Neurobiology of the Circadian Clock

昼夜节律钟的神经生物学

基本信息

批准号：
10446034
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/10446034
关键词：
ARNTL gene Address 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 Institutes 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 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 network novel optogenetics relating to nervous system 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.

项目概要神经科学的一个基本问题是基因表达的变化如何转化为神经元生理学，并最终影响大脑的 24 小时计时机制，或者说。生物钟是一个特别适合研究神经可塑性和基因行为的系统产生并驱动生理和行为昼夜节律的神经网络是。位于下丘脑视交叉上核 (SCN) 内的 SCN 神经元表现出内源性。自发尖峰频率的昼夜节律，即使是孤立的单个细胞，在这些神经元内也是如此一个定义的“时钟基因”网络，形成自动调节转录/翻译反馈环路（TTFL）产生近24小时的节奏。我们对 SCN 夹带和起搏器机制的了解存在重大差距与节律生成、实时动态 SCN 分子和神经网络不同，它具有可塑性。夹带过程中的反应以前是无法观察到的，因此关于这方面的知识有限我们已经开发并建立了新的方法。使用一种方法能够直接观察 SCN 分子和神经网络夹带拓扑它将时钟神经元电活动的 ChrimsonR 光遗传学操作与 PER2::LUC real- 相结合时钟基因激活的时间报告（EX vivo CIrcadian Timing and Entrainment，EXCITE 提供）。对隔离 SCN 进行重复输入刺激的精确定时、持续时间和强度，并跟踪 SCN 时钟离体分离的 SCN 在高时间和空间分辨率下进行 3-5 周的分子节律。该系统惊人地再现了完整动物生物钟夹带的典型特征，包括具有周期后效应、周期匹配和系统相位角差异的类光相位响应偏离 24 小时的刺激，以及最低可容忍夜间光周期的差异夹带。我们将使用 EXCITE 来检查 - (1) SCN 夹带的分子和神经网络拓扑可塑性，(2) SCN 神经网络夹带拓扑，以及 (3) 光周期分子机制诱导 SCN 网络可塑性的成功完成将为 SCN 提供新的见解。夹带和可塑性 - SCN 分子和神经网络如何通过光输入进行修改以产生定义 SCN 编码光历史和光周期的机制。为操纵 SCN 神经和转录网络以改善昼夜节律紊乱开辟了道路。