Two major risk factors for neurodevelopmental disorders are early life inflammation and biological sex. We have discovered a sex difference in the neuroimmune environment that may contribute to sex differences in vulnerability to neuropsychiatric disorders following inflammation: Males have significantly more brain mast cells than females during the early postnatal period. Mast cells are innate immune cells associated with peripheral allergy, but thousands of mast cells populate the healthy rat brain and synthesize serotonin, histamine, and inflammatory cytokines that have known roles in neurodevelopmental disorders. Our data shows that stimulating brain mast cell degranulation in neonatal male rats produces decreased social play behavior in adolescence analogous to those produced by immune challenge. Such disrupted play behavior is consistent with social behavior deficits in autism and is a sexually differentiated behavior. We hypothesize that sex differences in mast cells and their signaling regulate the development of the brain regions mediating social behavior and resultant male vulnerability to disruptions in social behavior. In this proposal, we aim to integrate mast cells into an overarching picture of how perinatal immune activation programs brain development and social behavior. To do so, we will 1) determine which brain regions in the social behavior circuit are activated by neonatal inflammation- induced mast cell degranulation; 2) determine whether serotonin, histamine and cytokine levels are increased in the brain following mast cell activation and 3) determine whether autistic-like deficits on social behavior assays normally induced by inflammatory challenge can be prevented by inhibiting mast cell degranulation.
Many neuropsychiatric disorders have developmental origins. Perinatal infection/inflammation and being male both increase risk for autism by 2-4 fold. We seek to fill a fundamental gap in knowledge of how immune cells and their signaling in the brain interact with biological sex to produce sex differences in brain in behavior, to ultimately gain insight into what renders males vulnerable to certain neurodevelopmental disorders and/or renders females resilient and discover novel treatment strategies for neuropsychiatric disorders.
