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Grant Abstract: Mechanisms of Choline Mitigation of Ethanol Toxicity in Developing DNS

Grant Number: 5R21AA023343-02
PI Name: Heaton
Project Title: Mechanisms of Choline Mitigation of Ethanol Toxicity in Developing DNS

Abstract: Exposure to ethanol during the development of the central nervous system (CNS) can produce a wide array of neuroanatomical, behavioral and cognitive abnormalities, termed Fetal Alcohol Spectrum Disorder (FASD), or the more severe Fetal Alcohol Syndrome (FAS). It is estimated that nearly 1 in 100 live births worldwide exhibit at least some adverse effects of prenatal ethanol exposure. A goal of FAS/FASD research has been to elucidate the mechanisms contributing to developmental ethanol neurotoxicity, and to devise therapeutic strategies for mitigating the severity of the resultant deficits. One recent lin of research has focused on the nutrient, choline, as a therapeutic tool for ameliorating ethanol-mediated damage to the developing brain. This substance, which serves several vital biological functions, produces dramatic, long-lasting improvement in a number of behavioral and cognitive measures, following early ethanol exposure. The mechanisms underlying this amelioration have not been fully characterized, however. The proposed studies will investigate a number of possible mechanisms whereby choline may modulate ethanol neurotoxicity. The three categories of processes chosen for these analyses, i.e., apoptosis, neurotrophic factor (NTF) expression, and neurogenesis, have been shown to be critical aspects of ethanol-related neuropathology in the developing CNS, and each has been shown to be amenable to choline modulation, but their role has not been investigated in the ethanol + choline paradigm. These analyses will be made in developing prefrontal cortex and hippocampus, following prenatal or neonatal treatment, and will be related to analyses of neuron number and performance on behavioral tasks known to be sensitive to damage within these regions. These CNS regions were chosen because choline supplementation has been shown to attenuate ethanol effects on behaviors dependent on their functional integrity. We hypothesize that choline-mediated mitigation of ethanol neurotoxicity will be accompanied by: (1) alteration in the expression of apoptosis-related proteins (e.g., Bax, Bcl-2) in a manner favoring neuronal survival; (2) up-regulation of neurotrophic factors BDNF and/or NGF; and (3) attenuation of ethanol-related disruption of fetal and/or adult neurogenesis. In addition, a manipulative study using cultured cortical and hippocampal neurons will begin a determination of the role of BDNF in the protective or reparative effects of choline with respect to ethanol toxicity. These multi-faceted studies will generate important new insights concerning critical mechanisms contributing to choline's neuroprotective actions, and may suggest molecular mechanisms which should be considered in formulating future therapeutic strategies.

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