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 trophic interactions during neurogenesis. We propose that chronic prenatal ethanol treatment (CPET) results in a decrease in the synthesis, availability, delivery, or biological activity of normally occurring neurotrophic substances, such as nerve growth factor (NGF), or may alter the capacity of target neurons to respond appropriately to these factors. These developing relationships will be studied in the fetal and neonatal rat septo-hippocampal system. This system was chosen because its importance to normal cognitive functioning makes it likely to be involved in the severe intellectual impairment seen in FAS. Prior study has shown that the septal nuclei and their target hippocampus are selectively vulnerable to ethanol insult following adult chronic ethanol treatment (CET) in both humans and animal models. The hippocampus is similarly vulnerable to ethanol during development, and there is some limited evidence indicating that the basal forebrain nuclei are also damaged following CPET. The hippocampus synthesizes NGF, basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF) and certain uncharacterized substances which provide normal trophic support for basal forebrain neurons. Initial experiments will examine developing basal forebrain neurons (of medial septal/vertical diagonal band of Broca nuclei [MS/VDB]) in control and CPET animals. Total population numbers will be compared, as will the number of cholinergic, GABAergic, and NGF-- receptor-positive neurons. In addition, autoradiographic studies will compare neuronal generation in MS/VDB in control and CPET groups. We will also examine the influence of CPET on the development of trophic activity in the hippocampal formation. In our prior studies in adult animals, we found that CET reduces trophic activity produced in the hippocampus. We will measure trophic activity of hippocampal extract from control and ethanol-exposed animals using both bioassays and ELISA quantifications (assessing NGF and bFGF content). We will also examine the influence of CPET on the capacity of septal and hippocampal neurons to respond normally to trophic factors (e.g., NGF, bFGF, hippocampal extract), and we will assess direct ethanol effects on cultured septal and hippocampal neurons, and septalhippocampal co-cultured explants, and the capacity of neurotrophic factors to ameliorate these effects. We will also investigate the ontogeny of cholinergic expression within the basal forebrain populations, in control and CPET animals. ChAT activity, high affinity choline uptake and ACh synthesis will be examined in vivo and in vitro. These studies have the potential to elucidate important cellular mechanisms underlying the devastating CNS damage seen in FAS, and could open the eventual possibility of therapeutic intervention in FAS mental retardation via neurotrophic factor replacement procedures.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA009128-02
Application #
3113253
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1992-08-01
Project End
1996-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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; 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
Heaton, M B; Mitchell, J J; Paiva, M (2000) Overexpression of NGF ameliorates ethanol neurotoxicity in the developing cerebellum. J Neurobiol 45:95-104

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