Posts tagged stress
Articles and news from the latest research reports.
Chrono, the last piece of the circadian clock puzzle?
In an article published today in PLOS Biology, researchers from the RIKEN Brain Science Institute in Japan report the identification of Chrono, a gene involved in the regulation of the body clock in mammals and that might be a key component of the body’s response to stress.
All organisms, from mammals to fungi, have daily cycles controlled by a tightly regulated internal clock, called the circadian clock. The whole-body circadian clock, influenced by the exposure to light, dictates the wake-sleep cycle. At the cellular level, the clock is controlled by a complex network of genes and proteins that switch each other on and off based on cues from their environment.
Most genes involved in the regulation of the circadian clock have been characterized, but Akihiro Goriki, Toru Takumi and their colleagues from RIKEN and Hiroshima University in Japan and University of Michigan in the United States knew that a key component was missing and sough to uncover it in mammals.
In the study, the team performed a genome-wide chromatin immunoprecipitation analysis for genes that were the target of BMAL1, a core clock component that binds to many other clock genes, regulating their transcription.
The authors characterize a new circadian gene that they name Chrono. They show that CHRONO functions as a transcriptional repressor of the negative feedback loop in the mammalian clock: the protein CHRONO binds to the regulatory region of clock genes, with its repressor function oscillating in a circadian manner. The expression of core clock genes is altered in mice lacking the Chrono gene, and the mice have longer circadian cycles.
"These results suggest that Chrono functions as a core clock repressor,” conclude the authors.
In addition, they demonstrate that the repression mechanism of Chrono is under epigenetic control and links, via a glucocorticoid receptor, to metabolic pathways triggered by behavioral stress.
These findings are confirmed by another study by the University of Pennsylvania, also published in PLOS Biology today. In the study, John Hogenesch and his team prove the existence of Chrono using a computer-based analysis.
New finding suggests a way to block stress’ damage
Ketamine, an anesthetic sometimes abused as a street drug, increases the synaptic connections between brain cells and in low doses acts as a powerful antidepressant, Yale researchers have found. However, stress has the opposite effect, shrinking the number of synaptic spines, triggering depression.
In the April 13 online issue of the journal Nature Medicine, Yale researchers found that expression of single gene called REDD1 enables stress to damage brain cells and cause depressive behavior.
“We found if we delete REDD1, we can block the effects of stress in mice,” said Ron Duman, the Elizabeth Mears and House Jameson Professor of Psychiatry and professor of neurobiology.
In recent studies, the Yale team showed that ketamine activates the mTORC1 pathway, which in turn spurs synthesis of synaptic proteins and connections. In the new study, they show that the REDD1 gene expression blocks mTORC1 activity and decreases the number of synaptic connections. The new study by Duman and lead author Kristie Ota showed that mice without the REDD1 gene were impervious to the synaptic and behavioral deficits caused by stress. By contrast, when the gene was over-expressed, mice exhibited loss of synaptic connections and increased depression and anxiety behaviors.
In addition, post-mortem examinations of people who had suffered from depression showed high levels of REDD1 in cortical regions associated with depression.
Yale’s work with ketamine has already led to development of new classes of antidepressants, which are currently in clinical trials. Duman said these new findings may provide a new drug target that directly blunts the negative impacts of stress.
The phenomenon has long been known in psychology: traumatic experiences can induce behavioural disorders that are passed down from one generation to the next. It is only recently that scientists have begun to understand the physiological processes underlying hereditary trauma. ”There are diseases such as bipolar disorder, that run in families but can’t be traced back to a particular gene”, explains Isabelle Mansuy, professor at ETH Zurich and the University of Zurich. With her research group at the Brain Research Institute of the University of Zurich, she has been studying the molecular processes involved in non-genetic inheritance of behavioural symptoms induced by traumatic experiences in early life.
Mansuy and her team have succeeded in identifying a key component of these processes: short RNA molecules. These RNAs are synthetized from genetic information (DNA) by enzymes that read specific sections of the DNA (genes) and use them as template to produce corresponding RNAs. Other enzymes then trim these RNAs into mature forms. Cells naturally contain a large number of different short RNA molecules called microRNAs. They have regulatory functions, such as controlling how many copies of a particular protein are made.
Small RNAs with a huge impact
The researchers studied the number and kind of microRNAs expressed by adult mice exposed to traumatic conditions in early life and compared them with non-traumatized mice. They discovered that traumatic stress alters the amount of several microRNAs in the blood, brain and sperm – while some microRNAs were produced in excess, others were lower than in the corresponding tissues or cells of control animals. These alterations resulted in misregulation of cellular processes normally controlled by these microRNAs.
After traumatic experiences, the mice behaved markedly differently: they partly lost their natural aversion to open spaces and bright light and had depressive-like behaviours. These behavioural symptoms were also transferred to the next generation via sperm, even though the offspring were not exposed to any traumatic stress themselves.
Even passed on to the third generation
The metabolism of the offspring of stressed mice was also impaired: their insulin and blood-sugar levels were lower than in the offspring of non-traumatized parents. “We were able to demonstrate for the first time that traumatic experiences affect metabolism in the long-term and that these changes are hereditary”, says Mansuy. The effects on metabolism and behaviour even persisted in the third generation.
“With the imbalance in microRNAs in sperm, we have discovered a key factor through which trauma can be passed on,” explains Mansuy. However, certain questions remain open, such as how the dysregulation in short RNAs comes about. “Most likely, it is part of a chain of events that begins with the body producing too much stress hormones.”
Importantly, acquired traits other than those induced by trauma could also be inherited through similar mechanisms, the researcher suspects. “The environment leaves traces on the brain, on organs and also on gametes. Through gametes, these traces can be passed to the next generation.”
Mansuy and her team are currently studying the role of short RNAs in trauma inheritance in humans. As they were also able to demonstrate the microRNAs imbalance in the blood of traumatized mice and their offspring, the scientists hope that their results may be useful to develop a blood test for diagnostics.
DNA Modifications Measured in Blood Signal Related Changes in the Brain
Research linked to stress in mice confirms blood-brain comparison is valid
Johns Hopkins researchers say they have confirmed suspicions that DNA modifications found in the blood of mice exposed to high levels of stress hormone — and showing signs of anxiety — are directly related to changes found in their brain tissues.
The proof-of-concept study, reported online ahead of print in the June issue of Psychoneuroendocrinology, offers what the research team calls the first evidence that epigenetic changes that alter the way genes function without changing their underlying DNA sequence — and are detectable in blood — mirror alterations in brain tissue linked to underlying psychiatric diseases.
The new study reports only on so-called epigenetic changes to a single stress response gene called FKBP5, which has been implicated in depression, bipolar disorder and post-traumatic stress disorder. But the researchers say they have discovered the same blood and brain matches in dozens more genes, which regulate many important processes in the brain.
“Many human studies rely on the assumption that disease-relevant epigenetic changes that occur in the brain — which is largely inaccessible and difficult to test — also occur in the blood, which is easily accessible,” says study leader Richard S. Lee, Ph.D., an instructor in the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. “This research on mice suggests that the blood can legitimately tell us what is going on in the brain, which is something we were just assuming before, and could lead us to better detection and treatment of mental disorders and for a more empirical way to test whether medications are working.”
For the study, the Johns Hopkins team worked with mice with a rodent version of Cushing’s disease, which is marked by the overproduction and release of cortisol, the primary stress hormone also called glucocorticoid. For four weeks, the mice were given different doses of stress hormones in their drinking water to assess epigenetic changes to FKBP5. The researchers took blood samples weekly to measure the changes and then dissected the brains at the end of the month to study what changes were occurring in the hippocampus as a result of glucocorticoid exposure. The hippocampus, in both mice and humans, is vital to memory formation, information storage and organizational abilities.
The measurements showed that the more stress hormones the mice got, the greater the epigenetic changes in the blood and brain tissue, although the scientists say the brain changes occurred in a different part of the gene than expected. This was what made finding the blood-brain connection very challenging, Lee says.
Also, the more stress hormone, the more RNA from the FKBP5 gene was expressed in the blood and brain, and the greater the association with depression. However, it was the underlying epigenetic changes that proved to be more robust. This is important, because while RNA levels may return to normal after stress hormone levels decrease or change due to small fluctuations in hormone levels, epigenetic changes persist, reflect overall stress hormone exposure and predict how much RNA will be made when stress hormone levels increase.
The team of researchers used an epigenetic assay previously developed in their laboratory that requires just one drop of blood to accurately assess overall exposure to stress hormone over 30 days. Elevated levels of stress hormone exposure are considered a risk factor for mental illness in humans and other mammals.
(Source: hopkinsmedicine.org)
Don’t beat yourself up, you’ll live longer
Brandeis researchers explore the relationship between self-compassion and health
We all have stress in our lives, whether it’s a daily commute, workplace pressures or relationship troubles. But how we deal with that stress could impact our health and longevity.
In a recently published paper in Brain, Behavior and Immunity, Brandeis University researchers report they found a connection between a self-compassionate attitude and lower levels of stress-induced inflammation. The discovery could lead to new techniques to lower stress and improve health.
The paper was authored by psychology professor Nicolas Rohleder, with postdoctoral fellows Juliana Breines and Myriam Thoma, and graduate students Danielle Gianferante, Luke Hanlin and Xuejie Chen.
It’s long known that psychological stress can trigger biological responses similar to the effects of illness or injury, including inflammation. While regulated inflammation can help stave off infection or promote healing, unregulated inflammation can lead to cardiovascular disease, cancer and Alzheimer’s.
Self-compassion describes behaviors such as self-forgiveness or, more colloquially, cutting yourself some slack. A person with high levels of self-compassion may not blame themselves for stress beyond their control or may be more willing to move on from an argument, rather than dwelling on it for days.
To understand the connection between self-compassion and inflammatory responses to stress, Rohleder and his team asked 41 participants to rank their levels of self-compassion. The participants ranked their agreement to statements such as, “I try to be understanding and patient toward aspects of my personality I do not like” and “I’m disapproving and judgmental about my own flaws and inadequacies.”
Then, the participants took one stress test a day for two days and their levels of interleukin-6 (IL-6), an inflammatory agent linked to stress, were recorded before and after each test. After the first stress test, participants with higher self-compassion had significantly lower levels of IL-6.
On the second day, Rohleder and his team found something unexpected. Those with low self-compassion had higher base levels of IL-6 before the test, suggesting that they may have been carrying the stress they experienced the day before.
“The high responses of IL-6 on the first day and the higher baseline levels on the second day suggest that people with low self-compassion are especially vulnerable to the adverse effects of this kind of stress,” Rohleder says.
The research illustrates how easy it is for stress to build over time and how a seemingly small daily stressor, such as traffic, can impact a person’s health if they don’t have the right strategies to deal with it.
“Hopefully, this research can provide more effective ways to cope with stress and reduce disease, not only by relieving negative emotions but by fostering positive ideas of self compassion,” Rohleder says.
Genes increase the stress of social disadvantage for some children
Genes amplify the stress of harsh environments for some children, and magnify the advantage of supportive environments for other children, according to a study that’s one of the first to document how genes interacting with social environments affect biomarkers of stress.
"Our findings suggest that an individual’s genetic architecture moderates the magnitude of the response to external stimuli—but it is the environment that determines the direction" says Colter Mitchell, lead author of the paper and a researcher at the University of Michigan Institute for Social Research (ISR).
The study, published today in the Proceedings of the National Academy of Sciences, uses telomere length as a marker of stress. Found at the ends of chromosomes, telomeres generally shorten with age, and when individuals are exposed to disease and chronic stress, including the stress of living in a disadvantaged environment.
For the study, Mitchell and colleagues used telomere samples from a group of 40 nine-year-old boys from two very different environments – one nurturing and the other harsh. Those in the nurturing environment came from stable families, with nurturing parenting, good maternal mental health, and positive socioeconomic conditions, while those in the harsh environment experienced high levels of poverty, harsh parenting, poor maternal mental health, and high family instability.
For those children with heightened sensitivity in the serotonergic and dopaminergic genetic pathways compared to other children, telomere length was shortest in a disadvantaged environment, and longest in a supportive environment.
Loneliness impacts DNA repair: The long and the short of telomeres
Telomeres are DNA-protein complexes that function as protective caps at the ends of chromosomes. Biologists and veterinarians at the Vetmeduni Vienna recently examined the telomere length of captive African grey parrots. They found that the telomere lengths of single parrots were shorter than those housed with a companion parrot, which supports the hypothesis that social stress can interfere with cellular aging and a particular type of DNA repair. It suggests that telomeres may provide a biomarker for assessing exposure to social stress. The findings have been published in the open access journal PLOS ONE.
In captivity, grey parrots are often kept in social isolation, which can have detrimental effects on their health and wellbeing. So far there have not been any studies on the effects of long term social isolation from conspecifics on cellular aging. Telomeres shorten with each cell division, and once a critical length is reached, cells are unable to divide further (a stage known as ‘replicative senescence’). Although cellular senescence is a useful mechanism to eliminate worn-out cells, it appears to contribute to aging and mortality. Several studies suggest that telomere shortening is accelerated by stress, but until now, no studies have examined the effects of social isolation on telomere shortening.
Using molecular genetics to assess exposure to stress
To test whether social isolation accelerates telomere shortening, Denise Aydinonat, a doctorate student at the Vetmeduni Vienna, conducted a study using DNA samples that she collected from African grey parrots during routine check-ups. African greys are highly social birds, but they are often reared and kept in isolation from other parrots (even though such conditions are illegal in Austria). She and her collaborators compared the telomere lengths of single birds versus pair-housed individuals with a broad range of ages (from 1 to 45 years). Not surprisingly, the telomere lengths of older birds were shorter compared to younger birds, regardless of their housing. However, the important finding of the study was that single-housed birds had shorter telomeres than pair-housed individuals of the same age group.
Reading signs of stress by erosion of DNA
“Studies on humans suggest that people who have experienced high levels of social stress and deprivation have shorter telomeres,” says Dustin Penn from the Konrad Lorenz Institute of Ethology at the Vetmeduni Vienna. “But this study is the first to examine the effects of social isolation on telomere length in any species.” Penn and his team previously conducted experiments on mice, which were the first to show that exposure to crowding stress causes telomere shortening. He points out that this new finding suggests that both extremes of social conditions affect telomere attrition. However, he also cautions “further ‘longitudinal’ studies, in which changes in telomeres of the same individuals over time, are needed to investigate the consequences of stress on telomere shortening and the subsequent effects on health and longevity.”
Vast gene-expression map yields neurological and environmental stress insights
A consortium led by scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) has conducted the largest survey yet of how information encoded in an animal genome is processed in different organs, stages of development, and environmental conditions. Their findings paint a new picture of how genes function in the nervous system and in response to environmental stress.
They report their research this week in the Advance Online Publication of the journal Nature.
The scientists studied the fruit fly, an important model organism in genetics research. Seventy percent of known human disease genes have closely related genes in the fly, yet the fly genome is one-thirtieth the size of ours. Previous fruit fly research has provided insights on cancer, birth defects, addictive behavior, and neurological diseases. It has also advanced our understanding of processes common to all animals such as body patterning and synaptic transmission.
In the latest scientific fruit from the fruit fly, the consortium, led by Susan Celniker of Berkeley Lab’s Life Sciences Division, generated the most comprehensive map of gene expression in any animal to date. Scientists from the University of California at Berkeley, Indiana University at Bloomington, the University of Connecticut Health Center, and several other institutions contributed to the research.
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.
New evidence that chronic stress predisposes brain to mental illness
University of California, Berkeley, researchers have shown that chronic stress generates long-term changes in the brain that may explain why people suffering chronic stress are prone to mental problems such as anxiety and mood disorders later in life.
Their findings could lead to new therapies to reduce the risk of developing mental illness after stressful events.
Doctors know that people with stress-related illnesses, such as post-traumatic stress disorder (PTSD), have abnormalities in the brain, including differences in the amount of gray matter versus white matter. Gray matter consists mostly of cells – neurons, which store and process information, and support cells called glia – while white matter is comprised of axons, which create a network of fibers that interconnect neurons. White matter gets its name from the white, fatty myelin sheath that surrounds the axons and speeds the flow of electrical signals from cell to cell.
How chronic stress creates these long-lasting changes in brain structure is a mystery that researchers are only now beginning to unravel.
In a series of experiments, Daniela Kaufer, UC Berkeley associate professor of integrative biology, and her colleagues, including graduate students Sundari Chetty and Aaron Freidman, discovered that chronic stress generates more myelin-producing cells and fewer neurons than normal. This results in an excess of myelin – and thus, white matter – in some areas of the brain, which disrupts the delicate balance and timing of communication within the brain.
“We studied only one part of the brain, the hippocampus, but our findings could provide insight into how white matter is changing in conditions such as schizophrenia, autism, depression, suicide, ADHD and PTSD,” she said.
The hippocampus regulates memory and emotions, and plays a role in various emotional disorders.
Kaufer and her colleagues published their findings in the Feb. 11 issue of the journal Molecular Psychiatry.
Does stress affect brain connectivity?
Kaufer’s findings suggest a mechanism that may explain some changes in brain connectivity in people with PTSD, for example. One can imagine, she said, that PTSD patients could develop a stronger connectivity between the hippocampus and the amygdala – the seat of the brain’s fight or flight response – and lower than normal connectivity between the hippocampus and prefrontal cortex, which moderates our responses.
“You can imagine that if your amygdala and hippocampus are better connected, that could mean that your fear responses are much quicker, which is something you see in stress survivors,” she said. “On the other hand, if your connections are not so good to the prefrontal cortex, your ability to shut down responses is impaired. So, when you are in a stressful situation, the inhibitory pathways from the prefrontal cortex telling you not to get stressed don’t work as well as the amygdala shouting to the hippocampus, ‘This is terrible!’ You have a much bigger response than you should.”
She is involved in a study to test this hypothesis in PTSD patients, and continues to study brain changes in rodents subjected to chronic stress or to adverse environments in early life.
Stress tweaks stem cells
Kaufer’s lab, which conducts research on the molecular and cellular effects of acute and chronic stress, focused in this study on neural stem cells in the hippocampus of the brains of adult rats. These stem cells were previously thought to mature only into neurons or a type of glial cell called an astrocyte. The researchers found, however, that chronic stress also made stem cells in the hippocampus mature into another type of glial cell called an oligodendrocyte, which produces the myelin that sheaths nerve cells.
The finding, which they demonstrated in rats and cultured rat brain cells, suggests a key role for oligodendrocytes in long-term and perhaps permanent changes in the brain that could set the stage for later mental problems. Oligodendrocytes also help form synapses – sites where one cell talks to another – and help control the growth pathway of axons, which make those synapse connections.
The fact that chronic stress also decreases the number of stem cells that mature into neurons could provide an explanation for how chronic stress also affects learning and memory, she said.
Kaufer is now conducting experiments to determine how stress in infancy affects the brain’s white matter, and whether chronic early-life stress decreases resilience later in life. She also is looking at the effects of therapies, ranging from exercise to antidepressant drugs, that reduce the impact of stress and stress hormones.