Posts tagged chronic stress
Articles and news from the latest research reports.
A New Brain-Based Marker of Stress Susceptibility
Some people can handle stressful situations better than others, and it’s not all in their genes: Even identical twins show differences in how they respond.
(Image: iStockphoto)
Researchers have identified a specific electrical pattern in the brains of genetically identical mice that predicts how well individual animals will fare in stressful situations.
The findings, published July 29 in Nature Communications, may eventually help researchers prevent potential consequences of chronic stress — such as post-traumatic stress disorder, depression and other psychiatric disorders — in people who are prone to these problems.
“In soldiers, we have this dramatic, major stress exposure, and in some individuals it’s leading to major issues, such as problems sleeping or being around other people,” said senior author Kafui Dzirasa, M.D., Ph.D., an assistant professor of psychiatry and behavioral sciences at Duke University Medical Center and a member of the Duke Institute for Brain Sciences. “If we can find that common trigger or common pathway and tune it, we may be able to prevent the emergence of a range of mental illnesses down the line.”
In the new study, Dzirasa’s team analyzed the interaction between two interconnected brain areas that control fear and stress responses in both mice and men: the prefrontal cortex and the amygdala. The amygdala plays a role in the ‘fight-or-flight’ response. The prefrontal cortex is involved in planning and other higher-level functions. It suppresses the amygdala’s reactivity to danger and helps people continue to function in stressful situations.
Implanting electrodes into the brains of the mice allowed the researchers to listen in on the tempo at which the prefrontal cortex and the amygdala were firing and how tightly the two areas were linked — with the ultimate goal of figuring whether the electrical pattern of cross talk could help decide how well animals would respond when faced with an acute stressor.
Indeed, in mice that had been subjected to a chronically stressful situation — daily exposure to an aggressive male mouse for about two weeks — the degree to which the prefrontal cortex seemed to control amygdala activity was related to how well the animals coped with the stress, the group found.
Next the group looked at how the brain reacted to the first instance of stress, before the mice were put in a chronically stressful situation. The mice more sensitive to chronic stress showed greater activation of their prefrontal cortex-amygdala circuit, compared with resilient mice.
“We were really both surprised and excited to find that this signature was present in the animals before they were chronically stressed,” Dzirasa said. “You can find this signature the very first time they were ever exposed to this aggressive dangerous experience.”
Dzirasa hopes to use the signatures to come up with potential treatments for stress. “If we pair the signatures and treatments together, can we prevent symptoms from emerging, even when an animal is stressed? That’s the first question,” he said.
The group also hopes to delve further into the brain, to see whether the circuit-level patterns can interact with genetic variations that confer risk for psychiatric disorders such as schizophrenia. The new study will enable Dzirasa and other basic researchers to segregate stress-susceptible and resilient animals before they are subjected to stress and look at their molecular, cellular and systemic differences.
(Source: today.duke.edu)
Neurobiologists find chronic stress in early life causes anxiety, aggression in adulthood
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.
This week, 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. They showed that in young mice, chronic social defeat induced high levels of anxiety and helplessness, and less social interaction, including 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 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,” Enikolopov observes.
Study in Mice Raises Question: Could PTSD Involve Immune Cell Response to Stress?
Chronic stress that produces inflammation and anxiety in mice appears to prime their immune systems for a prolonged fight, causing the animals to have an excessive reaction to a single acute stressor weeks later, new research suggests.
After the mice recovered from the effects of chronic stress, a single stressful event 24 days later quickly returned them to a chronically stressed state in biological and behavioral terms. Mice that had not experienced the chronic stress were unaffected by the single acute stressor.
The study further showed that immune cells called to action as a result of chronic stress ended up on standby in the animals’ spleens and were launched from that organ to respond to the later stressor.
Mice without spleens did not experience the same reactivation with the second stressor, signifying the spleen’s role as a reservoir for primed immune cells to remain until they’re activated in response to another stressor.
The excessive immune response and anxiety initiated by a brief stressor mimic symptoms of post-traumatic stress disorder.
The Ohio State University scientists are cautious about extending their findings to humans. But they say their decade of work with this model of stress suggests that the immune system has a significant role in affecting behavior. And they are the first to study this re-establishment of anxiety in animals with a later acute stressor.
“No one else has done a study of this length to see what happens to recovered animals if we subject them again to stress,” said Jonathan Godbout, a lead author of the study and associate professor of neuroscience at Ohio State. “That retriggering is a component of post-traumatic stress. The previously stressed mice are living a normal rodent life, and then this acute stress brings everything back. Animals that have never been exposed to stress before were unaffected by that one event – it didn’t change behavioral or physiological properties.”
The research is published online in the journal Biological Psychiatry.
(Source: researchnews.osu.edu)
Scientists find a new mechanism underlying depression
The World health Organization calls depression “the leading cause of disability worldwide,” causing more years of disability than cancer, HIV/AIDS, and cardiovascular and respiratory diseases combined. In any given year, 5-7% of the world’s population experiences a major depressive episode, and one in six people will at some point suffer from the disease.
Despite recent progress in understanding depression, scientists still don’t understand the biological mechanisms behind it well enough to deliver effective prevention and therapy. One possible reason is that almost all research focuses on the brain’s neurons, while the involvement of other brain cells has not been thoroughly examined.
Now researchers at the Hebrew University of Jerusalem have shown that changes in one type of non-neuronal brain cells, called microglia, underlie the depressive symptoms brought on by exposure to chronic stress. In experiments with animals, the researchers were able to demonstrate that compounds that alter the functioning of microglia can serve as novel and efficient antidepressant drugs.
The findings were published in Molecular Psychiatry, the premier scientific journal in psychiatry and one of the leading journals in medicine and the neurosciences.
The research was conducted by Prof. Raz Yirmiya, director of the Hebrew University’s Psychoneuroimmunology Laboratory, and his doctoral student Tirzah Kreisel, together with researchers at Prof. Yirmiya’s laboratory and at the University of Colorado in Boulder, USA.
The researchers examined the involvement of microglia brain cells in the development of depression following chronic exposure to stress. Comprising roughly 10% of brain cells, microglia are the representatives of the immune system in the brain; but recent studies have shown that these cells are also involved in physiological processes not directly related to infection and injury, including the response to stress.
The researchers mimicked chronic unpredictable stress in humans — a leading causes of depression — by exposing mice to repeated, unpredictable stressful conditions over a period of 5 weeks. The mice developed behavioral and neurological symptoms mirroring those seen in depressed humans, including a reduction in pleasurable activity and in social interaction, as well as reduced generation of new brain cells (neurogenesis) — an important biological marker of depression.
The researchers found that during the first week of stress exposure, microglia cells undergo a phase of proliferation and activation, reflected by increased size and production of specific inflammatory molecules, after which some microglia begin to die. Following the 5 weeks of stress exposure, this phenomenon led to a reduction in the number of microglia, and to a degenerated appearance of some microglia cells, particularly in a specific region of the brain involved in responding to stress.
When the researchers blocked the initial stress-induced activation of microglia with drugs or genetic manipulation, they were able to stop the subsequent microglia cell death and decline, as well as the depressive symptoms and suppressed neurogenesis. However, these treatments were not effective in “depressed” mice, which were already exposed to the 5-weeks stress period and therefore had lower number of microglia. Based on these findings, the investigators treated the “depressed” mice with drugs that stimulated the microglia and increased their number to a normal level.
Prof. Yirmiya said, “We were able to demonstrate that such microglia-stimulating drugs served as effective and fast-acting antidepressants, producing complete recovery of the depressive-like behavioral symptoms, as well as increasing the neurogenesis to normal levels within a few days of treatment. In addition to the clinical importance of these results, our findings provide the first direct evidence that in addition to neurons, disturbances in the functioning of brain microglia cells have a role in causing psychopathology in general, and depression in particular. This suggests new avenues for drug research, in which microglia stimulators could serve as fast-acting antidepressants in some forms of depressive and stress-related conditions.”
The Hebrew University’s technology transfer company, Yissum, has applied for a patent for the treatment of some forms of depression by several specific microglia-stimulating drugs.
Effects of Chronic Stress Can be Traced to Your Genes
New research shows that chronic stress changes gene activity in immune cells before they reach the bloodstream. With these changes, the cells are primed to fight an infection or trauma that doesn’t actually exist, leading to an overabundance of the inflammation that is linked to many health problems.
This is not just any stress, but repeated stress that triggers the sympathetic nervous system, commonly known as the fight-or-flight response, and stimulates the production of new blood cells. While this response is important for survival, prolonged activation over an extended period of time can have negative effects on health.
A study in animals showed that this type of chronic stress changes the activation, or expression, of genes in immune cells before they are released from the bone marrow. Genes that lead to inflammation are expressed at higher-than-normal levels, while the activation of genes that might suppress inflammation is diminished.
Ohio State University scientists made this discovery in a study of mice. Their colleagues from other institutions, testing blood samples from humans living in poor socioeconomic conditions, found that similarly primed immune cells were present in these chronically stressed people as well.
“The cells share many of the same characteristics in terms of their response to stress,” said John Sheridan, professor of oral biology in the College of Dentistry and associate director of Ohio State’s Institute for Behavioral Medicine Research (IBMR), and co-lead author of the study. “There is a stress-induced alteration in the bone marrow in both our mouse model and in chronically stressed humans that selects for a cell that’s going to be pro-inflammatory.
“So what this suggests is that if you’re working for a really bad boss over a long period of time, that experience may play out at the level of gene expression in your immune system.”
The findings suggest that drugs acting on the central nervous system to treat mood disorders might be supplemented with medications targeting other parts of the body to protect health in the context of chronic social stress.
Steven Cole, a professor of medicine and a member of the Cousins Center for Psychoneuroimmunology at UCLA, is a co-corresponding author of the study. The research is published in a recent issue of the journal Proceedings of the National Academy of Sciences.
The mind-body connection is well established, and research has confirmed that stress is associated with health problems. But the inner workings of that association – exactly how stress can harm health – are still under investigation.
Sheridan and colleagues have been studying the same mouse model for a decade to reveal how chronic stress – and specifically stress associated with social defeat – changes the brain and body in ways that affect behavior and health.
The mice are repeatedly subjected to stress that might resemble a person’s response to persistent life stressors. In this model, male mice living together are given time to establish a hierarchy, and then an aggressive male is added to the group for two hours at a time. This elicits a “fight or flight” response in the resident mice as they are repeatedly defeated by the intruder.
“These mice are chronically in that state, so our research question is, ‘What happens when you stimulate the sympathetic nervous system over and over and over, or continuously?’ We see deleterious consequences to that,” Sheridan said.
Under normal conditions, the bone marrow in animals and humans is making and releasing billions of red blood cells every day, as well as a variety of white blood cells that constitute the immune system. Sheridan and colleagues already knew from previous work that stress skews this process so that the white blood cells produced in the bone marrow are more inflammatory than normal upon their release – as if they are ready to defend the body against an external threat.
A typical immune response to a pathogen or other foreign body requires some inflammation, which is generated with the help of immune cells. But when inflammation is excessive and has no protective or healing role, the condition can lead to an increased risk for cardiovascular diseases, diabetes and obesity, as well as other disorders.
In this work, the researchers compared cells circulating in the blood of mice that had experienced repeated social defeat to cells from control mice that were not stressed. The stressed mice had an average fourfold increase in the frequency of immune cells in their blood and spleen compared to the normal mice.
Genome-wide analysis of these cells that had traveled to the spleen in the stressed mice showed that almost 3,000 genes were expressed at different levels – both higher and lower – compared to the genes in the control mice. Many of the 1,142 up-regulated genes in the immune cells of stressed mice gave the cells the power to become inflammatory rapidly and efficiently.
“There is no traditional viral or bacterial challenge – we’re generating the challenge via a psychological response,” said study first author Nicole Powell, a research scientist in oral biology at Ohio State. “This study provides a nice mechanism for how psychology impacts biology. Other studies have indicated that these cells are more inflammatory; our work shows that these cells are primed at the level of the gene, and it’s directly due to the sympathetic nervous system.”
The researchers confirmed that the sympathetic nervous system was activated by showing that a beta blocker reduced symptoms associated with chronic stress. The beta receptors that were turned off by this intervention are major participants in the sympathetic nervous system response.
Meanwhile, UCLA’s Cole performs specialized statistical analyses of genome function to determine how people’s perception of their surroundings affects their biology. He and colleagues analyzed blood samples both from Sheridan’s mice and from healthy young adult humans whose socioeconomic status had been previously characterized as either high or low.
The human analysis identified differing levels of expression of 387 genes between the low- and high-socioeconomic status adults – and as in the mice, the up-regulated genes were pro-inflammatory in nature. The researchers also noted that almost a third of the genes with altered expression levels in immune cells from chronically stressed humans were the same genes differentially expressed in mice that had experienced repeated social defeat – a much higher similarity than would occur by chance.
This same pro-inflammatory immune-cell profile has been seen in research on parents of children with cancer.
“What we see in this study is a convergence of animal and human data showing similar genomic responses to adversity,” Cole said. “The molecular information from animal research integrates nicely with the human findings in showing a significant up-regulation of pro-inflammatory genes as a consequence of stress – and not just experimental stress, but authentic environmental stressors humans experience in everyday life.”
Worms May Shed Light on Human Ability to Handle Chronic Stress
New research at Rutgers University may help shed light on how and why nervous system changes occur and what causes some people to suffer from life-threatening anxiety disorders while others are better able to cope.
Maureen Barr, a professor in the Department of Genetics, and a team of researchers, found that the architectural structure of the six sensory brain cells in the roundworm, responsible for receiving information, undergo major changes and become much more elaborate when the worm is put into a high stress environment.
Scientists have known for some time that changes in the tree-like dendrite structures that connect neurons in the human brain and enable our thought processes to work properly can occur under extreme stress, alter brain cell development and result in anxiety disorders like depression and Post Traumatic Stress Disorder affecting millions of Americans each year.
What scientists don’t understand for sure, Barr says, is the cause behind these molecular changes in the brain.
“This type of research provides us necessary clues that ultimately could lead to the development of drugs to help those suffering with severe anxiety disorders,” Barr says.
In the study published today in Current Biology, scientists at Rutgers have identified six sensory nerve cells in the tiny, transparent roundworm, known as the C. elegans and an enzyme called KPC-1/furin which triggers a chemical reaction in humans that is needed for essential life functions like blood-clotting.
While the enzyme also appears to play a role in the growth of tumors and the activation of several types of virus and diseases in humans, in the roundworm the enzyme enables its simple neurons to morph into new elaborately branched shapes when placed under adverse conditions.
Normally, this one-millimeter long worm develops from an embryo through four larval stages before molting into a reproductive adult. Put it under stressful conditions of overcrowding, starvation and high temperature and the worm transforms into an alternative larval stage known as the dauer that becomes so stress-resistant it can survive almost anything – including the Space Shuttle Columbia disaster in 2003 of which they were the only living things to survive.
“These worms that normally have a short life cycle turn into super worms when they go into the dauer stage and can live for months, although they are no longer able to reproduce,” Barr says.
What is so interesting to Barr is that when a perceived threat is over, these tiny creatures and their IL2 neurons transform back to a normal lifespan and reproductive state like nothing had ever happened. Under a microscope, the complicated looking tree-like connectors that receive information are pruned back and the worm appears as it did before the trauma occurred.
This type of neural reaction differs in humans who can suffer from extreme anxiety months or even years after the traumatic event even though they are no longer in a threatening situation.
The ultimate goal, Barr says, is to determine how and why the nervous system responds to stress. By identifying molecular pathways that regulate neuronal remodeling, scientists may apply this knowledge to develop future therapeutics.
(Source: news.rutgers.edu)
Chronic Stress During Pregnancy Prevents Brain Benefits of Motherhood
(Credit: Oleg Zabielin / Shutterstock)
A new study in animals shows that chronic stress during pregnancy prevents brain benefits of motherhood, a finding that researchers suggest could increase understanding of postpartum depression.
Rat mothers showed an increase in brain cell connections in regions associated with learning, memory and mood. In contrast, the brains of mother rats that were stressed twice a day throughout pregnancy did not show this increase.
The researchers were specifically interested in dendritic spines – hair-like growths on brain cells that are used to exchange information with other neurons.
Previous animal studies conducted by lead author Benedetta Leuner of Ohio State University showed that an increase of dendritic spines in new mothers’ brains was associated with improved cognitive function on a task that requires behavioral flexibility – in essence, enabling more effective multitasking. The dendritic spines increased by about 20 percent in these brain regions in new mothers, according to her findings.
The stress in this new study negated those brain benefits of motherhood, causing the stressed rats’ brains to match brain characteristics of animals that had no reproductive or maternal experience.
The stressed rats also had less physical interaction with their babies than did unstressed rats, a behavior observed in human mothers who experience postpartum depression.
“Animal mothers in our research that are unstressed show an increase in the number of connections between neurons. Stressed mothers don’t,” said Leuner, assistant professor of psychology and neuroscience at Ohio State and lead author of the study. “We think that makes the stressed mothers more vulnerable. They don’t have the capacity for brain plasticity that the unstressed mothers do, and somehow that’s contributing to their susceptibility to depression.”
(Source: newswise.com)