hormone Alcoholism and Drug Abuse Counselors Continuing Education Background Orexin, also called hypocretin, is secreted exclusively in a circuit emanating from the brain's hypothalamus, known to regulate arousal, wakefulness and reward. Panic attacks can be experimentally-induced by infusing susceptible humans with a normally innocuous salt called sodium lactate. The salt similarly triggers panic-like anxiety behaviors in susceptible rat strains, suggesting that something is altered in their arousal circuit. Since sodium lactate activated orexin-secreting neurons in panic-prone rats but not in control rats, the researchers hypothesized that something might be orexin. Results of This Study The investigators first discovered that increased gene expression in orexin-secreting neurons correlated with increases in anxiety-like behavior in panic-prone rats following sodium lactate infusions. Using a technique called RNA interference, they then protected the panic-prone rats from developing anxiety behaviors following the infusions by first injecting them with a genetically-engineered agent that prevented orexin genes from turning on. Blocking orexin receptors with a drug that specifically binds to it also blocked the anxiety like behavior following the infusions. This mirrored effects, seen in both rats and humans, of benzodiazepine medications used to treat panic disorder. The excess sleepiness of narcolepsy, traced a decade ago to loss of orexin-secreting neurons in the arousal circuit, might seem to be an opposite state of a panic attack. However, the researchers demonstrated in rats that such sedation could not account for orexin's effects on anxiety. Also in rats, they traced orexin neurons to their end target to pinpoint the specific brain site that accounts for the anxiety effects, disentangled from cardio-respiratory components of the panic response. Finally, by measuring orexin in cerebrospinal fluid of 53 patients, the researchers showed that those with just panic disorder had higher levels of orexin than those with both panic disorder and depression. Significance Taken together, these results and other evidence suggest a critical role for an overactive orexin system in producing panic attacks, say the researchers. What's Next? Medications that block the orexin receptor may provide a new therapeutic approach for the treatment of panic disorder, they add. The research was also supported, in part, by NIH's National Center for Research Resources. Reference A key role for orexin in panic anxiety. Johnson PL, Truitt W, Fitz SD, Kelley PE, Dietrich A, Sanghani S, Traskman-Bendz L, Goddard AW, Brundin, L, Shekhar A. Nature Medicine.

Excessive worrying may have co-evolved with intelligence

What is usually seen as pathology may aid survival of the species

Worrying may have evolved along with intelligence as a beneficial trait, according to a recent study by scientists at SUNY Downstate Medical Center and other institutions. Jeremy Coplan, MD, professor of psychiatry at SUNY Downstate, and colleagues found that high intelligence and worry both correlate with brain activity measured by the depletion of the nutrient choline in the subcortical white matter of the brain. According to the researchers, this suggests that intelligence may have co-evolved with worry in humans.

"While excessive worry is generally seen as a negative trait and high intelligence as a positive one, worry may cause our species to avoid dangerous situations, regardless of how remote a possibility they may be," said Dr. Coplan. "In essence, worry may make people 'take no chances,' and such people may have higher survival rates. Thus, like intelligence, worry may confer a benefit upon the species."

In this study of anxiety and intelligence, patients with generalized anxiety disorder (GAD) were compared with healthy volunteers to assess the relationship among intelligence quotient (IQ), worry, and subcortical white matter metabolism of choline. In a control group of normal volunteers, high IQ was associated with a lower degree of worry, but in those diagnosed with GAD, high IQ was associated with a greater degree of worry. The correlation between IQ and worry was significant in both the GAD group and the healthy control group. However, in the former, the correlation was positive and in the latter, the correlation was negative. Eighteen healthy volunteers (eight males and 10 females) and 26 patients with GAD (12 males and 14 females) served as subjects.

Previous studies have indicated that excessive worry tends to exist both in people with higher intelligence and lower intelligence, and less so in people of moderate intelligence. It has been hypothesized that people with lower intelligence suffer more anxiety because they achieve less success in life.

The results of their study, "The Relationship between Intelligence and Anxiety: An Association with Subcortical White Matter Metabolism," was published in a recent edition of Frontiers in Evolutionary Neuroscience, and can be read at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269637/pdf/fnevo-03-00008.pdf.

The study was selected and evaluated by a member of the Faculty of 1000 (F1000), placing it in their library of the top 2% of published articles in biology and medicine.

SUNY Downstate Medical Center, founded in 1860, was the first medical school in the United States to bring teaching out of the lecture hall and to the patient's bedside. A center of innovation and excellence in research and clinical service delivery, SUNY Downstate Medical Center comprises a College of Medicine, Colleges of Nursing and Health Related Professions, a School of Graduate Studies, a School of Public Health, University Hospital of Brooklyn, and an Advanced Biotechnology Park and Biotechnology Incubator.

SUNY Downstate ranks eighth nationally in the number of alumni who are on the faculty of American medical schools. More physicians practicing in New York City have graduated from SUNY Downstate than from any other medical school social worker continuing education