In a significant breakthrough, researchers at Penn State have discovered that a subtle activation of a particular subset of neurons in different regions of the brains of male and female mice can confer stress resistance, and even reverse the harmful impacts of chronic stress. These findings, reported in two studies in the journal Molecular Psychiatry, could potentially reshape our understanding of antidepressant drug efficacy and guide the development of novel drugs and therapies.
The research team devised a protocol to continuously activate neurons responsible for producing the signaling molecule somatostatin, which plays a crucial role in regulating multiple biological processes, within specific brain areas of mice. Intriguingly, when these neurons were activated in the prelimbic cortex, male mice became resilient to stress, yet this had no such effect on female mice. Conversely, activating these neurons in the ventral hippocampus made female mice stress-resistant, while leaving male mice unaffected.
“Stress is a leading factor contributing to the vulnerability of psychiatric disorders like major depressive disorder and post-traumatic stress disorder,” explained Bernhard Lüscher, a professor of biology, biochemistry, molecular biology, and psychiatry at Penn State, who led the research. “Similar to humans, stressed mice display symptoms of anxiety and anhedonia – a loss of interest in normally pleasurable activities when exposed to excessive or uncontrollable stress. Given that somatostatin-expressing neurons are known to modulate the brain’s stress response, we aimed to explore the molecular underpinnings of this phenomenon and investigate potential sex differences that could account for the known disparities in patient vulnerability.”
Somatostatin-positive neurons, a subset of GABAergic neurons, produce the neurotransmitter gamma-aminobutyric acid (GABA), often regarded as the “brakes” of the nervous system, as they slow down neural activity and prevent inappropriate neuron firing. “In a prior study, we demonstrated that experimentally removing GABA receptors from somatostatin-positive neurons – essentially enhancing their activity – had antidepressant-like behavioral effects in mice,” Lüscher noted. “In this current research, we sought to identify the specific brain regions mediating this effect.”
To achieve this, the researchers employed a technique known as “chemogenetics” to directly and selectively activate somatostatin-positive neurons in otherwise normal mice, focusing on the prelimbic cortex and hippocampus, regions known to be highly susceptible to stress. “We were astonished to find that the outcomes of our chemogenetic interventions in these two brain regions were strictly sex-dependent,” Lüscher said. “There is substantial evidence suggesting significant sex differences in human vulnerability to depression, yet current treatments are often applied uniformly to both genders, despite the fact that antidepressants seem to act broadly across the entire brain.”
In a follow-up study, the team revisited their previous mouse model, where GABA receptors had been removed from somatostatin neurons. They analyzed the complete set of genes, or transcriptome, expressed in the medial prefrontal cortex (a larger region encompassing the prelimbic cortex) of stress-resilient and non-resilient male mice. By examining gene expression in both stressed and unstressed states, they observed that gene expression changes in unstressed stress-resilient male mice closely mirrored those of stressed non-resilient male mice, and vice versa. Additionally, stressed stress-resilient mice exhibited signs of enhanced gene translation into proteins. In contrast, the prefrontal cortex of female mice did not display any gene expression changes that could explain stress resilience.
“The resemblance between gene expression in unstressed stress-resilient mice and those exposed to stress is captivating,” Lüscher commented. “It implies that certain levels of stress might induce lasting, protective alterations in the brain, somewhat analogous to exposure therapy. It will be fascinating to explore whether similar gene expression changes associated with stress resilience occur in the hippocampus of female mice.”
For those interested in further exploring related topics, a downloadable PDF copy of the research is available, and an eBook titled “NGS for Infectious Disease Surveillance,” which focuses on integrating genomics into public health for infectious disease monitoring, prevention, and mitigation using next-generation sequencing technology, can also be accessed for the latest insights in that domain.
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