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.

Public Health Relevance

Females are at a heightened risk for developing stress-related pathologies such as depression; however, a sex-specific mechanism for stress vulnerability has not been defined. This work will drive the field to be more inclusive of both sexes, particularly in the investigation of stress and the development of affective pathologies and associated cognitive deficits, where significant sex differences exist in humans. This study will provide a critical foundation to make predictions regarding risk factors and biomarkers underlying sex differences in vulnerability to the development of stress-induced cognitive impairments linked with affective pathology.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Van'T Veer, Ashlee V
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Brown University
Schools of Medicine
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Goodwill, Haley L; Manzano-Nieves, Gabriela; Gallo, Meghan et al. (2018) Early life stress leads to sex differences in development of depressive-like outcomes in a mouse model. Neuropsychopharmacology :
Goodwill, Haley L; Manzano-Nieves, Gabriela; LaChance, Patrick et al. (2018) Early Life Stress Drives Sex-Selective Impairment in Reversal Learning by Affecting Parvalbumin Interneurons in Orbitofrontal Cortex of Mice. Cell Rep 25:2299-2307.e4