Project 6 Interactions of Serotonin and Circadian Signaling Networks

5-羟色胺和大脑的昼夜节律基因和蛋白质网络具有广泛的相互作用， 显然会影响人类的心理健康。大脑的主要昼夜节律起搏器， 视交叉上核(SCN)直接接受5-羟色胺能神经支配，进而形成多突触 输出到中脑的5-羟色胺能核团。在基因网络水平上，SERT等5HT信号基因 SHTRs在SCN中表达，而生物钟基因在5-羟色胺能神经元中表达 中缝核团的神经元。项目6：5-羟色胺与昼夜节律信号网络的相互作用 麦克马洪将他的实验室的专业知识与多名孔特中心调查人员的专业知识相结合，以检查 5-羟色胺能系统的遗传变异和环境操纵对细胞和 5-羟色胺能神经元的分子特性、SCN回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，5-羟色胺能和昼夜节律网络 大脑通过遗传、生理和发育机制相互关联，而大脑中的扰动 一个系统影响另一个系统的功能，导致与人类有关的行为变化 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 5-羟色胺能和昼夜节律系统的信号分子以及表观遗传操作。 具体地说，他将使用电生理、分子、行为和实时基因表达成像 终点定义昼夜节律和5-羟色胺基因的遗传操作对(/)5-羟色胺神经元功能的影响 5-羟色胺基因网络中遗传操作/变异的昼夜节律功能；(Hi)5-羟色胺和 昼夜节律功能的环境调控和5-羟色胺网络的发展。长期的 拟议项目的目标是了解两国之间的具体机制联系 大脑的5-羟色胺能和昼夜节律网络。这样的理解将提供一个更广泛的基础 了解人类情绪障碍的病因、病理生理学和治疗干预 昼夜节律失调和5-羟色胺能功能紊乱混合在一起。中提出的实验 项目6将确定改变5-羟色胺分子信号对5-羟色胺神经元的功能影响 网络，描述了昼夜节律基因网络对5HT功能的影响，并定义了 明确的5-羟色胺调节行为的神经底物。通过这些努力，项目6将确定 新的基因相互作用将在Conte中心的合作项目中进一步探索，生成 关于5-羟色胺受体改变的分子、细胞和行为结果的新假说 和转运蛋白基因，并进一步阐明定义5-羟色胺神经元网络的机制 以及5HT网络对其神经指标的影响。

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.