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.

项目摘要 慢性重乙醇饮用和压力与认知灵活性受损有关，反映在习惯上 和强迫性饮酒。该建议旨在提高我们对这些影响神经基础的理解 通过将离体切片电生理研究与非侵入性磁共振光谱相结合 （MRS）在实验过程中对小鼠和非人类灵长类动物（NHP）受试者的测量 饮酒程序在整个INIA应激财团中常见。大脑切片的电生理记录 已经证明，建立习惯行为，包括大量饮酒，涉及和增加 神经元输入（E/I比）与中刺神经元（MSN）的抑制作用的兴奋 背纹纹状体（DLS），在原发性中被称为壳壳。专业MRS技术 量化特定大脑区域内的-氨基丁酸（GABA）和谷氨酸，使研究人员进入 在慢性压力的背景下，谷氨酸/GABA比反映E/I的建议，但是MRS 通过直接比较电生理记录，方法尚未得到验证。在目标1和2中 我们建议使用电生理学和MRS研究接受慢性间歇性乙醇暴露的小鼠， 结合强制游泳压力（CIE-FSS小鼠）。我们的实验将扩大我们对纹状体的理解 通过使用化学遗传和重组小鼠对压力和乙醇暴露的神经循环适应 表征皮质（兴奋性）和表达白蛋白的中间神经元（抑制性）的变化的菌株 输入DLS MSN。在同一只小鼠中，将用动态MRS方法来表征代谢性的Allostasis 该监测脑葡萄糖代谢和神经递质的合成以估计神经元三环羧基 实时实时酸性循环速率（VTCA），为解释谷氨酸/GABA比的生化环境， 这也将在这些小鼠中进行测量。在AIM 3中，平行化学发生操作和 在计划诱导的多次多维亚和 开放式饮酒。这些措施将直接与谷氨酸/GABA的MRS测定 和VTCA壳中的VTCA。这些结果将共同支持非侵入性策略的发展 测量与建立有关 繁重的饮酒行为。跨物种方法将对要得出的结论贡献可靠性， 并增强这项工作对未来在人类受试者中的应用的可翻译性。