Neurobiology of the Circadian Clock

昼夜节律钟的神经生物学

基本信息

批准号：
10705049
负责人：
DOUGLAS G MCMAHON
金额：
$ 32.16万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705049
关键词：
ARNTL gene Affect Aging Animals Behavior Biological Biological Clocks Bioluminescence Brain Cells Circadian Dysregulation Circadian Rhythms Cluster Analysis Color Cre driver Disease Exhibits Feedback Frequencies GRP gene Gene Activation Gene Expression Generations Genes Genetic Transcription Goals Health Hour Human Hypothalamic structure Image Intervention Knowledge Laboratories Lateral Length Light Mediating Membrane Potentials Mental Depression Metabolic syndrome Methods Molecular Mood Disorders Neurobiology Neuronal Plasticity Neurons Neurosciences Opsin Pacemakers Periodicity Peripheral Phase Phosphoric Monoester Hydrolases Photoperiod Physiology Problem behavior Process Property Recording of previous events Recurrence Reporting Research Resolution Schizophrenia Seasons Signal Pathway Signal Transduction Sleep Disorders Sleep Wake Cycle Specificity Stimulus Synapses System Testing Time Translating Translations Venus age related arm behavioral plasticity cell type circadian circadian pacemaker experimental study genetic manipulation insight knock-down molecular clock neural neural network novel optogenetics response sleep abnormalities small hairpin RNA suprachiasmatic nucleus transcriptomics

项目摘要

PROJECT SUMMARY A fundamental question in neuroscience is how changes in gene expression are translated into changes in neuronal physiology, and ultimately into changes in behavior. The brain’s 24-hour timing mechanism, or biological clock, is a system that is uniquely suited to the study of neural plasticity and the genes-to-behavior problem. The neural network that generates and drives circadian rhythms in physiology and behavior is located within the suprachiasmatic nuclei (SCN) of the hypothalamus. SCN neurons exhibit endogenous circadian rhythms in spontaneous spike frequency, even as single cells in isolation, and within these neurons is a defined network of “clock genes” that forms autoregulatory transcription/translation feedback loops (TTFLs) to generate near 24-hour rhythms. There are key gaps in our knowledge regarding the mechanisms of SCN entrainment and the pacemaker plasticity it induces. Unlike rhythms generation, real-time dynamic SCN molecular and neural network responses during entrainment have been previously un-observable, and thus knowledge is limited regarding the actual dynamic topologies of entrainment at those levels. We have developed and instituted novel methods enabling direct observation of SCN molecular and neural network entrainment topologies using an approach that combines ChrimsonR optogenetic manipulation of clock neuron electrical activity with PER2::LUC real- time reporting of clock gene activation (EX vivo CIrcadian Timing and Entrainment, EXCITE). EXCITE provides precise timing, duration and intensity of recurring input stimulation to the isolated SCN, and tracks SCN clock molecular rhythms at high temporal and spatial resolution for 3-5 weeks ex vivo. The isolated SCN in this system strikingly recapitulates canonical features of circadian clock entrainment in intact animals, including light-like phase responses with period after-effects, period matching and systematic phase angle differences to stimuli that deviate from 24 hours, and differential entrainment to photoperiods with a minimum tolerable night. We will use EXCITE to examine - (1) Molecular and Neural Network Topologies for SCN Entrainment and Plasticity, (2) SCN Neural Network Topology of Entrainment, and (3) Molecular Mechanisms of Photoperiod- Induced SCN Network Plasticity. Successful completion of these aims will provide novel insight into SCN entrainment and plasticity - how the SCN molecular and neural networks are modified by light input to result in behavioral plasticity. Defining the mechanisms by which the SCN encodes light history and photoperiod will open the way for manipulation of SCN neural and transcriptional networks to ameliorate circadian disorders.

项目摘要神经科学中的一个基本问题是，基因表达的变化如何转化为变化神经元生理，最终变成行为的变化。大脑的24小时计时机制或生物钟，是一种独特的系统，适合于神经塑性的研究和行为基因问题。产生和驱动生理和行为节奏的昼夜节律的神经网络是位于下丘脑的核（SCN）内。 SCN神经元暴露于内源性自发峰值频率中的昼夜节律，即使是孤立的单个细胞，并且在这些神经元内是形成自动调节转录/翻译反馈回路（TTFLS）的“时钟基因”的定义网络产生接近24小时的节奏。关于SCN入口机制和起搏器的机制，我们的知识有关键的差距可塑性会影响。与节奏生成不同，实时动态SCN分子和神经网络以前，在盛立过程中的反应是不可观察的，因此知识受到限制在这些级别上的实际动态拓扑。我们已经开发并建立了新颖的方法使用方法可以直接观察SCN分子和神经网络入口拓扑结合了Chrimsonr对时钟神经元电活动的光遗传学操纵与PER2 :: LUC REAL- 时钟基因激活的时间报告（离体昼夜节律的时间和夹带，激发）。激励提供对孤立的SCN的重复输入刺激的精确时序，持续时间和强度，并跟踪SCN时钟在高临时分辨率和空间分辨率下进行3-5周的分子节律。其中孤立的SCN 系统概括了完整动物的昼夜节律入口的规范特征，包括灯样期反应具有周期后效应，周期匹配和系统的相位角度差异从24小时偏离24小时的刺激，并具有最低耐受夜晚的光周期入口。我们将使用兴奋来检查 - （1）SCN夹带的分子和神经网络拓扑可塑性，（2）SCN神经网络夹带的神经网络拓扑，（3）光周期的分子机制诱导SCN网络可塑性。这些目标的成功完成将为SCN提供新颖的见解盛装和可塑性 - 如何通过光输入来修改SCN分子和神经网络以导致行为可塑性。定义SCN编码光历史和光周期的机制将为操纵SCN神经和转录网络的操纵开辟道路，以改善昼夜节律疾病。