Bruce E. Hunter - US grants

The overall objective of this program of research is to investigate important questions regarding the nature of chronic ethanol neurotoxicity. The effect of chronic ethanol treatment (CET) under nutritionally-controlled conditions will be investigated in the rat using neurphysiological measures to assess synaptic function. The hippocampus will be used as a model neural system to examine the characteristics and parameters of the destructive and possible compensatory alterations produced by CET. The research plan is devided into the following categories: 1) Further characterization of alterations in synaptic function in the hippocampus in response to CET. In this series extracellular field potential recording techniques will be used to assess synaptic strength, distribution and plasticity in a number of intrinsic hippocampal afferents. 2) Investigation of the commissural fibers of the hippocampus as a potentially sensitive target site of ethanol neurotoxicity. 3) The effect of CET on functional recovery following brain damage will be assessed using physiological techniques. 4) Analysis of recurrent inhibition in different hippocampal subfields after CET. 5) Plans for the development multiple neurophysiological preparations of the hippocampus to evaluate the potential mechanisms of ethanol neurotoxicity. The information derived from this animal model will serve to characterize the matrix of changes in brain produced by prolonged ethanol exposure and will add to the growing data base from which preventative and therapeutic techniques for the treatment of human alcoholism can be developed and modified.

Chronic ethanol abuse results in brain damage and neuronal dysfunction. Studies in laboratory animals have provided convincing evidence of the specificity of ethanol in inducing this neuronal dysfunction. Nevertheless, we still know little regarding the mechanisms underlying ethanol neurotoxicity nor the morphological or functional basis of the mnemonic deficits associated with chronic ethanol abuse. A major objective of this proposal is to begin to characterize the nature and mechanisms underlying the mnemonic deficit resulting from ethanol neurotoxicity. Chronic ethanol treatment has been shown to result in significant loss of hippocampal neurons, altered dendritic structure and function of surviving neurons and loss or rearrangement of synaptic connections. Long-term potentiation is now considered to be a significant physiological mechanism whereby the hippocampus and other brain regions encode or index experimental representations and evidence indicates that chronic ethanol treatment may profoundly alter the properties of long-term potentiation in the hippocampus. A major objective of this proposal is to characterize the manner in which chronic ethanol treatment disrupts long-term potentiation in the hippocampus using extracellular and intracellular physiological recording techniques. We also propose to begin to characterize the nature of the mechanisms whereby chronic ethanol treatment disrupts long-term potentiation. A considerable amount is known regarding the induction of long-term potentiation in the hippocampus. The induction of long-term potentiation requires activation of an n-methyl-d-aspartate (NMDA) receptor complex which leads to a calcium transient localized to restricted locations in the postsynaptic membrane. This calcium transient likely leads to a specific activation of one or more calcium-sensitive enzyme systems. This molecular cascade in some way results in an increase in the strength of synaptic transmission which can last for hours to days. A major hypothesis to be investigated in this proposal is that chronic ethanol treatment disrupts long-term potentiation through a mechanism that includes alterations in one or more of the steps involved in this molecular cascade. Our studies will focus upon basic chronic ethanol actions upon glutamatesynaptic transmission, intracellular calcium regulatory processes and protein kinase activity. We will utilize electrophysiological, biochemical, autoradiographic and immunocytochemical techniques as well as studies of gene expression to characterize the manner in which chronic ethanol treatment disrupts the induction of long-term potentiation. In view of corollary evidence indicating a role for glutamate synapses and intracellular calcium regulation in excitotoxicity in a variety of disease states, the results of our studies may also have more global implications for the mechanisms whereby ethanol produces neuronal toxicity and dysfunction.

Chronic ethanol abuse results in brain damage and neuronal dysfunction. Studies in laboratory animals have provided convincing evidence of the specificity of ethanol in inducing this neuronal dysfunction. Nevertheless, we still know little regarding the mechanisms underlying ethanol neurotoxicity nor the morphological or functional basis of the mnemonic deficits associated with chronic ethanol abuse. A major objective of this proposal is to begin to characterize the nature and mechanisms underlying the mnemonic deficit resulting from ethanol neurotoxicity. Chronic ethanol treatment has been shown to result in significant loss of hippocampal neurons, altered dendritic structure and function of surviving neurons and loss or rearrangement of synaptic connections. Long-term potentiation is now considered to be a significant physiological mechanism whereby the hippocampus and other brain regions encode or index experimental representations and evidence indicates that chronic ethanol treatment may profoundly alter the properties of long-term potentiation in the hippocampus. A major objective of this proposal is to characterize the manner in which chronic ethanol treatment disrupts long-term potentiation in the hippocampus using extracellular and intracellular physiological recording techniques. We also propose to begin to characterize the nature of the mechanisms whereby chronic ethanol treatment disrupts long-term potentiation. A considerable amount is known regarding the induction of long-term potentiation in the hippocampus. The induction of long-term potentiation requires activation of an n-methyl-d-aspartate (NMDA) receptor complex which leads to a calcium transient localized to restricted locations in the postsynaptic membrane. This calcium transient likely leads to a specific activation of one or more calcium-sensitive enzyme systems. This molecular cascade in some way results in an increase in the strength of synaptic transmission which can last for hours to days. A major hypothesis to be investigated in this proposal is that chronic ethanol treatment disrupts long-term potentiation through a mechanism that includes alterations in one or more of the steps involved in this molecular cascade. Our studies will focus upon basic chronic ethanol actions upon glutamatesynaptic transmission, intracellular calcium regulatory processes and protein kinase activity. We will utilize electrophysiological, biochemical, autoradiographic and immunocytochemical techniques as well as studies of gene expression to characterize the manner in which chronic ethanol treatment disrupts the induction of long-term potentiation. In view of corollary evidence indicating a role for glutamate synapses and intracellular calcium regulation in excitotoxicity in a variety of disease states, the results of our studies may also have more global implications for the mechanisms whereby ethanol produces neuronal toxicity and dysfunction.