Project 7/8: INIA Stress and Chronic Alcohol Interactions: Cross-species studies of metabolic allostasis and altered striatal circuitry

项目 7/8：INIA 压力和慢性酒精相互作用：代谢动态平衡和纹状体回路改变的跨物种研究

• 批准号: 10590709
• 负责人: Verginia Carmella Cuzon Carlson
• 金额: $ 48.63万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590709
• 关键词: Acetates; Acids; Affect; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Aminobutyric Acids; Anxiety; Behavior; Biochemical; Brain; Brain region; Cells; Cerebrum; Chronic; Chronic stress; Citric Acid Cycle; Corpus striatum structure; Coupling; Data; Development; Diagnosis; Electrophysiology (science); Ethanol; Experimental Designs; Future; Genetic; Glucose; Glutamates; Heavy Drinking; Homeostasis; Human; Impaired cognition; Interneurons; Light; Macaca mulatta; Magnetic Resonance Spectroscopy; Measurement; Measures; Metabolic; Metabolism; Methods; Monitor; Mouse Strains; Mus; Neurons; Neurotransmitters; Parvalbumins; Pathway interactions; Pattern; Polydipsia; Population; Primates; Procedures; Recombinants; Recording of previous events; Research; Research Personnel; Risk Factors; Role; Schedule; Severities; Slice; Stress; Swimming; Techniques; Time; Validation; Work; alcohol effect; alcohol exposure; alcohol use disorder; allostasis; blood glucose regulation; brain circuitry; brain dysfunction; brain metabolism; chronic alcohol ingestion; cognitive function; drinking; drinking behavior; experimental study; flexibility; frontal lobe; genetic manipulation; glucose metabolism; human subject; improved; in vivo; metabolic abnormality assessment; metabolomics; neural; neural circuit; neuroadaptation; neurochemistry; neuroimaging; neuromechanism; neuroregulation; nonhuman primate; preservation; putamen; restoration

PROJECT SUMMARY Chronic heavy ethanol drinking and stress are associated with impaired cognitive flexibility, reflected in habitual and compulsive drinking. This proposal seeks to improve our understanding of the neural basis of these effects by combining ex vivo slice electrophysiological studies with non-invasive magnetic resonance spectroscopy (MRS) measurements on mouse and nonhuman primate (NHP) subjects over the course of experimental drinking procedures common across the INIA-Stress consortium. Electrophysiological recordings of brain slices have demonstrated that establishment of habitual behaviors, including heavy drinking, involve and increase in the excitatory to inhibitory tone of neural input (the E/I ratio) to medium spiny neurons (MSNs) of the mouse dorsolateral striatum (DLS), which in primates is termed the putamen. Specialized MRS techniques for quantifying -aminobutyric acid (GABA) and glutamate within specific brain regions have led researchers to propose that the glutamate/GABA ratio reflects E/I, in the context of chronic stress, however the MRS approach has yet to be validated with direct comparisons to electrophysiological recordings. In Aims 1 and 2, we propose to use electrophysiology and MRS to study mice undergoing chronic intermittent ethanol exposure, combined with forced swim stress (CIE-FSS mice). Our experiments will expand our understanding of striatal neurocircuit adaptations to stress and ethanol exposure by using chemogenetic and recombinant mouse strains to characterize changes in cortical (excitatory) and parvalbumin-expressing interneuron (inhibitory) input to DLS MSNs. In the same mice, metabolic allostasis will be characterized with dynamic MRS methods that monitor cerebral glucose metabolism and neurotransmitter synthesis to estimate the neural tricarboxcylic acid cycle rate (VTCA) in real time, to provide a biochemical context for interpreting glutamate/GABA ratios, which will also be measured in these mice. In Aim 3, parallel chemogenetic manipulations and electrophysiological recordings will be performed in NHP subjects following schedule-induced polydipsia and open-access drinking. These measures will be directly compared to MRS determinations of glutamate/GABA and VTCA within the putamen. Together, these results will support the development of non-invasive strategies to measure stress and ethanol-induced changes in striatal neurocircuitry associated with the establishment of heavy drinking behaviors. The cross-species approach will contribute reliability to the conclusions to be drawn, and enhance the translatability of this work to future application in human subjects.

项目概要 长期大量饮酒和压力与认知灵活性受损有关，这反映在习惯性行为中 和强迫性饮酒。该提案旨在提高我们对这些效应的神经基础的理解 通过将离体切片电生理学研究与非侵入性磁共振波谱相结合 在实验过程中对小鼠和非人类灵长类动物 (NHP) 受试者进行 (MRS) 测量 INIA-Stress 联盟中常见的饮酒程序。脑切片的电生理记录 已经证明，习惯行为的养成，包括酗酒，会涉及并增加 小鼠中型多棘神经元 (MSN) 的神经输入的兴奋性与抑制性音调（E/I 比） 背外侧纹状体（DLS），在灵长类动物中被称为壳核。专门的 MRS 技术 定量特定大脑区域内的 γ-氨基丁酸 (GABA) 和谷氨酸使研究人员 提出在慢性应激的情况下，谷氨酸/GABA 比率反映了 E/I，但是 MRS 该方法尚未通过与电生理记录的直接比较来验证。在目标 1 和 2 中， 我们建议使用电生理学和 MRS 来研究经历慢性间歇性乙醇暴露的小鼠， 结合强迫游泳应激（CIE-FSS 小鼠）。我们的实验将扩大我们对纹状体的理解 使用化学遗传学和重组小鼠的神经回路适应压力和乙醇暴露 表征皮质（兴奋性）和表达小清蛋白的中间神经元（抑制性）变化的菌株 输入到 DLS MSN。在同一只小鼠中，代谢失衡将通过动态 MRS 方法进行表征 监测大脑葡萄糖代谢和神经递质合成，以估计神经三羧基 实时酸循环率 (VTCA)，为解释谷氨酸/GABA 比率提供生化背景， 这也将在这些小鼠中进行测量。在目标 3 中，并行化学遗传学操作和 电生理记录将在 NHP 受试者中进行日程诱发的烦渴和 开放饮酒。这些测量结果将直接与谷氨酸/GABA 的 MRS 测定进行比较 和壳核内的 VTCA。总之，这些结果将支持非侵入性策略的开发 测量与建立相关的纹状体神经回路的压力和乙醇诱导的变化 大量饮酒行为。跨物种方法将有助于得出结论的可靠性， 并增强这项工作未来在人类受试者中的应用的可转化性。