5/8 INIA Stress and Chronic Alcohol Interactions: Probing brain circuits that regulate alcohol stress interactions

5/8 INIA 压力和慢性酒精相互作用：探索调节酒精压力相互作用的大脑回路

• 批准号: 10574573
• 负责人: Thomas L. Kash
• 金额: $ 44.87万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-10 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574573
• 关键词: Address; Adrenergic Receptor; Affect; Affective; Agonist; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Anabolism; Anatomy; Area; Behavior; Behavior assessment; Biosensor; Brain; Brain imaging; Brain region; CRISPR/Cas technology; Chronic; Collaborations; Consumption; Coping Behavior; Coupled; Disease; Dopamine; Dynorphins; Electrophysiology (science); Evaluation; Exposure to; Female; Fiber; Functional Magnetic Resonance Imaging; Funding; Glutamates; Goals; Grant; Heavy Drinking; Individual; Investigation; Knock-out; Laboratory Finding; Modality; Modeling; Molecular; Mus; Neurons; Norepinephrine; Outcome; Outcome Measure; Output; Pathway Analysis; Persons; Photometry; Physiology; Play; Prevalence; Property; Receptor Signaling; Regulation; Research Project Grants; Role; Sex Differences; Signal Pathway; Signal Transduction; Slice; Stress; Stress and Coping; Structure; Structure of terminal stria nuclei of preoptic region; System; Testing; United States; Ventral Tegmental Area; Withdrawal; Work; activity marker; alcohol exposure; alcohol response; alcohol use disorder; anxiety-like behavior; gamma-Aminobutyric Acid; genetic manipulation; in vivo; individual variation; insight; kappa opioid receptors; male; multidrug abuse; negative affect; neurobiological mechanism; neuroregulation; nonhuman primate; noradrenergic; norepinephrine system; novel; pharmacologic; response

Project Summary In this project we will mechanistically explore two neuromodulatory systems within the extended amydala and how they regulate plasticity and behavior following alcohol exposure and stress. In particular, in aims 1 and 2 we will utilize novel CRISPR technology to manipulate signaling in discrete brain regions, building on our prior investigations. In aim 1, we will explore the role of central amygdala (CeA) Kappa Opioid Receptor (KOR) signaling in alcohol and stress driven alterations in plasticity and in vivo dynamics of specific bed nucleus of the stria terminalis (BNST) outputs. In aim 2, we will investigate the contribution of noradrenergic signaling to alcohol drinking and alcohol driven disruptions of behavior. In aim 3, we will collaborate within and across INIA consortia in three ways (i.) investigating how CeA KOR knock out regulates alcohol exposure induced disruptions of dopamine signaling in vivo (Jones/Holleran component) , (ii.) investigating adrenergic receptor modulation in the BNST following alcohol consumption (Grant/Schnitko), (iii.) whole brain cFos analysis following GPR88 agonism to reduce alcohol consumption (Kieffer/Harsan). Thus, these integrated, yet independent aims, will provide circuit specific mechanistic findings in critical nodes that have been established to contribute to multiple aspects of the positive and negative reinforcing properties of alcohol.

项目摘要 在这个项目中，我们将机械地探讨两个神经调节系统内的扩展 杏仁核以及它们如何调节酒精暴露和压力后的可塑性和行为。在 特别是，在目标1和2中，我们将利用新型CRISPR技术以离散方式操纵信号传导。 大脑区域，建立在我们之前的调查基础上在aim 1中，我们将探讨中央杏仁核的作用 (CeA)在酒精和压力驱动的可塑性改变中的κ阿片受体（KOR）信号传导， 终纹特定床核（BNST）输出的体内动力学。在目标2中，我们将研究 去甲肾上腺素能信号对饮酒和酒精驱动的 行为在目标3中，我们将通过三种方式在INIA联盟内部和之间进行合作：调查 CeA KOR基因敲除如何调节体内酒精暴露诱导的多巴胺信号转导中断 （Jones/Hollmann分量），（ii.）研究BNST中的肾上腺素能受体调节， 酒精消费（格兰特/施尼特科），（iii.）GPR 88激动后的全脑cFos分析， 减少饮酒（Kieffer/Harsan）。因此，这些综合而又独立的目标将提供 在关键节点中的电路特定机制发现已经建立，以促进多个 酒精的积极和消极强化特性的方面。