Mechanisms driving sex differences in cognitive outcomes following early life stress

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ABSTRACT' ! In the U.S. 16 million children live at or below the poverty line, with as many as 2.5 million children that are homeless during a given year, and over 700,000 confirmed cases of abuse and/or neglect. Poverty, displacement, and parental stress, represent some of the most common and potent sources of stress for young children. Females are at particularly high risk for stress-related pathology, and twice as likely as men to develop depression or PTSD, conditions that are highly comorbid with cognitive impairments and inflexibility. The goal of this proposal is to use a mouse model of early life stress (ELS) to identify mechanism underlying sex differences in risk for early life stress-induced cognitive dysfunction. We will test the novel hypothesis that ELS drives altered development of parvalbumin-positive interneurons in orbitofrontal cortex (OFC) of female but not male mice, an effect that underlies stress-associated deficits in rule-reversal learning females. In AIM 1, we will determine the effects of stress interneuron development in OFC and two control regions. Select cortical populations of Parvalbumin (PV) interneurons have been heavily implicated in cognitive control, and are significantly affected by stress. In AIM 2 we will test the hypothesis that inhibiting activity of PV-interneurons in OFC will phenocopy cognitive deficits observed in female mice reared under ELS conditions. In AIM 3, we will test the impact of ELS on physiology of PV-positive interneurons in OFC of control and ELS reared male and female mice to determine if ELS alters the functional development or integration of these cells into the OFC. Through the lens of ELS, the broad intellectual significance of this work is in its promise for informing the mechanisms driving sex differences in risk for pathology and the impact of the environment on brain and behavioral development. The questions addressed here are relevant to a broad scientific audience and also have immediate impact on the development of translational programming aimed at identifying factors mediating risk and resilience in children and animals exposed to early adversity.