Targeted inhibition of stress associated pathways to promote resilience against maternal immune activation

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Clinical evidence suggests that exposure to maternal immune activation (MIA) during the prenatal period (e.g., having the flu during pregnancy) increases the susceptibility for neurodevelopmental disorders such as schizophrenia and autism spectrum disorder. These disorders are associated with the manifestation of a heterogeneous set of symptoms, including social impairments, which emerge in later life. The mechanistic underpinnings of these social disruptions and how they interact with the environment are not well understood but are a likely path for identifying factors contributing to resilience vs susceptibility against challenges to mental health functioning. Using an animal model, we aim to determine how this adverse early health experience alters the development of brain circuitry in males and females, to find preventative interventions and treatments. Our recent work shows that MIA causes an overexpression of the stress sensitive gene corticotropin releasing factor (Crh), and its associated receptor Crhr1, in areas of the brain central to social behavior and cognition. Housing pregnant dams in environmental enrichment (a translationally relevant intervention) protects the fetus by maintaining the placental 11-beta hydroxysteroid dehydrogenase (11HSD)1 and 11HSD2 metabolism of maternal corticosterone at the time of prenatal immune challenge; this housing condition also protects against Crh and Crhr1 overexpression and related social impairments associated with MIA. To confirm that excessive levels of maternal plasma corticosterone are responsible for the later life overexpression of stress sensitive genes and social impairments (Aim 1), we will employ a clinically available inhibitor of cytochrome P450 11B1, mitochondrial (11β-hydroxylase), the enzyme that catalyzes the final step of cortisol synthesis in the adrenal cortex. We will use this inhibitor to attenuate the endocrine activation associated with MIA to test if this prevents these MIA-induced neural and social changes. Relatedly, we will explore protection against MIA-associated changes in Crhr1 signaling mechanisms and epigenetic machinery. In Aim 2, we will use a Crhr1 antagonist to determine if this pharmacological intervention can prevent and/or reverse the effects of MIA on social behaviors. Finally, using viral tools, we will begin studies to evaluate whether targeted deletion of Crhr1 can prevent the social consequences of MIA, and if overexpression can in turn counteract the protective effects of environmental enrichment housing. Together, these studies will help identify and confirm mechanisms by which clinically utilized environmental manipulations, such as enrichment, offer protection to the developing brain.