Integration of photic and nonphotic signaling in the circadian pacemaker

描述(申请人提供)：哺乳动物生物钟驱动并维持生理上的24小时节律，并将多个信号整合成与环境一致的相变。这项建议的研究目标是研究哺乳动物初级昼夜节律起搏器-视交叉上核(SCN)内这种整合的神经肽通讯。长期目标是提供必要的培训，以促进受赠者从有指导的博士后研究职位转变为独立的终身教职教师职位。在发起人的指导下，指导阶段将研究在SCN内光转导过程中由胃泌素释放肽(GRP)引起的神经生理变化的离子基础。这一阶段还将为教师寻找工作和关键的膜片钳电生理学培训提供必要的时间和指导，这些培训将用于为研究计划中概述的实验建立模型范例。为了研究SCN内的昼夜节律网络如何解释相互冲突的相移刺激，实时时钟基因成像、药理学和电生理终点将结合在一起，使用独特的动物模型(PER1：：GFP)来探索光和非光刺激的相互作用以及随后的神经生理学和分子节律的变化，该动物模型允许检查单个活的、表达PERT的细胞的神经生理特性。具体地说，我将使用Per7：：GFP和PER2：：Luc小鼠来：(1)确定并发的光和非光诱导刺激的相位依赖性和转导机制，(2)研究白天与GRP介导的光信号转导相关的神经电路和神经生理学，以及(3)确定非光递质神经肽Y(NPY)的神经生理学和分子效应是否在整个昼夜周期中发生变化。拟议的研究计划将极大地促进建立一个成功的研究昼夜节律神经生理学和行为的独立研究计划的长期目标。这些研究的结果对人类健康有影响，包括与情绪障碍和倒班工作相关的昼夜节律紊乱。 相关性：这项研究计划将调查大脑的生物钟如何在同时存在的情况下整合光和非光重置环境刺激(如压力、运动等)。这些研究的结果将对时差/轮班工作、昼夜节律紊乱以及那些患有情绪和发育障碍的人的昼夜节律紊乱的治疗发展产生影响。

DESCRIPTION (provided by applicant): The mammalian circadian clock drives and maintains 24-h rhythms in physiology and integrates multiple signals into a phase change consistent with the environment. The research goal of this proposal is to investigate neuropeptide communication underlying this integration within the primary, mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN). The long-term goal is to provide essential training that will facilitate the transition of the grantee from a mentored postdoctoral research position to an independent, tenure-track faculty position. Under the direction of the sponsor, the mentored phase will investigate the ionic basis for neurophysiological changes induced by the peptide, gastrin-releasing peptide (GRP), during intra- SCN photic transduction. This phase will also provide the time and mentoring necessary for a faculty job search and critical training in patch clamp electrophysiology that will be used to establish a model paradigm for the experiments outlined in the research plan. In order to investigate how the circadian network within the SCN interprets conflicting phase shifting stimuli, real-time clock gene imaging, pharmacological and electrophysiological endpoints will be combined to explore the interaction of photic and nonphotic stimuli and the subsequent changes in neurophysiology and molecular rhythms using a unique animal model (Per1::GFP) that allows examination of neurophysiological properties of individual, living, Pert-expressing cells. Specifically, I will use Per7::GFP and PER2::LUC mice to: (1) determine the phase dependence and transduction mechanisms for concurrent photic and nonphotic entraining stimuli, (2) investigate the neural circuitry and neurophysiology associated with GRP-mediated photic transduction during the day, and (3) determine whether the neurophysiological and molecular effects of the nonphotic transmitter, neuropeptide Y (NPY), vary across the circadian cycle. The proposed research plan will substantially contribute to the long- term goal of establishing a successful independent research program studying circadian neurophysiology and behavior. The results of these studies have implications for human health, including circadian rhythm disruptions associating with mood disorders and shift work. RELEVANCE: This research plan will investigate how the brain's biological clock integrates light and nonphotic resetting environmental stimuli (e.g. stress, exercise, etc) when present simultaneously. The results of these studies will have implications for jet lag/shift work, circadian rhythm disorders, as well as treatment developments for circadian disruptions in those suffering from mood and developmental disorders.