Chronic alcohol abuse leads to multiple behavioral changes and to irreversible memory loss. Recent data in rats show that ethanol-induced behavioral deficits can be ameliorated by transplantation of fetal, choline-rich tissue. These data imply that the projection from the basal forebrain to cerebral cortex is a specific target of ethanol. This projection system is one of the few to express nerve growth factor (NGF). Both NGF and acetylcholine are essential for maintaining neuronal plasticity. We hypothesize that the ethanol-induced memory loss results from losses in neuronal plasticity. This proposal describes studies which explore the structural consequences of ethanol exposure on the cholinergic system and the trophic support of basal forebrain neurons. Six experiments will be executed. (1) The effect of ethanol on the number of neurons in the basal forebrain and in the barrels of somatosensory cortex (segments which receive input from the mystacial vibrissae) will be determined using rigorous morphometric analyses. The number of neurons expressing choline acetyltrans-ferase (ChAT)[the enzyme which facilitates the synthesis of acetylcholine], acetyl-cholinesterase (AChE) [the enzyme which catalyzes the degradation of acetylcholine], and gamma-aminobutyric acid (GABA) will be determined. By using ChAT, AChE and GABA as markers for cholinergic and non-cholinergic neurons, respectively, we will be able to determine the specificity of the effects of ethanol. (2) The specificity of ethanol will further be examined by studying the effects of varying the duration of the exposure to ethanol. Are cholinergic or GABAergic neurons affected first? Does the nervous system compensate for these defects over time? If so, how? (3) The effects of ethanol on NGF and NGF receptors will be examined immunohistochemically. We will also examine the effects of ethanol on the transcription of mRNA for NGF and NGF receptors using in situ hybridization. (4) In a subsequent study, we will study the co-localization of NGF receptors in ChAT-immunoreactive neurons in the basal forebrain. (5) We will test the hypothesis that ethanol- induced changes in the cholinergic system lead to losses or impairments in neuronal plasticity. These studies will examine the effect of ethanol on the response of thalamocortical projections to peripheral damage to the vibrissae. (6) Two ways to remedy the effects of ethanol toxicity will be examined. In one study, fetal basal forebrain tissue will be transplanted into cortex, and in another, NGF will be administered. Following these manipulations, we will use the bioassays described above (tests for the specificity of the ethanol toxicity, the role of the NGF system, and the response of the nervous system to injury) to assess the success of the manipulation. Taken together, the proposed program outlines a unified battery of experiments which not only determine a mechanism of ethanol toxicity produced by chronic exposure, but also explore 2 ways in which ethanol- induced defects can be overcome.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA009611-01A2
Application #
2045871
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1995-05-01
Project End
2000-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Iowa
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Miller, Michael W (2003) Expression of transforming growth factor-beta in developing rat cerebral cortex: effects of prenatal exposure to ethanol. J Comp Neurol 460:410-24
Mooney, S M; Miller, M W (2001) Effects of prenatal exposure to ethanol on the expression of bcl-2, bax and caspase 3 in the developing rat cerebral cortex and thalamus. Brain Res 911:71-81
Jacobs, J S; Miller, M W (2001) Proliferation and death of cultured fetal neocortical neurons: effects of ethanol on the dynamics of cell growth. J Neurocytol 30:391-401
Luo, J; Miller, M W (2000) Ethanol enhances erbB-mediated migration of human breast cancer cells in culture. Breast Cancer Res Treat 63:61-9
Mooney, S M; Miller, M W (2000) Expression of bcl-2, bax, and caspase-3 in the brain of the developing rat. Brain Res Dev Brain Res 123:103-17
Miller, M W (2000) Expression of nerve growth factor and its receptors in the somatosensory-motor cortex of Macaca nemestrina. J Neurocytol 29:453-69
Miller, M W; Pitts, F A (2000) Neurotrophin receptors in the somatosensory cortex of the mature rat: co-localization of p75, trk, isoforms and c-neu. Brain Res 852:355-66
Miller, M W (1999) A longitudinal study of the effects of prenatal ethanol exposure on neuronal acquisition and death in the principal sensory nucleus of the trigeminal nerve: interaction with changes induced by transection of the infraorbital nerve. J Neurocytol 28:999-1015
Luo, J; Miller, M W (1999) Platelet-derived growth factor-mediated signal transduction underlying astrocyte proliferation: site of ethanol action. J Neurosci 19:10014-25
Mooney, S M; Miller, M W (1999) Effects of prenatal exposure to ethanol on systems matching: the number of neurons in the ventrobasal thalamic nucleus of the mature rat. Brain Res Dev Brain Res 117:121-5

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