Sex Differences and Alcohol Dependence: Hippocampal Neurochemistry and Function

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DESCRIPTION (provided by applicant): In vivo magnetic resonance spectroscopy (MRS) has been used to examine alterations in cellular health, integrity and metabolism across a variety of alcoholic populations, although almost no MRS studies have included sufficient numbers of women to examine sex differences in the impact of alcohol on cerebral metabolites. This novel proposal aims to compare GABA and glutamate metabolite levels in a region of the medial temporal lobe (MTL) that contains the hippocampus, and spatial and verbal memory function in 22-45 year old alcohol dependent (ALC) men and women examined in early abstinence (5-10 days), and healthy age- and sex-matched comparison subjects (NALC) reporting a minimal alcohol use history. To investigate the effects of menstrual cycle phase on brain metabolites, NALC women will be tested longitudinally, in both follicular and luteal phases of their menstrual cycle (confirmed by salivary hormone assays). Furthermore, a subset of NALC men will be scanned twice to assess MRS test-retest reliability. We will apply single voxel proton (1H) MRS at 4.0 Tesla to measure MTL metabolites using MEGAPRESS and 2D-JPRESS, sequences optimized for detection and quantification of GABA and glutamate, respectively, to minimize methodological challenges associated with peak overlap and susceptibility of the MTL to field inhomogeneities. Metabolite data will be examined relative to hippocampal-mediated memory function, an area of cognition that has not only demonstrated sex differences, but also is impaired in alcoholic populations. The results of this study will establish profiles of neurochemical correlates of memory function in healthy NALC adults, which may be menstrual cycle dependent (Specific Aims 1,2). Inclusion of ALC patients, especially those who are recently detoxified, will provide baseline data (Exploratory Aim) that will be used to design a future longitudinal study in alcoholics that examines MTL GABA and glutamate changes and associated improvements in cognitive function. Those findings could not only establish neurochemical correlates associated with successful recovery, but also identify potential markers of increased risk for relapse. PUBLIC HEALTH RELEVANCE: The overall aim of our proposed study is to compare GABA and glutamate metabolite levels in a region of the medial temporal lobe (MTL) that contains the hippocampus, and spatial and verbal memory function in 22-45 year old alcohol dependent (ALC) men and women examined in early abstinence, and healthy age- and sex-matched comparison subjects (NALC) by applying high field (4.0 Tesla) in vivo magnetic resonance spectroscopy (MRS) techniques in conjunction with neuropsychological assessment of verbal and spatial learning and memory. To investigate the effects of menstrual cycle phase on brain metabolites, NALC women will be tested longitudinally, in both follicular and luteal phases of their menstrual cycle (confirmed by salivary hormone assays). The results of this study will establish profiles of neurochemical correlates of memory function in healthy NALC adults, which may be menstrual cycle dependent, but also inclusion of ALC patients will provide baseline data that will be used to design a future longitudinal study in alcoholics that examines MTL GABA and glutamate changes and associated improvements in cognitive function, findings that could not only establish neurochemical correlates associated with successful recovery, but also identify potential markers of increased risk for relapse.