Component 4 - Deconstructing CRF circuits that modulate binge ethanol intake

第 4 部分 - 解构调节暴饮乙醇摄入量的 CRF 回路

• 批准号: 8975103
• 负责人: Thomas L. Kash
• 金额: $ 23.67万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8975103
• 关键词: Acute; Alcohol consumption; Alcohol dependence; Alcoholism; Amygdaloid structure; Anatomy; Animals; Automobile Driving; Behavior; Behavioral Assay; Brain; Cell Nucleus; Chloride Channels; Complex; Corticotropin-Releasing Hormone; Coupled; Electrophysiology (science); Elements; Fiber; Genetic study; Glutamates; Halorhodopsins; Lead; Mediating; Methods; Molecular; Mus; Neural Pathways; Neurons; Output; Pathogenesis; Pathway interactions; Physiologic pulse; Physiology; Play; Positioning Attribute; Property; Public Health; Research; Role; Signal Transduction; Slice; Stress; Structure of terminal stria nuclei of preoptic region; Synapses; Synaptic Transmission; Techniques; Testing; Time; addiction; alcohol behavior; alcohol exposure; awake; brain circuitry; design; drinking; drinking behavior; effective therapy; experience; gamma-Aminobutyric Acid; in vivo; light gated; neural circuit; neuronal circuitry; neurotransmission; novel; optogenetics; postsynaptic; preference

Repeated binge alcohol drinking is a major public health problem and is thought to lead to pathophysiological alterations in brain circuitry that contribute to alcohol dependence and addiction. While complex behaviors such as ethanol consumption are likely controlled by a distributed, interconnected network of brain nuclei, corticotropin releasing factor (CRF) producing neurons within the central nucleus of the amygdala (CeA) are thought to play a crucial role in progressively driving pathological ethanol consumption. The CeA is composed of numerous neurochemically distinct neurons, and therefore determining how endogenous CRF signaling modulates neural circuits via their functional connectivity with postsynaptic targets has proven difficult due to technical limitations in evaluating specific long-range synaptic projections. To circumvent this, we propose to use optogenetic techniques coupled with brain slice electrophysiology and behavioral assays to examine the properties of CRF neuronal circuits in the extended amygdala and to determine whether activation or inhibition of CRF containing neural circuit elements can alter binge ethanol intake. We hypothesize that CRF producing neurons within the CeA project to the bed nucleus of the stria terminalis (BNST), and that activation of this pathway will be enhanced and required for repeated binge ethanol intake. We will test this hypothesis using a multi-disiclplinary approach combining both in vivo and ex vivo analysis of function. In total, the proposed research will provide essential information concerning the role that the CRF projection from the CeA to the BNST plays in binge ethanol drinking.

反复酗酒是一个主要的公共卫生问题， 导致大脑回路病理生理学改变，从而导致酒精依赖和成瘾。 虽然复杂的行为，如乙醇消费可能是由一个分布式的，相互关联的控制， 脑神经核网络，促肾上腺皮质激素释放因子（CRF）产生的神经元内的中央核， 杏仁核（CeA）被认为在逐渐驱动病理性乙醇中起关键作用 消费CeA由许多神经化学上不同的神经元组成，因此 确定内源性CRF信号传导如何通过它们的功能连接调节神经回路， 突触后靶点已经被证明是困难的，由于技术限制，在评估特定的长距离突触 预测。为了规避这一点，我们建议使用光遗传学技术结合脑切片， 电生理学和行为分析，以检查CRF神经元回路的特性， 杏仁核，并确定是否激活或抑制CRF含有神经回路元件， 改变酒精摄入量我们假设，CRF产生的神经元内的CeA项目的床 终纹核（BNST），这一途径的激活将被增强，并需要 反复酗酒我们将使用多学科方法来测试这个假设， 功能的体内和离体分析。总的来说，拟议的研究将提供必要的 关于从CeA到BNST的CRF投影在酒精狂欢中所起作用的信息 喝酒