Investigator: Kevin Bath, Brown University
Scientific Theme: Neuroscience
Abstract: Here, we will use a mouse model of early life stress (ELS) to test a potential mechanism of increased female risk for early life stress-induced cognitive dysfunction. Poverty, displacement, and parental stress, represent some of the most common and potent sources of stress for young children. 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. Females are at particularly high risk for stress-related pathology, and twice as likely as males to develop depression or PTSD, conditions that are highly comorbid with cognitive impairments and inflexibility. The goal of this proposal is to provide novel insight into the mechanisms by which impaired early life care contributes to elevated risk for pathological development in females, using a mouse model of restricted access to maternal caregiving resources.
We will test the novel hypothesis that ELS drives altered development of parvalbumin-positive cells in orbitofrontal cortex (OFC) of female but not male mice, an effect that underlies stress-associated risk for cognitive disturbance in females. In Aim 1, we will use an attentional set shifting paradigm to assess cognitive functioning following ELS in male and female mice and test for potential developmental mechanisms driving this sex disparity in risk, focusing on the development of parvalbumin-positive interneurons. Parvalbumin (PV) interneurons have been heavily implicated as critical for cognitive control, and are significantly affected by stress. In Aim 2 we will test the hypothesis that inhibiting activity of PV- interneurons in OFC phenocopies key cognitive deficits observed in ELS female mice.
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. Data collected here will serve as key pilot data for a more extensive NIH RO1 application in which we will expand upon and extend this line of work to identify potential factors altering the development and survival of PV interneurons in male and female brain.
Human Health Relevance: This work supports a critical goal of the field to understand sex disparities in risk for pathology as well as the development of translational models to probe the mechanism driving sex differences in risk that exist in humans. These studies have the potential to identify specific mechanisms underlying female stress vulnerability and heightened risk for cognitive impairments comorbid with affective pathology. This work will also inform the basic biology relevant to the effects of ELS on PV interneuron development, as well as the role of these cells in specific attentional and cognitive operations.