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性的公共卫生问题， 迫切需要。酒精依赖的特征是大脑应激信号加剧 导致强迫性饮酒这种信号的一个主要组成部分是前压力 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， 应激，抗CRF作用特征，其阻断酒精依赖大鼠的强迫性饮酒。 然而，催产素发挥其抗强迫性饮酒作用的神经回路 不知道。因此，本独立之路奖提案的目的是 获得必要的培训，以识别，询问和操纵潜在的机制 催产素阻止强迫性饮酒的能力。技术培训将在 国家药物滥用研究所，校内研究计划，并准备候选人 在建议的和未来的实验中独立使用这些技术。培训将 并根据候选人的需求量身定制辅导和职业发展活动， 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伸出，允许催产素在部位局部释放。 在整个大脑，包括扩展杏仁核，一个收集脑核，其中CRF 在酒精依赖中调节失调的压力信号。这项建议首先旨在 绘制整个大脑的催产素投射图，并识别CRF细胞及其协同作用。 催产素受体在末端区域的表达。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测定。这将 允许识别具有催产素-CRF相互作用的高可能性的区域。第二 目的是用纤维光度法监测清醒状态下CRF-Cre中CRF细胞的活性 大鼠，在可能催产素-CRF相互作用的区域。这将允许在体内评估CRF细胞 在酒精依赖中的作用，以及对饮酒和催产素的反应 局第三个目的是利用光遗传学来激活或抑制催产素的释放 来自催产素-CRF可能相互作用区域的终末纤维。这将有助于确定 局部催产素在饮酒和其他行为失调中的因果作用， 酒精依赖（焦虑和疼痛）。这些研究的完成将提供新的见解 催产素和CRF的神经回路和相互作用，它们在 酒精依赖本项目对公共卫生非常重要，因为 基于催产素的药物对酒精中毒的潜在高治疗价值。

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.