Sexually dimorphic development of cognitive inflexibility following early life stress: the role of parvalbumin and the orbitofrontal cortex

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PROJECT SUMMARY Childhood trauma and neglect influence emotional development and increase the risk for and severity of affective pathology. Women have a heightened susceptibility to the effects of early life stress (ELS) and are twice as likely than men to develop stress-associated pathology, such as depression. Depressive pathology is highly comorbid with cognitive impairments and inflexibility, resulting predominantly from frontal lobe dysfunction. However, it is largely unknown how ELS affects cognitive function in males versus females, and if stress-induced cognitive deficits are supported at a cellular level. In the proposed study, a combination of cutting-edge behavioral, molecular and optogenetic techniques will be used to begin to test a possible mechanism of female vulnerability to ELS and stress-induced cognitive dysfunction. GABAergic interneurons containing the calcium binding protein parvalbumin (PV) are thought to facilitate cognitive function in the PFC and are significantly affected by stress. Thus, I propose a strategy to determine the role of PV cells in the sexually dimorphic development of stress-associated cognitive deficits. I aim to 1) test the influence of ELS on cognitive flexibility in adult male and female mice in an attentional set-shifting task; 2) test the effects of ELS on PV interneuron maturity and density in the orbitofrontal cortex (OFC); and, 3) determine the functional contribution of orbitofrontal PV interneurons to different facets of cognitive flexibility, including set shifting and reversal learning. Based on preliminary data, I hypothesize that female mice exposed to ELS will be more severely impaired than males in the rule-reversal phase of a cognitive flexibility task, and that these impairments will be correlated with altered expression of PV- interneurons in the orbitofrontal cortex. To assess PV cell maturity and density in the OFC of male and female mice exposed to ELS, I will use immunohistochemistry for PV cell counts and RT qPCR for PV and GAD67 mRNA analysis. Further, I propose that PV-interneurons in the OFC specifically mediate rule-reversal learning, and not other aspects of cognitive flexibility, including set shifting or initial rule learning. In awake, behaving animals I will use optogenetics to inhibit PV cells in the OFC throughout the rule reversal or rule shift phases of the attentional set-shifting task. In accordance with preliminary data, I hypothesize that this manipulation will lead to selective impairments in rule-reversal learning but not rule shifting, phenocopying impairments observed in ELS-exposed females. This work will address sexual dimorphism that exists in the development of affective pathology, which is a relevant and largely overlooked public health concern. It will lay the foundation for predictions regarding risk factors and biomarkers that underlie sex differences in vulnerability to stress and associated cognitive impairments linked with depression.