Sex Differences and Alcohol Dependence: Hippocampal Neurochemistry and Function

描述（由申请人提供）：体内磁共振波谱（MRS）已被用于检查各种酒精人群中细胞健康、完整性和代谢的变化，尽管几乎没有MRS研究包括足够数量的女性来检查酒精对脑代谢物影响的性别差异。这项新颖的研究旨在比较22-45岁酒精依赖（ALC）男性和女性在早期戒酒（5-10天）和健康年龄和性别匹配的比较受试者（NALC）中含有海马体的内侧颞叶（MTL）区域的GABA和谷氨酸代谢物水平，以及空间和言语记忆功能。为了研究月经周期阶段对脑代谢物的影响，NALC妇女将在其月经周期的卵泡期和黄体期进行纵向测试（通过唾液激素测定证实）。此外，一部分NALC男性将接受两次扫描，以评估MRS测试-重测的可靠性。我们将应用4.0特斯拉的单体素质子（1H） MRS，使用MEGAPRESS和2D-JPRESS分别对GABA和谷氨酸的检测和定量进行优化的序列来测量MTL代谢物，以最大限度地减少与峰重叠和MTL对场不均匀性的敏感性相关的方法学挑战。代谢物数据将与海马介导的记忆功能相关，海马介导的记忆功能不仅表现出性别差异，而且在酗酒人群中也受到损害。本研究的结果将建立健康NALC成人记忆功能的神经化学相关资料，这可能与月经周期有关（Specific Aims 1,2）。纳入ALC患者，特别是那些最近解毒的患者，将提供基线数据（探索性目标），用于设计未来对酗酒者的纵向研究，以检查MTL - GABA和谷氨酸的变化以及认知功能的相关改善。这些发现不仅可以建立与成功康复相关的神经化学物质，还可以确定复发风险增加的潜在标志。

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.