The Role of CLOCK in Ethanol-Related Behaviors

描述(申请人提供)：反复接触滥用药物会导致奖赏和压力相关神经回路的长期变化。这一环路的重要组成部分包括尾壳核、伏隔核、杏仁中央核和腹侧被盖区。一些研究表明，生物钟的分子成分在药物奖励和药物相关反应中扮演关键角色。McClung等人。(2005)确定了昼夜节律运动输出周期kaput(CLOCK)基因在药物奖励调节中的关键作用。携带Clock基因显性负突变的小鼠(Clock 19小鼠)表现出对可卡因的敏感性和偏好增加。此外，这些小鼠表现出更多的运动活动，减少焦虑和抑郁样行为，以较低的阈值增加颅内自我刺激(ICSS)，并增加VTA中的多巴胺能细胞活动(McClung等人，2005年；Roybal等人，2007年)。拟议的研究培训计划的目标是确定特定大脑区域的时钟作为酒精相关行为的中介所起的作用。首先，我们将通过原位杂交来确定长期酗酒如何调节大脑中与奖励和压力相关的区域时钟的表达水平。其次，我们将确定Clock的显性负突变(Clock 19小鼠)如何影响可操作的口服乙醇自我给药的措施。最后，我们将使用RNAi确定VTA中的时钟功能是否在调节酒精摄入和复发样饮酒行为中起重要作用。进一步研究昼夜节律基因在酒精相关行为中的作用将对治疗具有令人兴奋的翻译意义，因为许多正在康复的成瘾者表现出持续的昼夜节律紊乱，并导致复发。我对在分子和行为层面上进行酒精研究有着浓厚的兴趣。这项培训计划的目标是向我提供使用尖端技术和方法、将数据转换为高知名度出版物的详细专业知识，并为我过渡到独立做好准备。我有动力，勤奋，致力于推进酒精中毒的治疗。这项计划，再加上UTSW的优秀研究人员团队，将使我能够实现这项计划中概述的目标，并为我在酒精和药物滥用领域成功的独立研究生涯做好准备。这个NRSA申请的资金对我的成功起到了重要作用。

DESCRIPTION (provided by applicant): Repeated exposure to drugs of abuse leads to long lasting changes in reward- and stress-related neuronal circuitry. Important components of this circuitry include the caudate-putamen, nucleus accumbens, central nucleus of the amygdala, and the ventral tegmental area (VTA). Several studies have suggested a role for molecular components of the circadian clock as key players in drug reward and drug-associated responses. McClung et al. (2005) identified a key role for the circadian locomotor output cycles kaput (CLOCK) gene in the regulation of drug reward. Mice bearing a dominant negative mutation in the CLOCK gene (CLOCK 19 mice) exhibit increased cocaine sensitivity and preference. Furthermore, these mice exhibit increased locomotor activity, reduced anxiety-like and depression-like behavior, increased intracranial self-stimulation (ICSS) at a lower threshold, and increased dopaminergic cell activity in the VTA (McClung et al., 2005; Roybal et al., 2007). The goal of the proposed research training plan is to identify the role of CLOCK in specific brain regions as a mediator of ethanol-related behavior. First, we will determine how chronic binge ethanol consumption regulates expression levels of CLOCK in reward- and stress-related regions of the brain using in situ hybridization. Second, we will determine how a dominant negative mutation of CLOCK (CLOCK 19 mice) affects measures of operant oral ethanol self-administration. Finally, we will determine if CLOCK function in the VTA is important in modulating ethanol intake and relapse-like drinking behavior using RNAi. Further examination of the role of circadian genes in alcohol-related behaviors will have exciting translational significance for treatment, as many recovering addicts exhibit circadian disruptions that persist in recovery and contribute to relapse. I have a strong interest to perform alcohol research at the molecular and behavioral levels. The goal of this training plan is to provide me with detailed expertise in the use of cutting edge techniques and approaches, conversion of data into high-visibility publications, and prepare me for a transition to independence. I am motivated, diligent, and dedicated to advancing the treatment of alcoholism. This plan, combined with the excellent group of researchers at UTSW will allow me to obtain my goals outlined in this proposal, as well as prepare me for a successful independent research career in the alcohol and drug abuse field. The funding of this NRSA application is instrumental in my success.