Understanding Stress at a Deeper Level

It’s long been known that chronic stress, defined as a prolonged physical, mental, or emotional factor that results bodily or psychological tension, can alter the normal trajectories of childhood brain development (See “Early Life Experience, Critical Periods, and Brain Development”), leading to increased risk for neuropsychiatric disorders. What hasn’t been known are the various mechanisms by which stress can make those changes, negative or positive, to the brain. Bruce McEwen, a pioneering neuroscientist who has spent his career studying the effects of stress, as well as a member of the Dana Alliance for Brain Initiatives (DABI), said that stress is one of the most commonly used words in the English language, yet it means something different to each person. That’s because the effects of stress are dependent on both genetics and environment.

“There used to be a time when we argued about what was more important to development—genes or environment. But now we understand there is an almost seamless interaction between genes and the environment and that has consequences for the brain in how it responds to insults,” McEwen said. “Among those insults is something we call toxic stress, the worst form of stress. And what we are learning about how the brain responds to stress, at the molecular level, may surprise you.”

To highlight some of those surprises, McEwen chaired a press conference at Neuroscience 2017, the 47^th annual meeting of the Society for Neuroscience, introducing several studies that offer insights into how stress can make changes, big and small, to the brain.

Epigenetic alterations to the germ cell

Jennifer Chan, a researcher at the University of Pennsylvania, said that several studies have now offered evidence that there are measurable effects of a father’s lifetime experiences on the development and health of future offspring. For example, the Swedish famine studies demonstrated that men who lived through famine before having children had grandsons with longer lifespans. Conversely, the grandsons of men who lived in periods of great harvest had shorter lifespans.

“This is some of the first evidence of inter- and transgenerational inheritance of paternal and grandpaternal experiences in humans. Through animal models, we now understand that a father’s experiences can lead to epigenetic programming of germ cells, or epigenetic marks on the sperm,” Chan said. “But one question that hasn’t been addressed is how do Dad’s experiences actually change that germ cell. What is the sensor in Dad’s reproductive tract that detects the changes in the environment and then translate that into epigenetic programming of the sperm?”

To answer that question, Chan and colleagues looked to the epididymis, the part of the testicle where sperm cells mature and an area known to help regulate gene expression. After stressing mice with a chronic variable stress paradigm known to result in offspring with dysregulated stress response, they discovered that stress hormones such as cortisol can enter the epididymis and bind to glucocorticoid receptors, making changes to small RNAs that can go on and change the content of the sperm itself. When the researchers used genetic engineering to reduce the glucocorticoid receptors in the parent’s epididymis, they could rescue the offspring from the dysregulated stress response.

“What we see is that paternal stress leads to changes in the development of offspring—and, eventually the stress response of those offspring as well,” Chan said. “This kind of research can help us better understand the mechanisms by which these stressful exposures can lead to changes in offspring.”

Salivary biomarkers

Not all stressors are created equal, and no two people will respond the same way to identical stressors. That can make it difficult for clinicians to know who may be most at risk for later neuropsychiatric disease. To help identify potential biomarkers for toxic stress, Brianna Mulligan, a researcher at the University of New Mexico Health Sciences Center, looked to epigenetic markers in human hair and saliva.

“Survivors of trauma have a much bigger risk of developing mental and physical health issues in adulthood,” said Mulligan. “Long-term stress conditions can alter the DNA methylation profile of brain regions that regulate hormonal, immunological, and neural genes. But these changes are potentially reversible if we understand what are the biological changes that embed the memory of those traumas into the brain.”

Mulligan and colleagues collected hair and saliva samples from six children who had been referred to trauma-focused cognitive behavioral therapy and compared those samples to children who had not been referred or experienced a traumatic event. The traumatized children showed altered methylation patterns at 174 different gene sites. By understanding more about those methylation changes, Mulligan said, researchers could develop a cheek swab screen that could help clinicians pinpoint which children might be most at risk for later health troubles.

The effect of astrocytes

When it comes to stress and the brain, most researchers look towards changes in neurons and brain circuits. But new work from Meghan E. Jones and colleagues at the University of North Carolina at Chapel Hill suggest that astrocytes, the star-shaped glial cells that provide support to neurons, may also help mediate fear after stress.

Jones and colleagues compared the brain tissue of rats that had been exposed to chronic stress and developed a dysregulated fear response similar to post-traumatic stress disorder (PTSD), to those that had not. They found that the chronically stressed animals had relatively higher levels of Interleukin-1β, an immune protein linked to inflammation, in hippocampal astrocytes.

“Our work suggests this Interleukin-1β is coming from the astrocytes in response to the stress,” she said. “When we block that signal, we can prevent the later fear. It would seem that astrocyte signaling can influence how a stressor changes the way animals learn about fear—and may offer new insights into human PTSD, as well as how to prevent or treat it.”

Neurogenesis and stress relief

Neurogenesis, the creation of new neurons, has been linked to improved memory and cognition. Christoph Anacker, a neuroscientist at Columbia University, said that the development of new hippocampal neurons also might protect the brain from chronic stress.

“Chronic stress is a major risk factor for developing mental illnesses like depression and anxiety,” he said. “If we can understand how to better reduce the effects of stress on the brain, we may be able to help prevent those conditions.”

Previous work suggests that hippocampal neurogenesis can silence the activity of stress-responsive cells in the brain, resulting in less anxiety. Anacker and colleagues tested genetically modified mice that had a larger or lesser number of newly generated neurons in the hippocampus, to examine how the response to external stressors might change. They found that those with fewer new cells experienced more of a stress response, while those with more neurogenesis showed less of one.

“When we exposed the mice with the increased number of new brain cells in the hippocampus, we see that these stress-responsive cells are much less active and the mouse feels much less anxious,” he says. “This offers us the opportunity to use this knowledge to try and develop new antidepressant medications that can help increase the number of new brain cells or silence the activity of the stress-responsive cells in the hippocampus.” Aerobic exercise also is known to increase hippocampal volume.

Moving forward

New and further research into stress and the brain will help us to better understand the negative effects of this coupling—as well as provide new avenues to prevention and treatment, McEwen said. He and the other researchers cautioned that there is still much to learn, especially when it comes to individual differences. What may be chronic stress to one person may be a normal day at the office to another. The neuroscience research community still has a lot to learn about what factors are involved create such variety in stress responses.

“We need stress to motivate us. Yet, too much or too long and we see problems,” he said. “That said, these kinds of studies illuminate our understanding of the different effects of stress on the brain, and that there are likely ways to address the negative effects before too much damage occurs.”