The proposed research will investigate the hypothesis that an important mechanism leading to certain of the CNS anomalies seen in the fetal alcohol syndrome (FAS) is a disruption of normal neurotrophic interactions during neurogenesis. We propose that chronic prenatal or early postnatal ethanol treatment results in alterations in the synthesis, availability, delivery, and/or biological activity of normally occurring neutrophic factors, or may alter the capacity of neurons to respond appropriately to these factors. In addition, we hypothesize that cell death effector or repressor genes may modulate ethanol neurotoxicity during development, and that early ethanol exposure may affect this gene expression. These relationships will be studied in the fetal and neonatal rat and mouse septohippocampal system. This system was chosen because its importance to normal cognitive functioning makes it likely that disruptions in its development may be associated with the severe intellectual impairment seen in FAS. Experiments will examine the following: The influence of early postnatal ethanol treatment (PNET) on cholinergic, GABAergic, and neurotrophic factor receptor-positive basal forebrain neurons (of the medial septal/vertical diagonal band of Broca nuclei); the influence of PNET on neurotrophic factor (NTF) biological activity in the hippocampus (HC); the effect of chronic prenatal ethanol treatment (CPET) and PNET on NTF and NTF receptor gene expression in HC and septum, using quantitative Northern blot analyses of NTF and NTF receptor mRNAs and ELISA analyses of protein content; the influence of CPET on neuronal survival in NTF gene-deleted animals; the potential of overexpression of the bcl-2 anti-apoptosis gene to ameliorate ethanol neurotoxicity in vivo; the relative vulnerability of septohippocampal neurons from bcl-2 gene-deleted animals to ethanol neurotoxicity; and the influence of CPET and PNET on calcium homeostasis in septal and HC neurons, and on NTF stabilization of calcium homeostasis. In addition we will extend our tissue culture model system for ethanol neurotoxicity to include additional concomitants of in vivo ethanol exposure (e.g., hypoxia, hypoglycemia). These studies have the potential to elucidate important cellular mechanisms underlying the devastating CNS damage seen in FAS, and could eventually lead to therapeutic intervention in FAS mental retardation via neurotrophic factor replacement procedures.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Special Emphasis Panel (ZRG4-ALTX-3)
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University of Florida
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Moore, D Blaine; Madorsky, Irina; Paiva, Michael et al. (2004) Ethanol exposure alters neurotrophin receptor expression in the rat central nervous system: Effects of neonatal exposure. J Neurobiol 60:114-26
Moore, D Blaine; Madorsky, Irina; Paiva, Michael et al. (2004) Ethanol exposure alters neurotrophin receptor expression in the rat central nervous system: Effects of prenatal exposure. J Neurobiol 60:101-13
Heaton, Marieta Barrow; Paiva, Michael; Madorsky, Irina et al. (2003) Effects of ethanol on neurotrophic factors, apoptosis-related proteins, endogenous antioxidants, and reactive oxygen species in neonatal striatum: relationship to periods of vulnerability. Brain Res Dev Brain Res 140:237-52
Heaton, Marieta Barrow; Moore, D Blaine; Paiva, Michael et al. (2003) The role of neurotrophic factors, apoptosis-related proteins, and endogenous antioxidants in the differential temporal vulnerability of neonatal cerebellum to ethanol. Alcohol Clin Exp Res 27:657-69
Heaton, Marieta Barrow; Paiva, Michael; Madorsky, Irina et al. (2003) Ethanol effects on neonatal rat cortex: comparative analyses of neurotrophic factors, apoptosis-related proteins, and oxidative processes during vulnerable and resistant periods. Brain Res Dev Brain Res 145:249-62
Webb, Barbara; Walker, Don W; Heaton, Marieta B (2003) Nerve growth factor and chronic ethanol treatment alter calcium homeostasis in developing rat septal neurons. Brain Res Dev Brain Res 143:57-71
Heaton, Marieta Barrow; Madorsky, Irina; Paiva, Michael et al. (2002) Influence of ethanol on neonatal cerebellum of BDNF gene-deleted animals: analyses of effects on Purkinje cells, apoptosis-related proteins, and endogenous antioxidants. J Neurobiol 51:160-76
Heaton, Marieta Barrow; Paiva, Michael; Mayer, Joanne et al. (2002) Ethanol-mediated generation of reactive oxygen species in developing rat cerebellum. Neurosci Lett 334:83-6
Heaton, M B; Kim, D S; Paiva, M (2000) Neurotrophic factor protection against ethanol toxicity in rat cerebellar granule cell cultures requires phosphatidylinositol 3-kinase activation. Neurosci Lett 291:121-5
Heaton, M B; Mitchell, J J; Paiva, M (2000) Amelioration of ethanol-induced neurotoxicity in the neonatal rat central nervous system by antioxidant therapy. Alcohol Clin Exp Res 24:512-8

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