Cortical and Cognitive Development Following Synthetic Progestin Exposure

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The administration of synthetic progestins to pregnant women for the prevention of premature delivery has increased dramatically in recent years. Despite this increase, very little is known about the potential effects of synthetic progestins on the developing brain. Previous findings from rodent models suggest that progestins may play a role in the development of frontal cortex and the mesocortical dopamine system, a neurochemical pathway implicated in Attention Deficit Hyperactivity Disorder (ADHD). The objective of this proposal is to examine the effects of exposure to the synthetic progestin, 17α hydroxyprogesterone caproate in the development of the mesocortical dopamine pathway, the mesocortical serotonin pathway, and subsequent complex cognitive behaviors mediated by these circuits using a rodent model. Aim 1 will utilize HPLC/Mass Spec to quantify 17P levels in blood and brain following the administration of behaviorally-effective doses. Aim 2 will test the hypothesis that exposure to 17P during development will alter the number of dopaminergic cells in the midbrain ventral tegmental area, the number of serotonergic cells in the raphe nuclei, and will alter the density of dopaminergic and serotonergic fibers within the medial prefrontal and orbitofrontal cortex. Aim 3 will test the hypothesis that exposure to 17P during postnatal life will alter cognitive and executive function behaviors mediated by these pathways. Specifically, cognitive flexibility, attentional processing and sensorimotor gating, behavioral inhibition/impulsivity, impulsive decision making, hyperactivity, and risk taking behavior will be assessed in adolescence and adulthood in rats exposed to 17P during development. Results from these animal studies would vastly increase our knowledge about the potential effects of progestin exposure to generate specific hypotheses for future research regarding outcomes in children exposed in utero.