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: 7305763
• 负责人: DOUGLAS G MCMAHON
• 金额: $ 19.1万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7305763
• 关键词: Ablation; Address; Affect; Animal Model; Behavior; Behavioral; Biological Neural Networks; Brain; Cell Nucleus; Circadian Dysregulation; Circadian Rhythms; Development; End Point; 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; novel; programs; 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.

5HT 与大脑的昼夜节律基因和蛋白质网络具有广泛的相互作用， 明显影响人类心理健康。大脑的主要昼夜节律起搏器 视交叉上核（SCN）接受直接的血清素神经支配，进而产生多突触 输出到中脑血清素能核。在基因网络层面，5HT信号基因如SERT 和 SHTR 在 SCN 中表达，而生物钟基因在 5-羟色胺能细胞中表达 中缝核的神经元。在项目 6：5HT 和昼夜节律信号网络的相互作用中，Doug 麦克马洪将他的实验室的专业知识与多个孔特中心研究人员的专业知识相结合，以检查 血清素能系统的遗传变异和环境操纵对细胞和 血清素能神经元的分子特性、SCN 电路和易于量化的行为、昼夜节律 运动节律。麦克马洪的总体假设是，大脑的血清素能网络和昼夜节律网络 大脑通过遗传、生理和发育机制相互关联，并且扰动 一个系统影响另一个系统的功能，导致与人类相关的行为改变 情感障碍。他将使用具有特定基因改变的小鼠模型来检验这一假设。 血清素能和昼夜节律系统的信号分子以及表观遗传操作。 具体来说，他将使用电生理学、分子、行为和实时基因表达成像 终点定义对以下因素的影响：(/) 昼夜节律和 5HT 基因基因操作的 5HT 神经元功能 网络； (//) 5HT 基因网络中基因操作/变异的昼夜节律功能； （嗨）5HT 和 昼夜节律环境操纵的昼夜节律功能和 5HT 网络的发展。长期来看 拟议项目的目标是了解各因素之间的具体机制联系 大脑的血清素和昼夜节律网络。这种理解将为 了解人类情绪障碍的病因学、病理生理学和治疗干预， 昼夜节律失调和血清素功能混合在一起。中提出的实验 项目 6 将确定改变 5HT 分子信号传导对 5HT 神经元的功能影响 网络，表征昼夜节律基因网络对 5HT 功能的影响并定义 定义的 5HT 调节行为的神经基质。通过这些努力，项目 6 将确定 Conte 中心的合作项目将进一步探索新的基因相互作用，产生 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，并进一步阐明参与定义 5HT 神经元网络的机制 以及5HT网络对其神经目标的影响。