Component 4 - Deconstructing CRF circuits that modulate binge ethanol intake

反复酗酒是一个主要的公共健康问题，被认为是 导致大脑回路的病理生理变化，从而导致酒精依赖和成瘾。 而像乙醇消费这样的复杂行为很可能是由分布的、相互关联的 大脑中央核团内产生促肾上腺皮质激素释放因子(CRF)的神经元网络 杏仁核(CEA)被认为在逐步驱动病理性酒精的过程中起着关键作用。 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信号如何通过其与神经回路的功能连接来调节神经回路 由于评估特定远程突触的技术限制，突触后靶点被证明是困难的 投射。为了避免这一点，我们建议使用光遗传学技术结合脑切片。 电生理学和行为学检测延髓CRF神经元回路的特性 并确定是否激活或抑制含有神经回路元件的CRF可以 改变过量的酒精摄入量。我们假设CEA内产生CRF的神经元投射到床上 终纹核(BNST)，这一通路的激活将被增强，并需要 反复酗酒。我们将使用多学科相结合的方法来检验这一假设 进行体内和体外功能分析。总而言之，拟议的研究将提供必要的 有关CRF从CEA投射到BNST在酗酒中所起作用的信息 喝酒。

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.