Women are at increased risk to develop a stress-related psychopathology, including depression and anxiety. Unfortunately, the molecular mechanisms underlying this sex-specific vulnerability to stress remain unclear. The prefrontal cortex (PFC) is particularly sensitive to stress. Rodent-based research indicates that changes in prefrontal activity during exposure to chronic stress could underlie individual susceptibility to dysregulated emotional behaviors in male populations. However, this idea was never tested in females, and the molecular regulators to these stress-induced changes in prefrontal activity are yet to be identified. This information would not only advance the basic stress field, but could also have broad implications for treating stress-related mood disorders. Here, we will use interactions between sex-specific vulnerabilities and chronic stress paradigms to characterize a novel molecular mechanism underlying vulnerability to stress-induced dysregulation in emotional behaviors. Specifically, we will test the overall hypothesis that sex-specific plasticity of the prefrontal parvalbumin (PV) system determines the extent to which chronic stress leads to aberrant emotional behaviors in a sex- specific manner. Our recent work showed that 4-weeks of unpredictable chronic mild stress (UCMS) increases anxiety-like behaviors and PV interneurons (PV-I) activity in the PFC of female, but not male, mice. These findings suggest that chronic stress-induced changes in the prefrontal PV system could determine sex-specific stress-induced emotional dysregulation. It also suggests that females have a more sensitive prefrontal PV system, which could directly modulate their heightened vulnerability to stress-induced emotional disturbances. In this proposal, we will aim at testing these two ideas. First, we will use naturalistic interactions between sex and two different UCMS protocols that vary in length to verify that plasticity of prefrontal PV-I in response to stress correlates with the susceptibility of mice to display dysregulated emotional behaviors. Exposure to a short period (4 weeks) of UCMS has been reported to induce anxiety-like behaviors in female mice but not males, while a longer exposure (8 weeks) is necessary to induce a similar anxious phenotype in males. Molecular and ex vivo electrophysiology approaches will be used to correlate stress-induced changes in prefrontal PV-I activity with changes in emotional behaviors after exposure to UCMS. We will then use a chemogenetics approach (Designer Receptors Exclusively Activated by Designer Drugs ? DREADD) to decrease or increase the activity of prefrontal PV-I during exposure to UCMS, and demonstrate a causal relationship between the level of activity of PV-I during stress and the development of stress-induced emotional dysregulations. At completion of these experiments, we will have provided evidence that the plasticity of the prefrontal PV system during stress is a major mechanism underlying vulnerability to stress-related mood disorders, and that its increased sensitivity to stress in females drives their heightened vulnerability to emotional dysregulations after stress. We will have highlighted a novel key mechanism underlying vulnerability to stress- induced emotional dysregulation that could be used as a potential therapeutic target to treat these psychopathologies.
The proposed research is highly significant to public health, as it will provide novel insight into the mechanisms by which stress leads to dysregulation of emotional behaviors in susceptible individuals. This information will help with the diagnosis and prevention of stress-related mood disorders, and altogether can contribute to the development of personalized approaches for the treatment of mood disorders, including depression and anxiety. This proposal is well suited to elucidate neurobiological mechanisms relevant to specific RDoC domains and constructs as defined by the NIMH, including negative and positive valence systems.
