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.

项目总结