Project 6 Interactions of Serotonin and Circadian Signaling Networks

项目 6 血清素和昼夜节律信号网络的相互作用

• 批准号: 8134928
• 负责人: DOUGLAS G MCMAHON
• 金额: $ 18.27万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134928
• 关键词: Ablation; Address; Affect; Animal Model; Behavior; Behavioral; Biological Neural Networks; Brain; Cell Nucleus; Circadian Dysregulation; Circadian Rhythms; Development; Epigenetic Process; Etiology; Exposure to; Functional disorder; Gene Expression; Gene Mutation; Gene Proteins; Genes; Genetic; Genetic Variation; Glucocorticoid Receptor; Goals; Human; Image; In Vitro; Knock-out; Light; Link; Mental Health; Midbrain structure; Molecular; Mood Disorders; Mus; Mutation; Neurons; Outcome; Output; Periodicity; Physiological; Property; Reporter Genes; Research Personnel; Resources; Serotonin; Signal Transduction; Signaling Molecule; System; Testing; Therapeutic Intervention; Time; Variant; base; circadian pacemaker; gene interaction; genetic manipulation; mouse model; nerve supply; neuron development; novel; raphe nuclei; relating to nervous system; research study; serotonin transporter; suprachiasmatic nucleus; transcription factor

5HT and circadian gene and protein networks of the brain have extensive, reciprocal interactions that demonstrably impact human mental health. The master circadian pacemaker of the brain, the suprachiasmatic nucleus (SCN), receives direct serotonergic innervation and, in turn, makes polysynaptic output to the mid-brain serotonergic nuclei. At the gene network level, 5HT signaling genes such as SERT and SHTRs are expressed in the SCN, whereas circadian clock genes are expressed in serotonergic neurons of the raphe nuclei. In Project 6: Interactions of 5HT and Circadian Signaling Networks, Doug McMahon combines his lab's expertise with that of multiple Conte Center investigators to examine the effects of genetic variation in, and environmental manipulation of, the serotonergic system on the cellular and molecular properties of serotonergic neurons, SCN circuitry and a readily quantified behavior, circadian ocomotor rhythms. McMahon's overall hypothesis is that the serotonergic and circadian networks of the brain are interlocked through genetic, physiological and developmental mechanisms, and that perturbation in one system affects the function of the other, resulting in behavioral alterations associated with human affective disorders. He will test this hypothesis using mouse models with genetic alterations in specific signaling molecules of the serotonergic and circadian systems as well as epigenetic manipulations. Specifically, he will use electrophysiological, molecular, behavioral and real-time gene expression imaging endpoints to define the impact on: (/) 5HT neuron function of genetic manipulation of circadian and 5HT gene networks; (//) circadian function of genetic manipulation/variation in 5HT gene networks; (Hi) 5HT and circadian function of environmental manipulation of circadian and 5HT network development. The long-term goal of the proposed project is to gain an understanding of the specific mechanistic links between the serotonergic and circadian networks of the brain. Such an understanding will provide an expanded basis fo understanding the etiology, pathophysiology and therapeutic intervention into human mood disorders, in which dysregulation of circadian and serotonergic function are co-mingled. The experiments proposed in Project 6 will determine the functional consequences for 5HT neurons of altering the 5HT molecular signaling network, characterizing the impact of circadian gene network on 5HT function and defining the changes in the neural substrate for a defined 5HT-modulated behavior. Through these efforts, Project 6 will identify novel gene interactions to be further explored in the collaborating projects of the Conte Center, generating novel hypotheses regarding the molecular, cellular and behavioral outcomes of alterations in 5HT recepto and transporter genes and further elucidating the mechanisms involved in defining the 5HT neuron network and the influence of the 5HT network on its neural targets.

大脑的5HT和昼夜节律基因和蛋白质网络具有广泛的，相互的相互作用 明显影响人类心理健康。大脑的昼夜节奏起搏器大师 肌核上核（SCN），接收直接的血清素能神经，反过来又使多突触 输出到中脑血清素能核。在基因网络级别，5HT信号基因（例如Sert） SHTR在SCN中表达 raphe核的神经元。在项目6中：5HT和昼夜信号网络的相互作用，道格 麦克马洪将实验室的专业知识与多个孔戴中心调查员的专业知识相结合，以研究 血清素能系统对细胞的遗传变异和环境操纵的影响 血清素能神经元的分子特性，SCN电路和容易定量的行为，昼夜节律 Ocomotor节奏。麦克马洪的总体假设是 大脑通过遗传，生理和发育机制互锁，而这种扰动 一个系统会影响另一个系统的功能，从而导致与人相关的行为改变 情感障碍。他将使用特定的遗传改变的小鼠模型检验该假设 血清素能和昼夜节律系统以及表观遗传操作的信号分子。 具体而言，他将使用电生理，分子，行为和实时基因表达成像 定义对以下影响的终点：（/）5HT神经元的循环和5HT基因遗传操作的神经元功能 网络； （//）5HT基因网络中遗传操纵/变异的昼夜节律功能； （嗨）5HT和 昼夜节律和5HT网络开发环境操纵的昼夜节律功能。长期 拟议项目的目标是了解对特定机械联系的理解 大脑的血清素能和昼夜节律网络。这样的理解将为FO提供扩展的基础 了解对人情绪障碍的病因，病理生理学和治疗干预， 昼夜节律和血清素能功能的失调是共汇合的。提出的实验 项目6将确定改变5HT分子信号的5HT神经元的功能后果 网络，表征昼夜节律网络对5HT功能的影响并定义的变化 定义的5HT调节行为的神经底物。通过这些努力，项目6将确定 新颖的基因相互作用将在孔戴中心的合作项目中进一步探讨 关于5HT受体改变的分子，细胞和行为结果的新假设 和转运蛋白基因，并进一步阐明定义5HT神经元网络所涉及的机制 以及5HT网络对其神经靶标的影响。