9/11 Neuroimmunophysiology of excessive alcohol intake

项目总结/摘要 这个酒精中毒综合神经科学倡议（INIA-Neuroimmune，INIA-N）联盟的组成部分是为了 一个U 01研究项目，旨在确定神经免疫信号分子和神经胶质细胞如何有助于 促进过量饮酒的神经元适应性变化。此INIA之前的工作- N成分鉴定了与过度的神经元兴奋相关的丘脑核（NAc）中的神经元适应性变化。 酒精消费。特别是，我们发现酒精依赖和过量摄入与以下因素有关： 多巴胺D1受体表达的中型多棘神经元（D1 MSNs）上的多巴胺能突触的可塑性， 其包括NAc的主要输出途径，该途径与基于奖励的行为密切相关。最近 我们发现，虽然突触兴奋增强，但这些神经元的膜兴奋性并不 仅在急性戒断乙醇期间受到抑制，但与先前的乙醇强烈负相关 摄入我们将采用慢性和过度饮酒的小鼠行为模型，基因工程小鼠， 和脑切片电生理学来测试神经免疫活动有助于这些突触的假设。 和D1 MSNs的膜适应。具体目标1将评估神经元生理学是如何被 细胞因子白细胞介素-33（IL-33）以乙醇依赖的方式，它将使用基因工程小鼠， IL-33或其受体从特定细胞类型（小胶质细胞、星形胶质细胞和/或 神经元），以探测这种信号通路在酒精摄入量增加中的作用。具体目标2将采取 更广泛的方法，使用脑切片电生理学来询问NAc小胶质细胞是否表现出功能性 与酒精摄入量及其在D1 MSNs中的相关适应相关的适应。具体目标3将是 INIA-N研究人员确定的其他神经免疫信号传导和调节分子的合作研究 在过量酒精摄入中起作用。在这里，我们将再次使用脑切片电生理学， 确定这些神经免疫分子的操作是否可以改变NAc D1 MSN生理学， 控制酒精消费。这些研究将为NIAAA的使命服务， 关于酒精对大脑健康影响的知识，并寻求应用这些知识来确定新的 治疗过度饮酒的目标。

PROJECT SUMMARY/ABSTRACT This Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune, INIA-N) consortium component is for a U01 research project that seeks to determine how neuroimmune signaling molecules and glia contribute to neuronal adaptations in the nucleus accumbens that promote excessive ethanol drinking. Prior work by this INIA- N component identified neuronal adaptations in the nucleus accumbens (NAc) that are associated with excessive alcohol consumption. In particular, we found that ethanol dependence and excessive intake are associated with plasticity in glutamatergic synapses on dopamine D1 receptor-expressing medium spiny neurons (D1MSNs), which comprise a major output pathway of the NAc that is heavily involved in reward-based behaviors. Recently we discovered that, although synaptic excitation is enhanced, the membrane excitability of these neurons not only is suppressed during acute withdrawal from ethanol, but is strongly, inversely, correlated with prior ethanol intake. We will employ mouse behavioral models of chronic and excessive drinking, genetically engineered mice, and brain slice electrophysiology to test the hypothesis that neuroimmune activity contributes to these synaptic and membrane adaptations of D1MSNs. Specific aim 1 will evaluate how neuronal physiology is altered by the cytokine interleukin-33 (IL-33) in an ethanol-dependent manner, and it will use genetically-engineered mice for inducible and conditional deletion of IL-33, or its receptor, from specific cell types (microglia, astrocytes, and/or neurons) to probe the role of this signaling pathway in the escalation of alcohol intake. Specific aim 2 will take a broader approach, using brain slice electrophysiology to ask whether NAc microglia exhibit functional adaptations that correlate with alcohol intake and its associated adaptations in D1MSNs. Specific aim 3 will be collaborative studies on other neuroimmune signaling and regulatory molecules identified by INIA-N investigators’ as playing a role in excessive alcohol intake. Here we will again use brain slice electrophysiology and will determine whether manipulations of these neuroimmune molecules may alter NAc D1MSN physiology to regulate alcohol consumption. These studies will serve the mission of NIAAA by generating new, fundamental knowledge about the effects of alcohol on brain health, and seeks to apply such knowledge to identify new targets for the treatment of excessive alcohol consumption.