Chronic alcohol regulates circuitry structure and demand for alcohol

慢性酒精调节回路结构和对酒精的需求

• 批准号: 10373655
• 负责人: Jonathan Dean Hommel
• 金额: $ 8万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373655
• 关键词: Abstinence; Alcohol consumption; Alcohols; Anatomy; Automobile Driving; Behavior; Behavioral; Beverages; Biology; Brain; Brain region; Chronic; Cognitive; Consummatory Behavior; Data; Dendrites; Dopamine; Dopamine Receptor; Economic Models; Ethanol; Exhibits; Exposure to; Functional Imaging; Future; Glutamates; Goals; Human; Image; Immediate-Early Genes; Immunohistochemistry; Lesion; Measures; Mediating; Medical; Modeling; Motivation; Mus; Neurobiology; Neurologic; Neurons; Nucleus Accumbens; Pathway interactions; Patients; Pattern; Persons; Pharmacogenetics; Population; Protocols documentation; Rattus; Receptor Activation; Recording of previous events; Research; Resources; Rodent; Role; Self Administration; Structure; Synapses; Synaptic plasticity; System; Technology; Testing; Texas; Transgenic Organisms; Universities; Ventral Tegmental Area; Viral; Viral Vector; Work; World Health Organization; addiction; alcohol behavior; alcohol demand; alcohol effect; alcohol exposure; alcohol use disorder; base; behavioral economic analysis; behavioral economics; brain behavior; brain circuitry; frontal lobe function; insight; knowledgebase; nerve supply; neural circuit; neuroadaptation; neuronal excitability; novel; novel strategies; pre-clinical research; receptor; receptor expression

PROJECT SUMMARY We endeavor to drive new approaches to understand the effect of alcohol on the brain by establishing fresh mechanisms of action for alcohol exposure on dysregulating novel neurocircuitry. A candidate circuit altered by alcohol exposure is the downstream synaptic connectivity of the glutamatergic orbitofrontal cortex (OFC) to nucleus accumbens (NAc) pathway. The goal of this project is to establish that downstream connectivity of glutamatergic neurons from the OFC to the NAc are altered by repeated alcohol exposure, which modulates alcohol-driven behavior via dopamine receptor 1- expressing neurons projecting to the ventral tegmental area (VTA). In this proposal, we will investigate the neuroanatomical connectivity of the OFC → NAc pathway in the context of alcohol exposure. Our observations suggest that the OFC → NAc pathway exhibits downstream connectivity with the VTA of the accumbal direct pathway. This project is based upon the premise that repeated alcohol exposure will increase excitatory drive of the glutamatergic OFC → NAc pathway onto D1- expressing NAc → VTA to potentiate motivational effects of alcohol. We hypothesize that repeated alcohol exposure increases the synaptic connectivity of glutamatergic OFC projections onto D1-expressing NAc to VTA pathway neurons with concomitant increases in alcohol intake. We will test this hypothesis with the following specific aims: 1) Define the structural linkage within the OFC → NAc → VTA circuit after repeated alcohol consumption; and 2) Uncover the behavioral effect of repeated alcohol exposure on alcohol self-administration. To realize our Aims, we will employ contemporary strategies such as behavioral economics and transsynaptic neuroanatomical tracing to detail connectivity through three separate brain regions. Together, the proposed research will examine alcohol-evoked changes in connectivity as a mechanism that underlies increases in alcohol taking. Overall, these studies will impact the field by furthering our knowledgebase for understanding how previous alcohol exposure alters brain circuit connectivity to potentiate future alcohol consumption.

项目摘要 我们努力通过建立新的方法来了解酒精对大脑的影响， 酒精暴露对新型神经回路失调的新作用机制。候选 酒精暴露改变的回路是突触能神经元的下游突触连接。 眶额皮质（OFC）至丘脑核（NAc）通路。该项目的目标是 建立从OFC到NAc多巴胺能神经元的下游连接被改变 通过反复的酒精暴露，通过多巴胺受体1调节酒精驱动的行为， 表达投射到腹侧被盖区（VTA）的神经元。在本提案中，我们将 研究酒精环境下OFC → NAc通路的神经解剖学连接 exposure.我们的观察结果表明OFC → NAc通路具有下游连接性， 与腹侧被盖区的腹侧被盖区直接相连这个项目是基于这样一个前提， 酒精暴露会增加多巴胺能OFC → NAc通路对D1- 表达NAc → VTA以增强酒精的激励作用。我们假设重复的 酒精暴露增加了突触连接的神经元能OFC投射到 D1-表达NAc到VTA通路神经元伴随酒精摄入量增加。我们 我将以下列具体目标来检验这一假设：1）确定 反复饮酒后OFC → NAc → VTA回路的变化; 2）揭示行为效应 反复暴露于酒精中为了实现我们的目标，我们将 当代的策略，如行为经济学和跨突触神经解剖追踪， 通过三个独立的大脑区域详细连接。总之，拟议的研究将 研究酒精诱发的连接变化作为酒精增加的基础机制 拿。总的来说，这些研究将通过促进我们的知识基础来理解， 先前的酒精暴露如何改变大脑回路连接以增强未来的酒精 消费