Posts tagged stress
Posts tagged stress
Pregnant women may pass on the effects of stress to their fetus by way of bacterial changes in their vagina, suggests a study in mice. It may affect how well their baby’s brain is equipped to deal with stress in adulthood.
The bacteria in our body outnumber our own cells by about 10 to 1, with most of them found in our gut. Over the last few years, it has become clear that the bacterial ecosystem in our body – our microbiome – is essential for developing and maintaining a healthy immune system.
Our gut bugs also help to prevent germs from invading our bodies, and help to absorb nutrients from food.
A baby gets its first major dose of bacteria in life as it passes through its mother’s birth canal. En route, the baby ingests the mother’s vaginal microbes, which begin to colonise the newborn’s gut.
Chris Howerton, then at the University of Pennsylvania in Philadelphia, and his colleagues wanted to know if this initial population of bacteria is important in shaping a baby’s neurological development, and whether that population is influenced by stress during pregnancy.
The first step was to figure out what features of the mother’s vaginal microbiome might be altered by stress, and then see if any of those changes were transmitted to the offspring’s gut.
To do this, the team exposed 10 pregnant mice to a different psychologically stressful experience, such as exposing them to fox odour, keeping their cages lit at night, or temporarily restraining them every day for what would be the equivalent of the first trimester of their pregnancy. Another 10 pregnant mice were housed normally during the same time.
The team took samples of their vaginal bacteria throughout the pregnancy and again just after the mice had given birth. These samples were genetically sequenced to see what types of bacteria were present.
The microbiomes of the stressed mice were remarkably different to those of the unstressed mice after they had each given birth. There were more types of bacteria present, and the proportion of one common gut bacteria, Lactobacillus, was significantly reduced.
Like mother, like pup
To see whether these changes had been passed on to the pups, a few days after birth the pups’ nascent gut bacteria was removed from their colon and sequenced. Sure enough, the same bacterial patterns were seen in the pups of stressed mothers.
By analysing tissue from the pups’ hypothalamus – a brain area involved in hormone control, behaviour and sleep, among other things – the team was able to infer which genes were affected by the stress-induced changes in each mother’s microbiome.
They found that the expression of 20 genes was affected by the decrease in Lactobacillus, including genes related to the production of new neurons and the growth of synaptic connections in the brain.
These genetic outcomes in the brain are probably a result of a different suite of nutrients and metabolites circulating in the “stressed” pup’s blood, thanks to the altered gut flora they inherited. Indeed, when the team analysed the blood of the pups of the stressed mothers, they found that there were fewer molecules present necessary for the formation of essential neurotransmitters – chemicals that transmit signals to the brain. Furthermore, there were lower levels of a molecule thought to protect the brain from harmful oxidative stress.
"These changes are significant and are likely to be important for determining how the brain initially develops and how it will respond in the future to things like stress or changes in the environment," says Tracy Bale, Howerton’s supervisor during the research and director of the University of Pennsylvania lab.
As well as changing the nutrients available, the microbiome could also affect the brain via the immune system or by innervating the nerves in the gut that connect to it. “These three mechanisms aren’t mutually exclusive. It’s likely that they all play a role,” says Howerton.
If the same effects are seen in humans, there may be a straightforward solution. “We can easily manipulate the bacteria we have inside of us,” says Howerton. For example, if a certain cocktail of bacteria is found to be beneficial to the newborns of stressed mothers, we could give it to them right after birth, he suggests. This approach could also benefit babies born via C-section, who do not pass through their mother’s birth canal, or those born to mothers whose gut bacteria has been disrupted as a result of antibiotic use during pregnancy.
Bale is now investigating the link between bacteria and brain development in pregnant women who have been through several traumatic experiences to analyse the effects on their babies’ gut bacteria. She also intends to follow their children’s behaviour as they grow up.
"This is a remarkable trans-disciplinary study in how it bridged multiple organ systems to illuminate a complex question," says Catherine Hagan from the University of Missouri in Columbia. She says that more work needs to be done to show a causal link. "Mice are not tiny people – people are not big mice – more data is needed to understand how stress in mothers affects brain development in children," she says. "That said, mice and people have enough in common that this study provides a rationale for allocating resources to address such a concern."
"At the end of the day, most of what makes you ‘you’, and what drives your quality of life, comes down to the brain," says Bale. "It’s this very important, vulnerable tissue that is susceptible to many perturbations. If the microbiome is proven to be one of these driving forces, then it’s essential we know just how factors in our environment can change it and can reprogram the brain."
New research on pond snails has revealed that high levels of stress can block memory processes. Researchers from the University of Exeter and the University of Calgary trained snails and found that when they were exposed to multiple stressful events they were unable remember what they had learned.
Previous research has shown that stress also affects human ability to remember. This study, published in the journal PLOS ONE, found that experiencing multiple stressful events simultaneously has a cumulative detrimental effect on memory.
Dr Sarah Dalesman, a Leverhulme Trust Early Career Fellow, from Biosciences at the University of Exeter, formally at the University of Calgary, said: “It’s really important to study how different forms of stress interact as this is what animals, including people, frequently experience in real life. By training snails, and then observing their behaviour and brain activity following exposure to stressful situations, we found that a single stressful event resulted in some impairment of memory but multiple stressful events prevented any memories from being formed.”
The pond snail, Lymnaea stagnalis, has easily observable behaviours linked to memory and large neurons in the brain, both useful benefits when studying memory processes. They also respond to stressful events in a similar way to mammals, making them a useful model species to study learning and memory.
In the study, the pond snails were trained to reduce how often they breathed outside water. Usually pond snails breathe underwater and absorb oxygen through their skin. In water with low oxygen levels the snails emerge and inhale air using a basic lung opened to the air via a breathing hole.
To train the snails not to breathe air they were placed in poorly oxygenated water and their breathing holes were gently poked every time they emerged to breathe. Snail memory was tested by observing how many times the snails attempted to breathe air after they had received their training. Memory was considered to be present if there was a reduction in the number of times they opened their breathing holes. The researchers also assessed memory by monitoring neural activity in the brain.
Immediately before training, the snails were exposed to two different stressful experiences, low calcium - which is stressful as calcium is necessary for healthy shells - and overcrowding by other pond snails.
When faced with the stressors individually, the pond snails had reduced ability to form long term memory, but were still able to learn and form short and intermediate term memory lasting from a few minutes to hours. However, when both stressors were experienced at the same time, results showed that they had additive effects on the snails’ ability to form memory and all learning and memory processes were blocked.
Future work will focus on the effects of stress on different populations of pond snail.
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.”
Neonatologists seem to perform miracles in the fight to support the survival of babies born prematurely.
To promote their survival, cortisol-like drugs called glucocorticoids are administered frequently to women in preterm labor to accelerate their babies’ lung maturation prior to birth. Cortisol is a substance naturally released by the body when stressed. But the levels of glucocorticoids administered to promote lung development are higher than that achieved with typical stress, perhaps only mirrored in the body’s reaction to extreme stresses.
The benefit of glucocorticoids is undisputed and has certainly saved the lives of countless babies, but this exposure also may have some negative consequences. Indeed, excessive glucocorticoid levels may have effects on brain development, perhaps contributing to emotional problems later in life.
In this issue of Biological Psychiatry, Dr. Elysia Davis at the University of Denver and her colleagues report new findings on the effects of synthetic glucocorticoid on human brain development. Their study focused on healthy children who were born full-term, avoiding the confounding effects of premature birth.
The investigators conducted brain imaging sessions in and carefully assessed 54 children, 6-10 years of age. The mothers of the participating children also completed reports on their child’s behavior. The researchers then divided the children into two groups: those who were exposed to glucocorticoids prenatally and those who were not.
In this study, children with fetal glucocorticoid exposure showed significant cortical thinning, and a thinner cortex also predicted more emotional problems. In one particularly affected part of the brain, the rostral anterior cingulate cortex, it was 8-9% thinner among children exposed to glucocorticoids. Interestingly, other studies have shown that this region of the brain is affected in individuals diagnosed with mood and anxiety disorders.
"Fetal exposure to a frequently administered stress hormone is associated with consequences for child brain development that persist for at least 6 to 10 years. These neurological changes are associated with increased risk for stress and emotional problems," Davis explained of their findings. "Importantly, these findings were observed among healthy children born full term."
Although such a finding does not indicate that glucocorticoids ‘caused’ these changes, the researchers did determine that the findings can’t be explained by any obvious confounding differences between the groups. The two groups did not differ on weight or gestational age at birth, apgar scores, maternal factors, or any other basic demographics. Thus, the findings do suggest that glucocorticoid administration may somehow alter the trajectory of brain development of exposed children.
"This study provides evidence that prenatal exposure to stress hormones shapes the construction of the fetal nervous system with consequences for the developing brain that persist into the preadolescent period," she added.
"This study highlights potential links between early cortisol exposure, cortical thinning and mood symptoms in children. It may provide important insights into the development of the brain and the long-term impact of maternal stress," commented Dr. John Krystal, Editor of Biological Psychiatry.
Early life pain alters neural circuits in the brain that regulate stress, suggesting pain experienced by infants who often do not receive analgesics while undergoing tests and treatment in neonatal intensive care may permanently alter future responses to anxiety, stress and pain in adulthood, a research team led by Dr. Anne Murphy, associate director of the Neuroscience Institute at Georgia State University, has discovered.
An estimated 12 percent of live births in the U.S. are considered premature, researchers said. These infants often spend an average of 25 days in neonatal intensive care, where they endure 10-to-18 painful and inflammatory procedures each day, including insertion of feeding tubes and intravenous lines, intubation and repeated heel lance. Despite evidence that pain and stress circuitry in the brain are established and functional in preterm infants, about 65 percent of these procedures are performed without benefit of analgesia. Some clinical studies suggest early life pain has an immediate and long-term impact on responses to stress- and anxiety-provoking events.
The Georgia State study examined whether a single painful inflammatory procedure performed on male and female rat pups on the day of birth alters specific brain receptors that affect behavioral sensitivity to stress, anxiety and pain in adulthood. The findings demonstrated that such an experience is associated with site-specific changes in the brain that regulate how the pups responded to stressful situations. Alterations in how these receptors function have also been associated with mood disorders.
The study findings mirror what is now being reported clinically. Children who experienced unresolved pain following birth show reduced responsiveness to pain and stress.
“While a dampened response to painful and stressful situations may seem advantageous at first, the ability to respond appropriately to a potentially harmful stimulus is necessary in the long term,” Dr. Murphy said.
“The fact that less than 35 percent of infants undergoing painful and invasive procedures receive any sort of pre- or post-operative pain relief needs to be re-evaluated in order to reduce physical and mental health complications associated with preterm birth.”
About a dozen years ago, scientists discovered that a hormone called ghrelin enhances appetite. Dubbed the “hunger hormone,” ghrelin was quickly targeted by drug companies seeking treatments for obesity — none of which have yet panned out.
MIT neuroscientists have now discovered that ghrelin’s role goes far beyond controlling hunger. The researchers found that ghrelin released during chronic stress makes the brain more vulnerable to traumatic events, suggesting that it may predispose people to posttraumatic stress disorder (PTSD).
Drugs that reduce ghrelin levels, originally developed to try to combat obesity, could help protect people who are at high risk for PTSD, such as soldiers serving in war, says Ki Goosens, an assistant professor of brain and cognitive sciences at MIT, and senior author of a paper describing the findings in the Oct. 15 online edition of Molecular Psychiatry.
“Perhaps we could give people who are going to be deployed into an active combat zone a ghrelin vaccine before they go, so they will have a lower incidence of PTSD. That’s exciting because right now there’s nothing given to people to prevent PTSD,” says Goosens, who is also a member of MIT’s McGovern Institute for Brain Research.
Lead author of the paper is Retsina Meyer, a recent MIT PhD recipient. Other authors are McGovern postdoc Anthony Burgos-Robles, graduate student Elizabeth Liu, and McGovern research scientist Susana Correia.
Stress and fear
Stress is a useful response to dangerous situations because it provokes action to escape or fight back. However, when stress is chronic, it can produce anxiety, depression and other mental illnesses.
At MIT, Goosens discovered that one brain structure that is especially critical for generating fear, the amygdala, has a special response to chronic stress. The amygdala produces large amounts of growth hormone during stress, a change that seems not to occur in other brain regions.
In the new paper, Goosens and her colleagues found that the release of the growth hormone in the amygdala is controlled by ghrelin, which is produced primarily in the stomach and travels throughout the body, including the brain.
Ghrelin levels are elevated by chronic stress. In humans, this might be produced by factors such as unemployment, bullying, or loss of a family member. Ghrelin stimulates the secretion of growth hormone from the brain; the effects of growth hormone from the pituitary gland in organs such as the liver and bones have been extensively studied. However, the role of growth hormone in the brain, particularly the amygdala, is not well known.
The researchers found that when rats were given either a drug to stimulate the ghrelin receptor or gene therapy to overexpress growth hormone over a prolonged period, they became much more susceptible to fear than normal rats. Fear was measured by training all of the rats to fear an innocuous, novel tone. While all rats learned to fear the tone, the rats with prolonged increased activity of the ghrelin receptor or overexpression of growth hormone were the most fearful, assessed by how long they froze after hearing the tone. Blocking the cell receptors that interact with ghrelin or growth hormone reduced fear to normal levels in chronically stressed rats.
When rats were exposed to chronic stress over a prolonged period, their circulating ghrelin and amygdalar growth hormone levels also went up, and fearful memories were encoded more strongly. This is similar to what the researchers believe happens in people who suffer from PTSD.
“When you have people with a history of stress who encounter a traumatic event, they are more likely to develop PTSD because that history of stress has altered something about their biology. They have an excessively strong memory of the traumatic event, and that is one of the things that drives their PTSD symptoms,” Goosens says.
New drugs, new targets
Over the last century, scientists have described the hypothalamic-pituitary-adrenal (HPA) axis, which produces adrenaline, cortisol (corticosterone in rats), and other hormones that stimulate “fight or flight” behavior. Since then, stress research has focused almost exclusively on the HPA axis.
After discovering ghrelin’s role in stress, the MIT researchers suspected that ghrelin was also linked to the HPA axis. However, they were surprised to find that when the rats’ adrenal glands — the source of corticosterone, adrenaline, and noradrenaline — were removed, the animals still became overly fearful when chronically stressed. The authors also showed that repeated ghrelin-receptor stimulation did not trigger release of HPA hormones, and that blockade of the ghrelin receptor did not blunt release of HPA stress hormones. Therefore, the ghrelin-initiated stress pathway appears to act independently of the HPA axis. “That’s important because it gives us a whole new target for stress therapies,” Goosens says.
Pharmaceutical companies have developed at least a dozen possible drug compounds that interfere with ghrelin. Many of these drugs have been found safe for humans, but have not been shown to help people lose weight. The researchers believe these drugs could offer a way to vaccinate people entering stressful situations, or even to treat people who already suffer from PTSD, because ghrelin levels remain high long after the chronic stress ends.
PTSD affects about 7.7 million American adults, including soldiers and victims of crimes, accidents, or natural disasters. About 40 to 50 percent of patients recover within five years, Meyer says, but the rest never get better.
The researchers hypothesize that the persistent elevation of ghrelin following trauma exposure could be one of the factors that maintain PTSD. “So, could you immediately reverse PTSD? Maybe not, but maybe the ghrelin could get damped down and these people could go through cognitive behavioral therapy, and over time, maybe we can reverse it,” Meyer says.
Working with researchers at Massachusetts General Hospital, Goosens’ lab is now planning to study ghrelin levels in human patients suffering from anxiety and fear disorders. They are also planning a clinical trial of a drug that blocks ghrelin to see if it can prevent relapse of depression.
Work, home, even in the car, stress is a constant struggle for many people. But it’s more than just exhausting and annoying. Unmanaged stress can lead to serious health conditions such as high blood pressure, heart disease, obesity and diabetes.
“The American lifestyle is fast-paced and productive, but it can be extremely stressful. If that stress is not addressed, our bodies and minds can suffer,” said Dr. Aaron Michelfelder, professor of Family Medicine at Loyola University Chicago Stritch School of Medicine.
Our bodies need sleep to rejuvenate and if we are uptight and stressed we aren’t able to get the rest we need. This can lead to serious physical and mental health issues, which is why it’s extremely important to wind down, both body and mind, after a stressful day.
According to Michelfelder, one of best ways to unwind and reconnect after a stressful day is by taking a walk. Though any walking is good, walking in the woods or in nature has been proven to be even better at reducing stress and improving your health.
“When we get to nature, our health improves,” Michelfelder said. “Our stress hormones rise all day long in our bloodstream and taking even a few moments while walking to reconnect with our inner thoughts and to check in with our body will lower those damaging stress hormones. Walking with our family or friends is also a great way to lower our blood pressure and make us happier.”
Research out of Japan shows that walking in the woods also may play a role in fighting cancer. Plants emit a chemical called phytoncides that protects them from rotting and insects. When people breathe it in, there is an increase in the number of “natural killer” cells , which are part of a person’s immune response to cancer.
“When we walk in a forest or park, our levels of white blood cells increase and it also lowers our pulse rate, blood pressure and level of the stress hormone cortisol,” Michelfelder said.
He also suggests reading, writing, meditating or reflecting to help calm the mind after long day. To help calm the body yoga and breathing exercises also are good.
“If you want to wind down, stay away from electronic screens as they activate the mind. Electronic devices stimulate brain activity and someone’s post on Facebook or a story on the evening news might cause more stress,” Michelfeder said.
Findings Point to New Potential Drug Target—GABA Neurons—to Treat Patients with Depression and Other Mood Disorders
A new drug target to treat depression and other mood disorders may lie in a group of GABA neurons (gamma-aminobutyric acid –the neurotransmitters which inhibit other cells) shown to contribute to symptoms like social withdrawal and increased anxiety, Penn Medicine researchers report in a new study in the Journal of Neuroscience.
Experts know that people suffering from depression and other mood disorders often react to rejection or bullying by withdrawing themselves socially more than the average person who takes it in strides, yet the biological processes behind these responses have remained unclear.
Now, a preclinical study, from the labs of Olivier Berton, PhD, an assistant professor in the department of Psychiatry, with Collin Challis of the Neuroscience Graduate Group, and Sheryl Beck, PhD, a professor in the department of Anesthesiology at Children’s Hospital of Philadelphia, found that bullying and other social stresses triggered symptoms of depression in mice by activating GABA neurons, in a never-before-seen direct relationship between social stimuli and this neural circuitry. Activation of those neurons, they found, directly inhibited levels of serotonin, long known to play a vital role in behavioral responses—without it, a depressed person is more likely to socially withdrawal.
Conversely, when the researchers successfully put the brake on the GABA neurons, mice became more resilient to bullying and didn’t avoid once -perceived threats.
“This is the first time that GABA neuron activity—found deep in the brainstem—has been shown to play a key role in the cognitive processes associated with social approach or avoidance behavior in mammals,” said Dr. Berton. “The results help us to understand why current antidepressants may not work for everyone and how to make them work better—by targeting GABA neurons that put the brake on serotonin cells.”
Less serotonin elicits socially defensive responses such as avoidance or submission, where enhancement—the main goal of antidepressants—induces a positive shift in the perception of socio-affective stimuli, promoting affiliation and dominance. However, current antidepressants targeting serotonin, like SSRIs, are only effective in about 50 percent of patients.
These new findings point to GABA neurons as a new, neural drug target that could help treat the other patients who don’t respond to today’s treatment.
For the study, “avoidant” mice were exposed to brief bouts of aggression from trained “bully” mice. By comparing gene expression in the brains of resilient and avoidant mice, Berton and colleagues discovered that bullying in avoidant mice puts GABA neurons in a state where they become more excitable and the mice exhibit signs of social defeat. Resilient mice, however, had no change in neuron levels and behavior.
To better understand the link between GABA and the development of stress resilience, Berton, Beck, and colleagues also devised an approach to directly manipulate levels: Lifting GABA inhibition of serotonin neurons reduced social and anxiety symptoms in mice exposed to bullies and also fully prevented neurobiological changes due to stress.
“Our paper provides a novel cellular understanding of how social defensiveness and social withdrawal develop in mice and gives us a stepping stone to better understand the basis of similar social symptoms in humans,” said Berton. “This has important implications for the understanding and treatment of mood disorders.”
New research shows that in a dynamic mind-body interaction during the interpretation of prolonged stress, cells from the immune system are recruited to the brain and promote symptoms of anxiety.
The findings, in a mouse model, offer a new explanation of how stress can lead to mood disorders and identify a subset of immune cells, called monocytes, that could be targeted by drugs for treatment of mood disorders.
The Ohio State University research also reveals new ways of thinking about the cellular mechanisms behind the effects of stress, identifying two-way communication from the central nervous system to the periphery – the rest of the body – and back to the central nervous system that ultimately influences behavior.
Unlike an infection, trauma or other problems that attract immune cells to the site of trouble in the body, this recruitment of monocytes that can promote inflammation doesn’t damage the brain’s tissue – but it does lead to symptoms of anxiety.
The research showed that the brain under prolonged stress sends signals out to the bone marrow, calling up monocytes. The cells travel to specific regions of the brain and generate inflammation that causes anxiety-like behavior.
In experiments conducted in mice, the research showed that repeated stress exposure caused the highest concentration of monocytes migrating to the brain. The cells surrounded blood vessels and penetrated brain tissue in several areas linked to fear and anxiety, including the prefrontal cortex, amygdala and hippocampus, and their presence led to anxiety-like behavior in the mice.
“In the absence of tissue damage, we have cells migrating to the brain in response to the region of the brain that is activated by the stressor,” said John Sheridan, senior author of the study, professor of oral biology and associate director of Ohio State’s Institute for Behavioral Medicine Research (IBMR).
“In this case, the cells are recruited to the brain by signals generated by the animal’s interpretation of social defeat as stressful.”
The research appears in the Aug. 21, 2013, issue of The Journal of Neuroscience.
Mice in this study were subjected to stress that might resemble a person’s response to persistent life stressors. In this model of stress, male mice living together are given time to establish a hierarchy, and then an aggressive male is added to the group for two hours. This elicits a “fight or flight” response in the resident mice as they are repeatedly defeated. The experience of social defeat leads to submissive behaviors and the development of anxiety-like behavior.
Mice subjected to zero, one, three or six cycles of this social defeat were then tested for anxiety symptoms. The more cycles of social defeat, the higher the anxiety symptoms; mice took longer to enter an open space and opted for darkness rather than light when given the choice. Anxiety symptoms corresponded to higher levels of monocytes that had traveled to the animals’ brains from the blood.
Additional experiments showed that these cells did not originate in the brain, but traveled there from the bone marrow. In previous studies, this same research group showed that cells in the brain called microglia, the brain’s first line of immune defense, are activated by prolonged stress and are partly responsible for the signals that call up monocytes from the bone marrow.
“There are different moving parts from the central and peripheral components, and what’s novel is them coming together to influence behavior,” said Jonathan Godbout, a senior co-author of the paper and an associate professor of neuroscience at Ohio State.
Exactly what happens at this point in the brain remains unknown, but the research offers clues. The monocytes that travel to the brain don’t respond to natural anti-inflammatory steroids in the body and have characteristics signifying they are in a more inflammatory state. These results indicate that inflammatory gene expression occurs in the brain in response to the stressor.
“The monocytes are coming out of the bone marrow and they are not responsive to steroid regulation, so they overproduce proinflammatory signals when they’re stimulated. We think this is the key to the prolonged anxiety-like disorders that we see in these animals,” Sheridan said.
These findings do not apply to all forms of anxiety, the scientists noted, but they are a game-changer in research on stress-related mood disorders.
“Our data alter the idea of the neurobiology of mood disorders,” said Eric Wohleb, first author of the study and a predoctoral fellow in Ohio State’s Neuroscience Graduate Studies Program. “These findings indicate that a bidirectional system rather than traditional neurotransmitter pathways may regulate some forms of anxiety responses. We’re saying something outside the central nervous system – something from the immune system – is having a profound effect on behavior.”
Predicting the weather under stress
The team from Bochum has examined 80 subjects, 50 per cent of whom were given a drug blocking mineralocorticoid receptors in the brain. The remaining participants took a placebo drug. Twenty participants from each group were subjected to a stress-inducing experience. Subsequently, all participants underwent a learning test, the so-called weather prediction task. The subjects were shown playing cards with different symbols and had to learn which combinations of cards meant rain and which meant sunshine. The researchers used MRI to record the respective brain activity.
Learning unconsciously or consciously
There are two different approaches to master the weather prediction test: some subjects tried consciously to formulate a rule that would enable them to predict sunshine and rain. Others learned unconsciously to give the right answer, following their gut feeling, as it were. The team of Lars Schwabe demonstrated in August 2012 that, under stress, the brain prefers unconscious to conscious learning. “This switch to another memory system happens automatically,” says Lars Schwabe. “It makes sense for the organism to react in this manner. Thus, learning efficiency can be maintained even under stress.” However, this works only with fully functional mineralocorticoid receptors. Once the researchers blocked these receptors by applying the drug Spironolactone, the participants switched over to the unconscious strategy less frequently, thus demonstrating a poorer learning efficiency.
Effects also visible in brain activity
These effects also became evident in MRI data. Usually, stress causes the brain activity to shift from the hippocampus – a structure for conscious learning – to the dorsal striatum, which manages unconscious learning. However, this stress-induced switch took place only in the placebo group, not in subjects who had been given the mineralocorticoid receptor blocker. Consequently, the mineralocorticoid receptors play a crucial role in enabling the brain to adapt to stressful situations.