The objective of the proposed research Is to make novel discoveries regarding the functional and structural central nervous system (CNS) pathology that results from eariy prenatal alcohol exposure (PAE). Extending our previous research illustrating exposure stage-dependent patterns of brain dysmorphology in fetal mice, we propose to examine 3 distinct, but interrelated forebrain circuits that are expected to play key roles in the behavioral or functional manifestations of alcohol neuroteratogenesis in the postnatal animal. The proposed studies will utilize a well-established FASD mouse model, with acute, as well as dietary maternal alcohol administration at times equivalent to 3-6 weeks of human gestation. Innovative technologies and approaches will be employed to address 3 Aims.
Aim 1 is designed to test the hypothesis that eariy PAE induces hippocampal pathology (esp. altered hippocampal volume and related fiber tract Integrity and circuitry) and deficiencies in the performance of hippocampus-mediated learning and memory tasks in adult mice. For this work, high-resolution ex vivo diffusion tensor imaging will be utilized to define structural deficiencies associated with PAE, while a behavioral test battery will be used to probe hippocampal-dependent learning and memory.
Aim 2 is designed to test the hypothesis that early PAE causes defects in medial hypothalamic and pituitary circuitry as well as altered HPA axis regulation in adulthood. For this, immunohlstochemistry and in situ hybridization will be employed to characterize hypothalamic and pituitary pathology in fetal mice. HPA axis function will be examined in adults by measurement of adrenocorticotropic hormone and corticosterone plasma levels both prior and subsequent to an acute alcohol challenge or an acute restraint stress.
Aim 3 is designed to test the hypothesis that eariy PAE results in deficient inhibitory GABAergic circuitry in corticostriatal circuits underiying reward perception and alcohol intake. For this, intracranial self-stimulation (ICSS), intermittent access drinking, and designbased stereology will be employed. Overall, the proposed work is in keeping with the binge alcohol pathology/neurocircuitry-directed central goal of the Alcohol Research Center (ARC) and will profit from ARC support and interaction. The results of the proposed studies promise to fill a significant FASD research void, inform human clinical research, and continue to highlight the first trimester as a critical period for alcoholinduced CNS defects.
Structural and functional neurological defects are major components of Fetal Alcohol Spectrum Disorder (FASD) and remain a major public health problem. With exploration of forebrain pathology, learning and memory deficits, drug reward perception and HPA axis alterations, the proposed basic research promises to provide important new, clinically-relevant FASD data.
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