Relieving chronic stress in the brains of male and female mice
Subtle activation of a small subset of neurons in one region of the brain can make male mice resilient to, and even reverse, the detrimental effects of chronic stress. The same is true for female mice, but in a totally different region of the brain. Researchers at Penn State developed a protocol to continuously activate neurons that produce the signaling molecule somatostatin in specific brain regions in mice. They found that doing so in a region of the brain called the prelimbic cortex made male mice resilient to stress, but failed to do so in female mice. Doing so in the ventral hippocampus made female mice resilient, but not males. In a separate study, they then compared the set of genes that are active in the prefrontal cortex of resilient and non-resilient mice before and after stress to understand the molecular mechanisms underlying these changes.
The two studies were recently published in the journal Molecular Psychiatry and could help explain the efficacy, or lack thereof, of certain antidepressant drugs and inform the development of new drugs and therapies.
“Stress is a major contributor to vulnerability for psychiatric disorders like major depressive disorder and post-traumatic stress disorder,” said Bernhard Lüscher, professor of biology, biochemistry and molecular biology, and of psychiatry at Penn State and the leader of the research team. “Much like humans, stressed mice develop signs of anxiety and anhedonia, a lack of interest in things they normally find pleasurable, when they are exposed to excessive or otherwise uncontrollable stress. Neurons that express the neurotransmitter somatostatin have been shown to regulate the brain’s response to stress, so we wanted to delve into why and how this works at the molecular level and whether mice show sex differences that could explain sex differences in vulnerability known to occur in patients.”
Somatostatin-positive neurons are a subset of GABAergic neurons. These neurons produce the neurotransmitter gamma-aminobutyric acid (GABA) and are generally thought of as the ‘brakes’ of the nervous system. They slow the nervous system down and help to prevent neurons from firing inappropriately.
“In a previous study, we showed that if you experimentally remove GABA receptors from somatostatin-positive neurons — essentially removing the brake from the brake, making the brake stronger and thereby making these neurons more active— it has antidepressant drug-like behavioral effects on the mice,” Lüscher said. “Here we wanted to see if we could determine which regions of the brain mediate this effect.”
The researchers used a technique called ‘chemogenetics’ which allowed them to directly and selectively activate somatostatin-positive neurons in specific brain regions. They focused on the prelimbic cortex and hippocampus, which are known to be highly vulnerable to stress.
“We were surprised to find that the effects of our chemogenetic manipulations in the two brain regions were strictly sex-specific,” Lüscher said. “There is abundant evidence that in humans there are prominent sex differences in the vulnerability to depression, although we treat male and female patients the same and the treatments are similarly effective because the antidepressants seem to work broadly across the entire brain.”
In the second study, the researchers characterized the complete set of genes — known as the transcriptome — that are being expressed in the medial prefrontal cortex, a larger brain region that includes the prelimbic cortex of male mice resilient to stress and non-resilient mice. They found that gene expression changes in the prefrontal cortex of unstressed stress-resilient male mice looked a lot like those of stressed non-resilient male mice, and the reverse was also true: gene expression changes in stressed stress-resilient mice resembled unstressed non-resilient mice. The stressed stress-resilient mice also showed signs of enhanced translation of genes into proteins. In contrast to males, the prefrontal cortex of female mice showed none of the gene expression changes that would explain resilience.
“The fact that gene expression in unstressed stress-resilient mice resembles that of stress exposure is intriguing,” Lüscher said. “It suggests that some stress may produce lasting and protective changes in the brain, somewhat akin to exposure therapy. It will be interesting to see if similar gene expression changes that explain stress resilience occur in the hippocampus of female mice.”
In addition to Lüscher, the research team for the first paper, titled “Sex-specific GABAergic microcircuits that switch vulnerability into resilience to stress and reverse the effects of chronic stress exposure,” included graduate students Tong Jiang and Mengyang Feng, who is now a postdoctoral research at MIT, and undergraduate student Alexander Hutsell.
The research team for the second paper, titled “Transcriptome signatures of the medial prefrontal cortex underlying GABAergic control of resilience to chronic stress exposure,” included graduate students, Meiyu Shao and Deepro Banerjee, undergraduate student Julia Botvinov, and Santhosh Girirajan, department head and T. Ming Chu Professor of Biochemistry and Molecular Biology in the Department of Biochemistry and Molecular Biology.
The National Institute of Mental Health and Penn State funded the studies.