Project 4-The ability of Circadian Genes in the VTA-Nac circuit to regulate mood

项目4的重点是腹侧被盖区(VTA)-伏隔核中昼夜节律基因的能力。 (NAC)调节情绪和动机状态的回路。这与人们认识到异常情绪有关 许多抑郁症患者的其他症状显示出明显的昼夜波动。我们有 证明了NPAS2(神经元PAS结构域蛋白2)是一种与 时钟，调节动物对情绪刺激的反应，包括它们在动物模型中的活动 抑郁症。有趣的是，NPAS2在下丘脑的视交叉上核(SCN)中不表达。 对昼夜节律振荡及其环境照明的夹带很重要的区域。相反， NPAS2在NAC中表达最高。我们的假设是，NPAS2在NAC内起作用 导致情绪、运动活动和动机的昼夜节律变化。与此同时，我们有 建立了时钟本身对情绪的强大影响：缺乏功能时钟蛋白的小鼠表现出 一系列让人联想到躁狂的行为症状。这种表型被锂逆转了，我们 越来越多的证据表明，VTA中的时钟活动本身是这种行为的重要中介 表型。 拟议研究的目标是对NPAS2、CLOCK、 以及相关的昼夜节律基因产物在VTA和NAC中的表达 动力。这将通过使用具有这些不同基因突变的小鼠和病毒来实现。 有选择地操纵VTA-NAC内基因活性的载体。此外，我们还将进一步 慢性暴露对VTA和NAC昼夜节律基因表达的调节 压力和抗抑郁治疗。此外，我们还将通过以下方式识别和表征目标基因 哪些NPAS2、Clock和其他昼夜节律基因作为转录因子调节VTA-NAC 巡回赛。我们还对这些昼夜节律基因和CREB之间的相互作用感兴趣。CREB已知的是 调节SCN中的某些昼夜节律基因，我们在VTA-NAC中也发现了类似的调节。此外， CREB和昼夜节律转录因子共享一些相同的靶基因(例如，CCK)。 这些大脑奖励区域。

Project 4 focuses on the ability of circadian genes in the ventral tegmental area (VTA)-nucleus accumbens (NAc) circuit to regulate mood and motivational state. This is related to the knowledge that abnormal mood and other symptoms in many patients with depression show prominent circadian oscillations. We have demonstrated that NPAS2 (neuronal PAS domain protein 2), a transcription factor highly homologous to Clock, regulates an animal's responsiveness to emotional stimuli, including their activity in animal models of depression. Interestingly, NPAS2 is not expressed in the suprachiasmatic nucleus (SCN), a hypothalamic region important for circadian oscillations and their entrainment by environmental lighting. Rather, the highest expression of NPAS2 is seen in the NAc. Our hypothesis is that NPAS2acting within the NAc contributes to circadian variations in mood, locomotor activity, and motivation. In parallel, we have established a powerful influence of Clock itself on mood: mice lacking functional Clock protein exhibit a striking array of behavioral symptoms reminiscent of mania. This phenotype is reversed by lithium, and we have growing evidence that Clock action in the VTA per se is an important mediator of this behavioral phenotype. The goal of the proposed studies is to carry out a systematic evaluation of the role played by NPAS2, Clock, and related circadian gene products expressed in the VTA and NAc in the regulation of mood and motivation. This will be accomplished by use of mice with mutations in these various genes and of viral vectors that selectively manipulate the activity of the genes within the VTA-NAc. In addition, we will further establish the regulation of circadian gene expression in the VTA and NAc in response to chronic exposure to stress and antidepressant treatments. As well, we will identify and characterize the target genes through which NPAS2, Clock, and other circadian genes, acting as transcription factors, regulate the VTA-NAc circuit. We are also interested in cross talk between these circadian genes and CREB. CREB is known to regulate certain circadian genes in SCN, and we have found similar regulation in the VTA-NAc. Moreover, CREB, and circadian transcription factors, share some of the same target genes (e.g., cholecystokinin) in these brain reward regions.