Chronic alcohol regulates circuitry structure and demand for alcohol

项目总结 我们努力推动新的方法来了解酒精对大脑的影响，通过建立 酒精暴露对新的神经回路失调的新作用机制。一位候选人 酒精暴露改变的回路是谷氨酸能神经元的下游突触连接 眶前叶皮质(OFC)至伏核(NAC)通路。这个项目的目标是 证实从OFC到NAC的谷氨酸能神经元的下游连接发生了改变 通过反复酒精暴露，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。在这项提案中，我们将 在酒精环境下研究OFC→NAc通路的神经解剖学连接性 曝光。我们的观察表明，OFC→NAC途径表现出下游连通性 伏隔直达通路的室上性心动过速。这个项目是基于这样一个前提：反复 酒精暴露会增加谷氨酸能OFC→NAC通路对D1NAC的兴奋性驱动 表达NAc→Vta以增强酒精的激励作用。我们假设重复一次 酒精暴露增加谷氨酸能OFC投射的突触连接性 在酒精摄入量增加的情况下，向VTA通路神经元表达D1的NAC增加。我们 我将通过以下具体目标来检验这一假设：1)定义 重复饮酒后OFC→NAC→Vta回路；2)发现行为效应 反复酒精暴露对酒精自我管理的影响。为了实现我们的目标，我们将聘用 当代策略，如行为经济学和跨突触神经解剖学追踪 通过三个不同的大脑区域详细说明连接。总之，拟议的研究将 研究酒精引起的连接性变化作为酒精增加的基础机制 夺取。总体而言，这些研究将通过进一步了解我们的知识基础来影响该领域 既往酒精暴露如何改变大脑回路连接以增强未来酒精含量 消费。

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.