How stress can boost the immune system

The study's findings provide a thorough overview of how a triad of stress hormones affects the main cell subpopulations of the immune system. They also offer the prospect of, someday, being able to manipulate stress-hormone levels to improve patients' recovery from surgery or wounds or their responses to vaccines.

You've heard it a thousand times: Stress is bad for you. And it's certainly true that chronic stress, lasting weeks and months, has deleterious effects including, notably, suppression of the immune response. But short-term stress -- the fight-or-flight response, a mobilization of bodily resources lasting minutes or hours in response to immediate threats -- stimulates immune activity, said lead author Firdaus Dhabhar, PhD, an associate professor of psychiatry and behavioral sciences and member of the Stanford Institute for Immunity, Transplantation and Infection.

And that's a good thing. The immune system is crucial for wound healing and preventing or fighting infection, and both wounds and infections are common risks during chases, escapes and combat.

Working with colleagues at Stanford and two other universities in a study published online June 22 inPsychoneuroendocrinology, Dhabhar showed that subjecting laboratory rats to mild stress caused a massive mobilization of several key types of immune cells into the bloodstream and then onto destinations including the skin and other tissues. This large-scale migration of immune cells, which took place over a time course of two hours, was comparable to the mustering of troops in a crisis, Dhabhar said. He and colleagues had previously shown that a similar immune-cell redistribution in patients experiencing the short-term stress of surgery predicts enhanced postoperative recovery.

In the new study, the investigators were able to show that the massive redistribution of immune cells throughout the body was orchestrated by three hormones released by the adrenal glands, in different amounts and at different times, in response to the stress-inducing event. These hormones are the brain's call-to-arms to the rest of the body, Dhabhar said.

"Mother Nature gave us the fight-or-flight stress response to help us, not to kill us," said Dhabhar, who has been conducting experiments for well over a decade on the effects of the major stress hormones on the immune system. Last summer, Dhabhar received the International Society for Psychoneuroendocrinology's Curt. P. Richter Award for his work in this area, culminating in the new study.

The findings paint a clearer picture of exactly how the mind influences immune activity. "An impala's immune system has no way of knowing that a lion is lurking in the grass and is about to pounce, but its brain does," Dhabhar said. In such situations, it benefits lion and impala alike when pathogen-fighting immune cells are in positions of readiness in such places as the skin and mucous membranes, which are at high risk for damage and consequent infection.

So it makes perfect evolutionary sense that predator/prey activity and other situations in nature, such as dominance challenges and sexual approaches, trigger stress hormones. "You don't want to keep your immune system on high alert at all times," Dhabhar said. "So nature uses the brain, the organ most capable of detecting an approaching challenge, to signal that detection to the rest of the body by directing the release of stress hormones. Without them, a lion couldn't kill, and an impala couldn't escape." The stress hormones not only energize the animals' bodies -- they can run faster, jump higher, bite harder -- but, it turns out, also mobilize the immune troops to prepare for looming trouble.

The response occurs across the animal kingdom, he added. You see pretty much the same pattern of hormone release in a fish that has been picked up out of the water.

The experiments in this study were performed on rats, which Dhabhar subjected to mild stress by confining them (gently, and with full ventilation) in transparent Plexiglas enclosures to induce stress. He drew blood several times over a two-hour period and, for each time point, measured levels of three major hormones -- norepinephrine, epinephrine and corticosterone (the rat analog of cortisol in humans) -- as well as of several distinct immune-cell types in the blood.

What he saw was a pattern of carefully choreographed changes in blood levels of the three hormones along with the movement of many different subsets of immune cells from reservoirs such as the spleen and bone marrow into the blood and, finally, to various "front line" organs.

To show that specific hormones were responsible for movements of specific cell types, Dhabhar administered the three hormones, separately or in various combinations, to rats whose adrenal glands had been removed so they couldn't generate their own stress hormones. When the researchers mimicked the pattern of stress-hormone release previously observed in the confined rats, the same immune-cell migration patterns emerged in the rats without adrenal glands. Placebo treatment produced no such effect.

The general pattern, Dhabhar said, was that norepinephrine is released early and is primarily involved in mobilizing all major immune-cell types -- monocytes, neutrophils and lymphocytes -- into the blood. Epinephrine, also released early, mobilized monocytes and neutrophils into the blood, while nudging lymphocytes out into "battlefield" destinations such as skin. And corticosterone, released somewhat later, caused virtually all immune cell types to head out of circulation to the "battlefields."

The overall effect of these movements is to bolster immune readiness. A study published by Dhabhar and his colleagues in 2009 in the Journal of Bone and Joint Surgery assessed patients' recovery from surgery as a function of their immune-cell redistribution patterns during the stress of the operation. Those patients in whom the stress of surgery mobilized immune-cell redistributions similar to those seen in the confined rats in the new study did significantly better afterward than patients whose stress hormones less adequately guided immune cells to appropriate destinations.

The mechanisms Dhabhar has delineated could lead to medical applications, such as administering low doses of stress hormones or drugs that mimic or antagonize them in order to optimize patients' immune readiness for procedures such as surgery or vaccination. "More study will be required including in human subjects, which we hope to conduct, before these applications can be attempted," Dhabhar said. Closer at hand is the monitoring of patients' stress-hormone levels and immune-cell distribution patterns during surgery to assess their surgical prognosis, or during immunization to predict vaccine effectiveness.

The study was funded by the John D. & Catherine T. MacArthur Foundation, the Dana Foundation, the DeWitt Wallace Foundation, the Carl & Elizabeth Naumann Fund and the National Institutes of Health. The medical school's Department of Psychiatry and Behavioral Sciences also supported this work. Dhabhar's co-authors were statistician Eric Neri at Stanford, and neuroendocrinologists at Ohio State University and Rockefeller University.

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The above story is reprinted from materials provided byStanford University Medical Center. The original article was written by Bruce Goldman.

Stanford University Medical Center (2012, June 21). How stress can boost immune system.ScienceDaily. Retrieved April 15, 2013, from http://www.sciencedaily.com­/releases/2012/06/120621223525.htm

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Daily Stress Takes a Toll on Long-Term Mental Health

"Our emotional responses to the stresses of daily life may predict our long-term mental health, according to a new study published inPsychological Science, a journal of the Association for Psychological Science.

Psychological scientist Susan Charles of the University of California, Irvine and colleagues conducted the study in order to answer a long-standing question: Do daily emotional experiences add up to make the straw that breaks the camel’s back, or do these experiences make us stronger and provide an inoculation against later distress?

Using data from two national surveys, the researchers examined the relationship between daily negative emotions and mental health outcomes ten years later.

Participants’ overall levels of negative emotions predicted psychological distress (e.g., feeling worthless, hopeless, nervous, and/or restless) and diagnosis of an emotional disorder like anxiety or depression a full decade after the emotions were initially measured.

Participants’ negative emotional responses to daily stressors — such as argument or a problem at work or home — predicted psychological distress and self-reported emotional disorder ten years later.

The researchers argue that a key strength of the study was their ability to tap a large, national community sample of participants who spanned a wide age range. The results were based on data from 711 participants, both men and women, who ranged in age from 25 to 74. They were all participants in two national, longitudinal survey studies: Midlife Development in the United States (MIDUS) and National Study of Daily Experiences (NSDE).

According to Charles and her colleagues, these findings show that mental health outcomes aren’t only affected by major life events — they also bear the impact of seemingly minor emotional experiences. The study suggests that chronic nature of these negative emotions in response to daily stressors can take a toll on long-term mental health.

In addition to Charles, co-authors on the study include Jennifer Piazza of California State University, Fullerton; and Jacqueline Mogle, Martin Sliwinski, and David Almeida of Pennsylvania State University."

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For more information about this study, please contact: Susan T. Charles at scharles@uci.edu.

The APS journal Psychological Science is the highest ranked empirical journal in psychology. For a copy of the article "The Wear and Tear of Daily Stressors on Mental Health" and access to other Psychological Science research findings, please contact Anna Mikulak at 202-293-9300 oramikulak@psychologicalscience.org.

Source: Association for Psychological Science

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Stressed Men Are More Social

Freiburg researchers have refuted the common belief that stress always causes aggressive behavior. A team of researchers led by the psychologists and neuroscientists Prof. Markus Heinrichs and Dr. Bernadette von Dawans at the University of Freiburg, Germany, examined in a study how men react in stressful situations -- and have refuted a nearly 100-year-old doctrine with their results.

According to this doctrine, humans and most animal species show the "fight-or-flight" response to stress. Only since the late 1990s have some scientists begun to argue that women show an alternate "tend-and-befriend" response to stress -- in other words, a protective ("tend") and friendship-offering ("befriend") reaction. Men, in contrast, were still assumed to become aggressive under stress. Von Dawans refuted this assumption, saying: "Apparently men also show social approach behavior as a direct consequence of stress."

With this study, the research team experimentally investigated male social behavior under stress for the first time. The results are published in the  journal Psychological Science. The economists Prof. Ernst Fehr of the University of Zurich, Switzerland, and Prof. Urs Fischbacher of the University of Konstanz, Germany, as well as the psychologist Prof. Clemens Kirschbaum from the Technical University of Dresden, Germany, also participated in the study. Last year, Heinrichs and von Dawans already developed a standardized procedure for inducing stress in groups using a public speaking task. The researchers examined the implications of this stressor for social behavior using specially designed social interaction games.. These games allowed them to measure positive social behavior -- for example, trust or sharing -- and negative social behavior -- for example, punishment.

In the study, subjects who were under stress showed significantly more positive social behavior than control subjects who were not in a stressful situation. Negative social behavior, on the other hand, was not affected by stress. For Markus Heinrichs, this has far-reaching consequences for our understanding of the social significance of stress: "From previous studies in our laboratory, we already knew that positive social contact with a trusted individual before a stressful situation reduces the stress response. Apparently, this coping strategy is anchored so strongly that people can also change their stress responses during or immediately after the stress through positive social behavior."

Source: Albert-Ludwigs-Universität Freiburg [May 21, 2012]

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Healthy aging begins in the womb

Ageing is a complex process involving physical, psychological, and environmental factors. Scientists believe that ageing can be programmed in the womb. One example of stress during pregnancy is the administration of glucocorticoids, i. e. synthetic stress hormones to accelerate fetal lung maturation in premature labor to allow breathing after birth. Could exposure to these stress hormones have an effect on health later in life? 

"We know from previous studies that children whose mothers received glucocorticoids during pregnancy are less stress tolerant and have more concentration problems than their peers," reported Professor Matthias Schwab, the Neurologist heading the project. "Stress signal regulation is permanently disturbed and appears to lead to early ageing, in particular, of the brain", he added. 

The scientists examine several risk groups. One consists of 10-year-olds born at the University Hospital Jena whose mothers had treatment with glucocorticoids during pregnancy. Two other groups are being followed up by psychologists at the University of Leuven in Belgium and include two-year-olds and 25-year-olds whose mothers suffered from stress during pregnancy. 

"A unique group studied at the Academic Medical Centre, University of Amsterdam includes persons born in Holland during the Dutch „Hunger Winter", of 1944/45," reported Prof. Schwab. 

Scientists involved in the project use state-of-the art neuropsychological, neurophysiological, and MRI methods to analyse and compare biological and real age of the brain. The biotechnology companies Life Length in Madrid and Biocrates in Innsbruck measure biological age in chromosomes and screen blood samples to determine metabolic blood markers of age. 

"Environmental factors such as exposure to stress hormones or malnutrition during pregnancy change the readout of genetic information permanently," reported Matthias Platzer, Head of Genome Analysis at the Leibniz Institute for Age Research in Jena. 

"These epigenetic processes significantly change stress sensitivity for the rest of life," explained Prof Schwab. „Increased stress sensitivity makes one vulnerable to age-related diseases such as stroke and depression," he added. 

In experimental studies, researchers aim to determine the period during pregnancy in which the brain is particularly vulnerable to stress. An important aspect of the research also involves studying a group of primates kept in Texas for possible translation of the findings to human subjects. 

Understanding the biology of healthy ageing is desperately needed due to the worldwide ageing population and the economic costs of treating age-related diseases. 

"Environmental influences during life in the womb are early determinants for life-long good health and may be a target for preventive measures against early-ageing and age-related diseases," explained Prof. Schwab.  

Source: Friedrich-Schiller-Universitaet Jena [March 08, 2012]

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Stressed kids more likely to become obese

The more ongoing stress children are exposed to, the greater the odds they will become obese by adolescence, reports Cornell environmental psychologist Gary Evans in the journal Pediatrics (129:1). 

Nine-year-old children who were chronically exposed to such stressors as poverty, crowded housing and family turmoil gain more weight and were significantly heavier by age 13 than they would have been otherwise, the study found. The reason, Evans and his co-authors suggest, is that ongoing stress makes it tougher for children to control their behavior and emotions -- or self-regulate. That, in turn, can lead to obesity by their teen years. 

"These children are heavier, and they gain weight faster as they grow up. A very good predictor of adults' ability to follow healthy habits is their ability to self-regulate. It seems reasonable that the origins of that are probably in childhood. This [research] is starting to lay that out," said Evans, the Elizabeth Lee Vincent Professor of Human Ecology in the Departments of Design and Environmental Analysis and of Human Development in Cornell's College of Human Ecology. 

Evans conducted the study with former students Thomas Fuller-Rowell, Ph.D. '10, now a Robert Wood Johnson postdoctoral fellow at the University of Wisconsin-Madison, and Stacey Doan, Ph.D. '10, an assistant professor of psychology at Boston University. 

The researchers measured the height and weight of 244 9-year-olds in rural New York state and calculated their various physical and psycho-social stressors -- for example, exposure to violence, living in a substandard house or having no access to such resources as books. They also measured the children's ability to delay gratification by offering them a choice between waiting for a large plate of candy versus having a medium plate immediately. The researchers measured the children's height and weight again four years later. 

While the study doesn't prove that a child's inability to delay gratification causes her to gain weight, there's strong evidence to suggest that it does, Evans said. First, previous studies have shown that chronic stress is linked to weight gain in children and teenagers, and that children eat more sugary, fatty foods when stressed. 

Second, there's a plausible neurocognitive mechanism that may help better understand this behavior, Evans said. "There's some evidence that parts of the brain that are vulnerable and sensitive to stress, particularly early in life, are some of the same parts involved in this self-regulatory behavior." 

The study has implications for education policies such as No Child Left Behind that emphasize testing cognitive abilities but ignore children's ability to control their behavior and emotions, Evans said. 

"A child's ability to self-regulate is not just predictive of things like whether you're going to have trouble with weight -- it predicts grades, graduating from high school. A 4-year-old's ability to self-regulate even predicts SAT scores. This is a very powerful phenomenon," he said. 

The findings also have implications for interventions and policies aimed at reducing individual stressors. "If it's the cumulative impact of stress on these families that is important, that means an intervention that only looks at one stressor -- say, just drug abuse, which is how most interventions are designed -- is doomed to fail," Evans concluded. 

Author: Susan Kelley | Source: Cornell University [January 21, 2012]

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A novel mechanism regulating stress is identified

Neuroscience researchers from Tufts have demonstrated, for the first time, that the physiological response to stress depends on neurosteroids acting on specific receptors in the brain, and they have been able to block that response in mice. This breakthrough suggests that these critical receptors may be drug therapy targets for control of the stress-response pathway. This finding may pave the way for new approaches to manage a wide range of neurological disorders involving stress. 

The stress-control pathway, more technically known as the Hypothalamus-Pituitary-Adrenal (HPA) axis, determines the levels of cortisol and other stress hormones in the human body. In addition to being implicated in the types of emotional and psychological stress that can lead to major depression, disorders of the stress-control pathway are also associated with obesity, premenstrual syndrome, postpartum depression, Cushing's syndrome (hypercortisolism) and diseases including epilepsy and osteoporosis. 

"We have identified a novel mechanism regulating the body's response to stress by determining that neurosteroids are required to mount the physiological response to stress. Moreover, we were able to completely block the physiological response to stress as well as prevent stress-induced anxiety," said author Jamie Maguire, PhD, assistant professor in the department of neuroscience at Tufts University School of Medicine and a member of the Neuroscience and Pharmacology & Experimental Therapeutics program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts. 

Using the brain tissues of adult mice, the research team identified mechanisms controlling the activity of Corticotrophin Releasing Hormone (CRH) neurons involved in the control of the stress pathway. By monitoring the activity of CRH neurons following stress and measuring levels of corticosterone in the blood, they found that the production of stress hormones required the action of neurosteroids on specific receptors on CRH neurons. 

Apart from the finding that stress causes a neurosteroid-induced increase in blood corticosterone levels, the researchers also found that blocking the synthesis of neurosteroids is sufficient to block the stress-induced elevations in corticosterone and prevent stress-induced, anxiety-like behavior in mice. Previous research had identified the presence of specialized CRH-nerve-cell receptors in the HPA axis, but the findings had been controversial because of limited studies showing any connection between these receptors and the regulation of the CRH nerve cells. 

"We have found a definite role of neurosteroids on the receptors regulating CRH nerve cells and the stress response. The data suggest that these receptors may be novel targets for control of the stress-control pathway. Our next work will focus on modulating these receptors to treat disorders associated with stress, including epilepsy and depression-like behaviors," said Maguire. 

Source: Tufts University, Health Sciences Campus [December 13, 2011]

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