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

项目4-VTA-Nac回路中昼夜节律基因调节情绪的能力

• 批准号: 8114144
• 负责人: STEVEN L MCKNIGHT
• 金额: $ 14.57万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114144
• 关键词: Animal Model; Animals; Antidepressive Agents; Behavior; Behavioral; Behavioral Symptoms; Brain; CREB1 gene; Cholecystokinin; Chronic; Circadian Rhythms; Clock protein; Employee Strikes; Evaluation; Exhibits; Exposure to; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Goals; Hypothalamic structure; Knowledge; Lighting; Lithium; Manic; Mediator of activation protein; Mental Depression; Molecular; Molecular Target; Moods; Motivation; Motor Activity; Mus; Mutation; Neurons; Nucleus Accumbens; Patients; Phenotype; Play; Proteins; Regulation; Rewards; Role; Stress; Symptoms; Tertiary Protein Structure; Variant; Ventral Tegmental Area; Viral Vector; emotional stimulus; interest; mood regulation; response; suprachiasmatic nucleus; transcription factor

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.

项目4关注腹侧被盖区（VTA）——伏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 许多抑郁症患者的其他症状表现出明显的昼夜节律波动。我们有 证明 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 沮丧。有趣的是，NPAS2 在下丘脑的视交叉上核 (SCN) 中不表达。 该区域对于昼夜节律振荡及其受环境照明的影响非常重要。相反， NPAS2 的最高表达出现在 NAc 中。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 确定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 一系列引人注目的行为症状让人想起躁狂症。这种表型被锂逆转，我们 越来越多的证据表明，VTA 本身的时钟动作是这种行为的重要调节因素 表型。 拟议研究的目标是对 NPAS2、时钟、 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。这将通过使用这些不同基因突变的小鼠和病毒来实现 选择性操纵 VTA-NAc 内基因活性的载体。此外，我们还将进一步 建立 VTA 和 NAc 中昼夜节律基因表达的调节，以响应长期暴露 压力和抗抑郁治疗。此外，我们将通过以下方式识别和表征目标基因： 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。我们还对这些昼夜节律基因和 CREB ​​之间的交互感兴趣。据了解，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。而且， CREB ​​和昼夜节律转录因子在生物钟中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。