How physical exercise protects the brain from stress-induced depression

Physical exercise has many beneficial effects on human health, including the protection from stress-induced depression. However, until now the mechanisms that mediate this protective effect have been unknown. In a new study in mice, researchers at Karolinska Institutet in Sweden show that exercise training induces changes in skeletal muscle that can purge the blood of a substance that accumulates during stress, and is harmful to the brain. The study is being published in the prestigious journal Cell.

“In neurobiological terms, we actually still don’t know what depression is. Our study represents another piece in the puzzle, since we provide an explanation for the protective biochemical changes induced by physical exercise that prevent the brain from being damaged during stress,” says Mia Lindskog, researcher at the Department of Neuroscience at Karolinska Institutet.

It was known that the protein PGC-1a1 (pronounced PGC-1alpha1) increases in skeletal muscle with exercise, and mediates the beneficial muscle conditioning in connection with physical activity. In this study researchers used a genetically modified mouse with high levels of PGC-1a1 in skeletal muscle that shows many characteristics of well-trained muscles (even without exercising).

These mice, and normal control mice, were exposed to a stressful environment, such as loud noises, flashing lights and reversed circadian rhythm at irregular intervals. After five weeks of mild stress, normal mice had developed depressive behaviour, whereas the genetically modified mice (with well-trained muscle characteristics) had no depressive symptoms.

“Our initial research hypothesis was that trained muscle would produce a substance with beneficial effects on the brain. We actually found the opposite: well-trained muscle produces an enzyme that purges the body of harmful substances. So in this context the muscle’s function is reminiscent of that of the kidney or the liver,” says Jorge Ruas, principal investigator at the Department of Physiology and Pharmacology, Karolinska Institutet.

The researchers discovered that mice with higher levels of PGC-1a1 in muscle also had higher levels of enzymes called KAT. KATs convert a substance formed during stress (kynurenine) into kynurenic acid, a substance that is not able to pass from the blood to the brain. The exact function of kynurenine is not known, but high levels of kynurenine can be measured in patients with mental illness. In this study, the researchers demonstrated that when normal mice were given kynurenine, they displayed depressive behaviour, while mice with increased levels of PGC-1a1 in muscle were not affected. In fact, these animals never show elevated kynurenine levels in their blood since the KAT enzymes in their well-trained muscles quickly convert it to kynurenic acid, resulting in a protective mechanism.

“It’s possible that this work opens up a new pharmacological principle in the treatment of depression, where attempts could be made to influence skeletal muscle function instead of targeting the brain directly. Skeletal muscle appears to have a detoxification effect that, when activated, can protect the brain from insults and related mental illness,” says Jorge Ruas.

Depression is a common psychiatric disorder worldwide. The World Health Organization (WHO) estimates that more than 350 million people are affected.

Research hints at why stress is more devastating for some

Some people take stress in stride; others are done in by it. New research at Rockefeller University has identified the molecular mechanisms of this so-called stress gap in mice with very similar genetic backgrounds — a finding that could lead researchers to better understand the development of psychiatric disorders such as anxiety and depression.

“Like people, each animal has unique experiences as it goes through its life. And we suspect that these life experiences can alter the expression of genes, and as a result, affect an animal’s susceptibility to stress,” says senior author Bruce McEwen, Alfred E. Mirsky Professor and head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology. “We have taken an important step toward explaining the molecular origins of this stress gap by showing that inbred mice react differently to stress, with some developing behaviors that resemble anxiety and depression, and others remaining resilient.”

The results, published September 2 in Molecular Psychiatry, point toward potential new markers to aid the diagnosis of stress-related disorders, such as anxiety and depression, and a promising route to the development of new treatments for these devastating disorders.

In experiments, researchers stressed the mice by exposing them to daily, unpredictable bouts of cage tilting, altered dark-light cycles, confinement in tight spaces and other conditions mice dislike with the goal of reproducing the sort of stressful experiences thought to be a primary cause of depression in humans. Afterward, in tests to see if the mice displayed the rodent equivalent of anxiety and depression symptoms, they found about 40 percent showed high levels of behaviors that included a preference for a dark compartment over a brightly lit one, or a loss of interest in sugar water. The remaining 60 percent recovered well from the stress. This distinction between the susceptible mice and the resilient ones was so fundamental that it emerged even before the mice were subjected to stress; some unstressed mice showed an anxiety-like preference for a dark compartment over a lighted one.

The researchers found that the highly stress-susceptible mice had less of an important molecule known as mGlu2 in a stress-involved region of the brain known as the hippocampus. The mGlu2 decrease, they determined, resulted from an epigenetic change, which affects the expression of genes, in this case the gene that codes for mGlu2.

“If you think of the genetic code as words in a book, the book must be opened in order for you to read it. These epigenetic changes, which affect histone proteins associated with DNA, effectively close the book, so the code for mGlu2 cannot be read,” says first author Carla Nasca, a postdoc in the lab and a fellow of the American Foundation for Suicide Prevention. Previously, she and colleagues implicated mGlu2 in depression when they showed that a promising potential treatment known as acetyl carnitine rapidly alleviated depression-like symptoms in rats and mice by reversing these epigenetic changes to mGlu2 and causing its levels to increase.

“Currently, depression is diagnosed only by its symptoms,” Nasca says. “But these results put us on track to discover molecular signatures in humans that may have the potential to serve as markers for certain types of depression. Our work could also lead to a new generation of rapidly acting antidepressants, such as the candidate acetyl carnitine, which would be particularly important to reduce the risk of suicide.”

A reduction in mGlu2 matters because this molecule regulates the neurotransmitter glutamate. While glutamate plays a crucial role relaying messages between neurons as part of many important processes, too much can lead to harmful structural changes in the brain.

“The brain is constantly changing. When stressful experiences lead to anxiety and depressive disorders the brain becomes locked in a state it cannot spontaneously escape,” McEwen says. “Studies like this one are increasingly focusing on the regulation of glutamate as an underlying mechanism in depression and, we hope, opening promising new avenues for the diagnosis and treatment of this devastating disorder.”

Biomarker Could Reveal Why Some Develop Post-Traumatic Stress Disorder

Blood expression levels of genes targeted by the stress hormones called glucocorticoids could be a physical measure, or biomarker, of risk for developing Post-Traumatic Stress Disorder (PTSD), according to a study conducted in rats by researchers at the Icahn School of Medicine at Mount Sinai and published August 11 in Proceedings of the National Academy of Sciences (PNAS). That also makes the steroid hormones’ receptor, the glucocorticoid receptor, a potential target for new drugs.  

Post-Traumatic Stress Disorder (PTSD) is triggered by a terrifying event, either witnessed or experienced. Symptoms may include flashbacks, nightmares and severe anxiety, as well as uncontrollable thoughts about the event. Not everyone who experiences trauma develops PTSD, which is why the study aimed to identify biomarkers that could better measure each person’s vulnerability to the disorder.  

“Our aim was to determine which genes are differentially expressed in relation to PTSD,” said lead investigator Rachel Yehuda, PhD, Professor of Psychiatry and Neuroscience and Director of the Traumatic Stress Studies Division at the Icahn School of Medicine at Mount Sinai. “We found that most of the genes and pathways that are different in PTSD-like animals compared to resilient animals are related to the glucocorticoid receptor, which suggests we might have identified a therapeutic target for treatment of PTSD,” said Dr. Yehuda, who also heads the Mental Health Patient Care Center and PTSD Research Program at the James J. Peters Veterans Affairs Medical Center in the Bronx.

The research team exposed a group of male and female rats to litter soiled by cat urine, a predatory scent that mimics a life-threatening situation. Most PTSD studies until now have used only male rats. Mount Sinai researchers included female rats in this study since women are more vulnerable than men to developing PTSD. The rats were then categorized based on their behavior one week after exposure to the scent. The authors also examined patterns of gene expression in the blood and in stress-responsive brain regions.

After one week of being exposed to soiled cat litter for 10 minutes, vulnerable rats exhibited higher anxiety and hyperarousal, and showed altered glucocorticoid receptor signaling in all tissues compared with resilient rats. Moreover, some rats were treated with a hormone that activates the glucocorticoid receptor called corticosterone one hour after exposure to the cat urine scent. These rats showed lower levels of anxiety and arousal one week later compared with untreated, trauma-exposed rats.

“PTSD is not just a disorder that affects the brain,” said co-investigator Nikolaos Daskalakis, MD, PhD, Associate Research Scientist in the Department of Psychiatry at the Icahn School of Medicine at Mount Sinai. “It involves the entire body, which is why identifying common regulators is key. The glucocorticoid receptor is the one common regulator that consistently stood out.”

(Image: photos.com)

Stress tied to change in children’s gene expression related to emotion regulation, physical health

Children who have been abused or neglected early in life are at risk for developing both emotional and physical health problems. In a new study, scientists have found that maltreatment affects the way genes are activated, which has implications for children’s long-term development. Previous studies focused on how a particular child’s individual characteristics and genetics interacted with that child’s experiences in an effort to understand how health problems emerge. In the new study, researchers were able to measure the degree to which genes were turned “on” or “off” through a biochemical process called methylation. This new technique reveals the ways that nurture changes nature—that is, how our social experiences can change the underlying biology of our genes.

The study, from researchers at the University of Wisconsin, Madison, appears in the journal Child Development. Nearly 1 million children in the United States are neglected or abused every year.

The researchers found an association between the kind of parenting children had and a particular gene (called the glucocorticoid receptor gene) that’s responsible for crucial aspects of social functioning and health. Not all genes are active at all times. DNA methylation is one of several biochemical mechanisms that cells use to control whether genes are turned on or off. The researchers examined DNA methylation in the blood of 56 children ages 11 to 14. Half of the children had been physically abused.

They found that compared to the children who hadn’t been maltreated, the maltreated children had increased methylation on several sites of the glucocorticoid receptor gene, also known as NR3C1, echoing the findings of earlier studies of rodents. In this study, the effect occurred on the section of the gene that’s critical for nerve growth factor, which is an important part of healthy brain development.

There were no differences in the genes that the children were born with, the study found; instead, the differences were seen in the extent to which the genes had been turned on or off. “This link between early life stress and changes in genes may uncover how early childhood experiences get under the skin and confer lifelong risk,” notes Seth D. Pollak, professor of psychology and pediatrics at the University of Wisconsin, Madison, who directed the study.

Previous studies have shown that children who have experienced physical abuse, sexual abuse, and neglect are more likely to develop mood, anxiety, and aggressive disorders, as well as to have problems regulating their emotions. These problems, in turn, can disrupt relationships and affect school performance. Maltreated children are also at risk for chronic health problems such as cardiac disease and cancer. The current study helps explain why these childhood experiences can affect health years later.

The gene identified by the researchers affects the hypothalamic-pituitary-adrenal (HPA) axis in rodents. Disruptions of this system in the brain would make it difficult for people to regulate their emotional behavior and stress levels. Circulating through the body in the blood, this gene affects the immune system, leaving individuals less able to fight off germs and more vulnerable to illnesses.

"Our finding that children who were physically maltreated display a specific change to the glucocorticoid receptor gene could explain why abused children have more emotional difficulties as they age," according to Pollak. "They may have fewer glucocorticoid receptors in their brains, which would impair the brain’s stress-response system and result in problems regulating stress."

The findings have implications for designing more effective interventions for children, especially since studies of animals indicate that the effects of poor parenting on gene methylation may be reversible if caregiving improves. The study also adds to what we know about how child maltreatment relates to changes in the body and mind, findings that were summarized recently in an SRCD Social Policy Report by Sara R. Jaffee and Cindy W. Christian.

Researcher shows how stress hormones promote brain’s building of negative memories

When a person experiences a devastating loss or tragic event, why does every detail seem burned into memory whereas a host of positive experiences simply fade away?

It’s a bit more complicated than scientists originally thought, according to a study recently published in the journal Neuroscience by ASU researcher Sabrina Segal.

When people experience a traumatic event, the body releases two major stress hormones: norepinephrine and cortisol. Norepinephrine boosts heart rate and controls the fight-or-flight response, commonly rising when individuals feel threatened or experience highly emotional reactions. It is chemically similar to the hormone epinephrine – better known as adrenaline.

In the brain, norepinephrine in turn functions as a powerful neurotransmitter or chemical messenger that can enhance memory.

Research on cortisol has demonstrated that this hormone can also have a powerful effect on strengthening memories. However, studies in humans up until now have been inconclusive – with cortisol sometimes enhancing memory, while at other times having no effect.

A key factor in whether cortisol has an effect on strengthening certain memories may rely on activation of norepinephrine during learning, a finding previously reported in studies with rats.

In her study, Segal, an assistant research professor at the Institute for Interdisciplinary Salivary Bioscience Research at ASU, and her colleagues at the University of California-Irvine showed that human memory enhancement functions in a similar way.

Conducted in the laboratory of Larry Cahill at U.C. Irvine, Segal’s study included 39 women who viewed 144 images from the International Affective Picture Set. This set is a standardized picture set used by researchers to elicit a range of responses, from neutral to strong emotional reactions, upon view.

Segal and her colleagues gave each of the study’s subjects either a dose of hydrocortisone – to simulate stress – or a placebo just prior to viewing the picture set. Each woman then rated her feelings at the time she was viewing the image, in addition to giving saliva samples before and after. One week later, a surprise recall test was administered.

What Segal’s team found was that “negative experiences are more readily remembered when an event is traumatic enough to release cortisol after the event, and only if norepinephrine is released during or shortly after the event.”

“This study provides a key component to better understanding how traumatic memories may be strengthened in women,” Segal added, “because it suggests that if we can lower norepinephrine levels immediately following a traumatic event, we may be able to prevent this memory enhancing mechanism from occurring, regardless of how much cortisol is released following a traumatic event.”

Further studies are needed to explore to what extent the relationship between these two stress hormones differ depending on whether you are male or female, particularly because women are twice as likely to develop disorders from stress and trauma that affect memory, such as in Posttraumatic Stress Disorder (PTSD). In the meantime, the team’s findings are a first step toward a better understanding of neurobiological mechanisms that underlie traumatic disorders, such as PTSD.

(Image: Wikimedia Commons)

Only 25 Minutes of Mindfulness Meditation Alleviates Stress

Mindfulness meditation has become an increasingly popular way for people to improve their mental and physical health, yet most research supporting its benefits has focused on lengthy, weeks-long training programs.

New research from Carnegie Mellon University is the first to show that brief mindfulness meditation practice — 25 minutes for three consecutive days — alleviates psychological stress. Published in the journal “Psychoneuroendocrinology,” the study investigates how mindfulness meditation affects people’s ability to be resilient under stress.

"More and more people report using meditation practices for stress reduction, but we know very little about how much you need to do for stress reduction and health benefits," said lead author J. David Creswell, associate professor of psychology in the Dietrich College of Humanities and Social Sciences.

For the study, Creswell and his research team had 66 healthy individuals aged 18-30 years old participate in a three-day experiment. Some participants went through a brief mindfulness meditation training program; for 25 minutes for three consecutive days, the individuals were given breathing exercises to help them monitor their breath and pay attention to their present moment experiences. A second group of participants completed a matched three-day cognitive training program in which they were asked to critically analyze poetry in an effort to enhance problem-solving skills.

Following the final training activity, all participants were asked to complete stressful speech and math tasks in front of stern-faced evaluators. Each individual reported their stress levels in response to stressful speech and math performance stress tasks, and provided saliva samples for measurement of cortisol, commonly referred to as the stress hormone.

The participants who received the brief mindfulness meditation training reported reduced stress perceptions to the speech and math tasks, indicating that the mindfulness meditation fostered psychological stress resilience. More interestingly, on the biological side, the mindfulness meditation participants showed greater cortisol reactivity.

"When you initially learn mindfulness mediation practices, you have to cognitively work at it — especially during a stressful task," said Creswell. "And, these active cognitive efforts may result in the task feeling less stressful, but they may also have physiological costs with higher cortisol production."

Creswell’s group is now testing the possibility that mindfulness can become more automatic and easy to use with long-term mindfulness meditation training, which may result in reduced cortisol reactivity.