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Grant Abstract: 1/8 NADIA U01 Effects of Adolescent Alcohol Exposure on Hippocampal Function in Adulthood

Grant Number: 3U01AA019925-12S1
PI Name: Swartzwelder
Project Title: 1/8 NADIA U01 Effects of Adolescent Alcohol Exposure on Hippocampal Function in Adulthood

Abstract: Adolescence is critical for cognitive, affective, social, and neurological maturation. Repeated alcohol exposure during adolescence produces brain and behavioral deficits that persist into adulthood and possibly throughout the lifespan. We have reported enduring effects of adolescent intermittent ethanol (AIE) exposure on hippocampal structure and function and the behaviors they regulate, such as memory and anxiety, and that many of these AIE effects can be ameliorated by the anticholinesterase drug, donepezil (Aricept). This cholinergic mediation of AIE effects lead us to hypothesize that dietary choline supplementation during AIE could prevent or ameliorate the long-term effects of AIE on brain and behavior. We have shown that early dietary choline supplementation enhances memory-related hippocampal function and is neuroprotective for hippocampal cells. Importantly, recent studies indicate that both perinatal and adolescent choline supplementation reduce the severity of neural and behavioral deficits associated with perinatal alcohol exposure. Adolescent choline supplementation (ACS), specifically, has been shown to reverse memory deficits induced by perinatal ethanol exposure and to diminish anxiety-like behavior in adult rats (which is elevated by AIE and driven, in part, by hippocampal circuits), and has also been shown to alter gene promoter methylation in the hippocampus. Moreover, dietary choline supplementation has been shown to ameliorate memory deficits in children with fetal alcohol spectrum disorder (FASD), underscoring the safety of choline supplementation in humans. Thus, we hypothesize that dietary choline supplementation during adolescence will prevent or ameliorate AIE-induced memory deficits, loss of Ch1-2 cholinergic neurons, hippocampal neuroinflammatory markers, and dysregulation of neurogenesis and cell death cascades. Specific Aim 1 will test the hypothesis that dietary ACS will prevent AIE-induced memory deficits in adulthood. Male and female rats will receive either ACS or a matched control diet during AIE exposure. Later, in adulthood, spatial and temporal object recognition (stOR) memory will be tested as in our previous studies. Specific Aim 2 will test the hypothesis that ACS will prevent the AIE-induced reduction of ChAT immunoreactive cells in the upstream hippocampal projection areas, Ch1-2, which we have previously reported. One week after stOR testing Under Aim 1, animals will be sacrificed, and brains prepared for immunohistochemical (IHC) quantification of ChATpositive immunoreactive neurons in Ch1-2. Specific Aim 3 will test the hypothesis that ACS will prevent the AIEinduced promotion of neuroinflammatory and cell death marker activity, and decrease of neurogenesis marker activity, in the hippocampus that we have reported previously. Hippocampi from the brains of animals in Aim 1 will undergo IHC analysis and quantification of the receptor for advanced glycation end-products (RAGE - neuroinflammation), doublecortin (neurogenesis), and caspase-3 (cell death) immunoreactivity in the hippocampal formation. These studies will have translational, mechanistic, and public health significance.

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