Pathologies of the cerebellum are leading contributors to social, communicative, cognitive and affective deficits associated with neuropsychiatric disorders with origins in development. These include autism spectrum disorders, attention deficit and hyperactivity and early onset schizophrenia. Neuroinflammation early in life is a leading environmental risk for these disorders and being male is a leading biological predictor. Using the laboratory rat we have identified a previously unknown sensitive period in cerebellar development that involves an intrinsic gene expression profile that creates a vulnerability to dysregulation by inflammation. Specifically, in the healthy cerebellum the prostaglandin PGE2 stimulates the aromatase enzyme leading to increased estradiol production and regulation of the growth of Purkinje neurons. The 2nd postnatal week is a sensitive period and perturbation of this pathway during that time impairs Purkinje neuron development and results in long-term behavioral deficits revealed by assays of social play, cognition and somatosensory thresholds. For reasons that are not understood, behavioral deficits are greater in males. The sensitive period is defined by a peak in expression of both the gene coding for aromatase (Cyp19a) and the estrogen receptor (Esr1) during the 2nd postnatal week. Microglia are the brains innate immune cells and we also find that ?semi-activated? microglia peak during the 2nd postnatal week in the healthy cerebellum. Microglia both respond to and produce PGE2, creating a positive feedback loop. Initial findings suggest that an inflammatory insult during the sensitive period induces enduring inflammation that is detectable until at least late adolescence, leading to our overarching hypothesis: Inflammation during the sensitive period generates enduring inflammation that is mediated by over active microglia and alters the developmental trajectory of the cerebellum. Pilot data suggests enduring inflammation is more severe in males. Therefore we further hypothesize that behavioral changes in males are secondary to enduring inflammation. We will test these hypotheses in SA1 with a comprehensive characterization of enduring inflammation in both sexes. In SA2 we determine the role of microglia in both establishing and maintaining enduring inflammation. SA3 explores the epigenetic underpinnings of enduring inflammation at the candidate gene level and the genome-wide methylome of microglia.
The final aim, SA4, determines whether the greater vulnerability of males is encoded by earlier hormonally-mediated sexual differentiation of the brain. Therapeutic interventions that either stop the establishment of or reverse the maintenance of enduring inflammation are explored in multiple aims and offer a clear path towards future translation to humans.
Cerebellar abnormalities are strongly associated with neuropsychiatric disorders with developmental origins. Neuroinflammation is equally strongly associated with these same disorders. We have identified a sensitive period in cerebellar development during which an acute insult establishes enduring inflammation leading to changes in social and cognitive behaviors in adolescent animals. We now seek to understand the causes of the enduring inflammation and explore therapeutic treatments to prevent or reverse it. We further seek to understand why the deleterious consequences we observe are more severe in males.
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