Opposing Contributions of Oxytocin and Corticotropin-Release Factor to Alcohol Dependence

项目摘要 酒精使用障碍是一个全球公共卫生问题，对此有更有效的治疗方法 急需之物。酒精依赖的特征是大脑应激信号加剧 这就导致了强迫性饮酒。这一信号的一个主要组成部分是促应激 神经肽促肾上腺皮质激素释放因子(CRF)。催产素是一种神经肽，具有抗- 应激，抗CRF作用，阻止酒精依赖大鼠的强迫性饮酒。 然而，催产素发挥其抗强迫饮酒作用的神经回路 是未知的。因此，目前独立之路奖提案的目的是 获得必要的培训以识别、询问和操作潜在的机制 催产素阻止强迫性饮酒的能力。技术培训将在以下地点进行 国家药物滥用研究所，校内研究计划和准备候选人 在拟议的和未来的实验中独立使用这些技术。培训将是 为应聘者量身定做的导师指导和职业发展活动 在校外研究机构获得终身教职的目标。 催产素纤维从下丘脑投射出来，使催产素在局部部位释放 整个大脑，包括延伸的杏仁核，这是一个大脑核团的集合，CRF 在酒精依赖中调节失调的压力信号。这项提议将首先旨在 绘制整个大脑的催产素投射图，并识别CRF细胞和它们的联合 与催产素受体在终末区域的表达。突触之间的相互作用 催产素纤维和CRF细胞将使用免疫电子显微镜进行测定。这将是 允许识别催产素-CRF相互作用的高可能性区域。第二 目的：用纤维光度法监测清醒状态下CRF-CRE中CRF细胞的活性 大鼠，在可能的催产素-CRF相互作用的区域。这将使CRF细胞的体内评估成为可能 在酒精依赖以及对饮酒和催产素的反应中的作用 行政管理。第三个目标是利用光遗传学来激活或抑制催产素的释放。 来自可能与催产素-促肾上腺皮质激素释放因子相互作用的终末纤维。这将允许确定 局部催产素作用在饮酒及其他行为异常中的作用 酒精依赖(焦虑和疼痛)。这些研究的完成将提供新的见解 研究催产素和促肾上腺皮质激素释放激素的神经回路和相互作用，这两种激素在 酒精依赖。本项目对公共卫生具有高度重要性，因为 以催产素为基础的药物对酒精中毒的潜在治疗价值。

Project Summary Alcohol use disorder is a global public health issue for which more effective treatments are urgently needed. Alcohol dependence is characterized by exacerbated brain stress signaling that drives compulsive drinking. A major component of this signaling is the pro-stress neuropeptide corticotropin releasing factor (CRF). Oxytocin is a neuropeptide with an anti- stress, anti-CRF profile of action, which blocks compulsive drinking in alcohol-dependent rats. However, the neuronal circuitry through which oxytocin exerts its anti-compulsive drinking effect is not known. Therefore, the aim of the present Pathway to Independence Award proposal is to obtain the necessary training to identify, interrogate, and manipulate mechanisms underlying oxytocin’s ability to block compulsive alcohol drinking. Technical training will be conducted at the National Institute on Drug Abuse, Intramural Research Program and prepare the candidate to use these techniques independently in the proposed and future experiments. Training will be complimented with mentorship and career development activities tailored toward the candidate’s goal of securing a tenure-track academic position at an extramural research institute. Oxytocin fibers project from the hypothalamus to allow local release of oxytocin in sites throughout the brain, including the extended amygdala, a collection of brain nuclei in which CRF mediates dysregulated stress signaling in alcohol dependence. This proposal will first aim to map oxytocin projections throughout the whole brain, and identify CRF cells and their co- expression with the oxytocin receptor in terminal regions. The synaptic interaction between oxytocin fibers and CRF cells will be determined using immuno-electron microscopy. This will allow the identification of regions with high likelihood of oxytocin-CRF interaction. The second aim is to use fiber photometry to monitor the activity of CRF cells in awake-behaving CRF-Cre rats, in regions of likely oxytocin-CRF interaction. This will allow in vivo assessment of CRF cell function in alcohol dependence, as well as in response to alcohol drinking and oxytocin administration. The third aim is to use optogenetics to activate or inhibit the release of oxytocin from terminal fibers in regions of likely oxytocin-CRF interaction. This will allow determination of a causal role of local oxytocin action in alcohol drinking and other behaviors dysregulated in alcohol dependence (anxiety and pain). Completion of these studies will provide novel insights into the neurocircuitry and interaction of oxytocin and CRF, which have opposing roles in alcohol dependence. The present project is of high importance for public health, given the potentially high therapeutic value of oxytocin-based medications for alcoholism.