The role of corticotropin releasing factor in binge-like ethanol drinking

项目摘要 酒精（乙醇）依赖和戒酒者的复发是整个世界的主要健康问题。 目前正在研究调节这些疾病的世界和神经化学途径。然而，在这方面， 酗酒是一种危险的行为模式，这种行为模式会导致 依赖性，受到的关注要少得多。因此，识别神经回路是至关重要的， 调节酗酒的大脑，因为这些知识将提供对酒精初始阶段的洞察力 使用障碍（AUDs），并将在开发之前为治疗早期AUDs提供新的途径 的依赖。在该资助的最后一个资助期内，我们的实验室提供了聚合证据， 促肾上腺皮质激素释放因子（CRF）受体信号，通过神经回路提供大脑之间的串扰， 整合情绪/压力反应与激励奖励寻求行为的区域，调节 老鼠的酒精狂饮。此外，本补助金中描述的初步数据提供了融合 有证据表明，一种连接压力和奖励系统的新回路调节了性行为中酒精的摄入量， 这是一个非常重要的发现，因为我们对这种机制的理解非常有限， 驱动乙醇摄入量和AUDs的性别差异。整合奖励导向行为的一个关键因素是 外侧下丘脑（LH），我们提供的初步证据表明，阻断CRF 1型受体（CRF1R）， LH以及从中央杏仁核（CeA）到LH的CRF+途径的化学发生沉默， 酒精摄入量在雄性小鼠中呈暴饮暴食状态，但在雌性小鼠中则不然。目前赠款的指导假设是，CRF LH中的受体信号调节酗酒样乙醇饮酒，这涉及CRF + CeA → LH途径， 并且，酗酒的酒精饮用史将促进CRF回路中的可塑性， 奖励系统，都是以性别为基础的。我们将使用强大的和创新的化学基因，转基因， 电生理学和组织学方法来检验LH输注CRF1R拮抗剂 和CRF 2型受体（CRF2R）激动剂，以及LH中CRF1R的敲低，将防止暴食样 乙醇饮用（目的1），化学发生失活或激活CRF + CeA神经元，投射到LH将 分别减少或增加酗酒样乙醇摄入量（目标2），以及反复酗酒样饮酒史 事件将与CRF和CRF受体水平的变化以及CeA → LH信号传导相关。 神经回路因为我们的初步数据提供了一致的证据， 主要在雄性小鼠中调节酗酒样乙醇饮用，每个目标都有足够的动力来表征 性别差异该基金的目的是解决CRF在弥合 整合压力/情绪的大脑区域与调节奖励的大脑区域之间的功能性沟通， 寻求，提供新的洞察机制，指导性别差异，在狂欢样乙醇摄入量，并将 揭示了在依赖性发展之前治疗早期AUDs的新途径。

Project Summary Alcohol (ethanol) dependence and relapse in abstinent alcoholics are major health problems throughout the world and neurochemical pathways that modulate these disorders are currently under investigation. However, the neurobiology underlying binge drinking, a dangerous pattern of behavior that proceeds and contributes to dependence, has received far less attention. Thus, it is of paramount importance to identify the neurocircuitry in the brain that modulates binge drinking as such knowledge will provide insight into the initial stages of alcohol use disorders (AUDs) and will shed new light on avenues for treating early-stage AUDs prior to the development of dependence. During the last funding period of this grant, our laboratory has provided converging evidence that corticotropin releasing factor (CRF) receptor signaling, via neurocircuitry providing cross-talk between brain regions that integrate emotions/stress responses with those that motivate reward-seeking behaviors, modulates binge-like ethanol drinking in mice. Furthermore, preliminary data described in this grant provide converging evidence that of a novel circuit linking stress and reward systems modulates binge-like ethanol intake in a sex- dependent manner, a highly significant discovery given our very limited understanding of the mechanisms that drive sex differences in ethanol intake and AUDs. A critical player in integrating reward-directed behaviors is the lateral hypothalamus (LH), and we provide preliminary evidence that blocking CRF type-1 receptors (CRF1R) in the LH, as well as chemogenetic silencing of a CRF+ pathway from the central amygdala (CeA) to the LH, reduce binge-like ethanol intake in male, but not female mice. The guiding hypothesis for the current grant is that CRF receptor signaling in the LH modulates binge-like ethanol drinking, which involves the CRF+ CeA → LH pathway, and that a history of binge-like ethanol drinking will promote plasticity within this CRF circuit linking stress and reward systems, all in a sex-dependent manner. We will use powerful and innovative chemogenetic, transgenic, electrophysiological, and histological approaches to test the hypothesis that LH-infusion of CRF1R antagonist and CRF type-2 receptor (CRF2R) agonist, and knockdown of CRF1R in the LH, will protect against binge-like ethanol drinking (Aim 1), chemogenetic inactivation or activation of CRF+ CeA neurons that project to the LH will blunt or increase binge-like ethanol intake, respectively (Aim 2), and a history of repeated binge-like drinking episodes will be associated with changes in CRF and CRF receptor levels and signaling in the CeA → LH neurocircuitry. Because our preliminary data provided converging evidence that CRF signaling in this pathway modulates binge-like ethanol drinking primarily in male mice, each aim is sufficiently powered to characterize sex differences. The aims of this grant will address a critical gap in the literature on the role of CRF in bridging functional communication between brain regions integrating stress/emotion with those the modulate reward- seeking, provide novel insight into mechanisms that guide sex differences in binge-like ethanol intake, and will shed new light on avenues for treating early-stage AUDs prior to the development of dependence.