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

项目4主要研究腹侧被盖区（VTA）-丘脑核的昼夜节律基因的能力 (NAc)调节情绪和动机状态的电路。这与情绪异常的知识有关 许多抑郁症患者的生理和其他症状表现出明显的昼夜节律振荡。我们有 证明NPAS2（神经元PAS结构域蛋白2），一种与 生物钟，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。 萧条有趣的是，NPAS2在下丘脑视交叉上核（SCN）中不表达， 对昼夜节律振荡及其被环境照明夹带很重要的区域。而是 在NAc中观察到NPAS2的最高表达。我们的假设是NPAS2在国家行动委员会内采取行动c 有助于情绪、运动活动和动机的昼夜变化。同时，我们有 建立了时钟本身对情绪的强大影响：缺乏功能性时钟蛋白的小鼠表现出一种 一系列令人联想到躁狂的行为症状这种表型被锂逆转，我们 越来越多的证据表明，VTA中的时钟动作本身就是这种行为的重要媒介。 表型。 拟议研究的目标是对NPAS2，Clock， 以及在VTA和NAc中表达的相关昼夜节律基因产物在调节情绪和 动机这将通过使用在这些不同基因中具有突变的小鼠和病毒载体来实现。 选择性操纵VTA-NAc内基因活性的载体。此外，我们将进一步 建立VTA和NAc中昼夜节律基因表达的调节，以响应慢性暴露于 压力和抗抑郁治疗。同时，我们将通过以下方式识别和表征靶基因： 其中NPAS2、Clock和其他昼夜节律基因作为转录因子调节VTA-NAc， 电路.我们也对这些昼夜节律基因和CREB之间的相互作用感兴趣。众所周知，CREB 调节SCN中的某些昼夜节律基因，我们在VTA-NAc中发现了类似的调节。此外，委员会认为， CREB和昼夜节律转录因子共享一些相同的靶基因（例如，胆囊收缩素） 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.