Hippocampal Cellular Rhythms

海马细胞节律

基本信息

批准号：
8932746
负责人：
KARL H OBRIETAN
金额：
$ 38.43万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-24 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8932746
关键词：
Address Aging-Related Process Alzheimer&apos s Disease Animal Mammary Glands Automobile Driving Behavioral Biochemical Process Birds Boxing Brain Brain Pathology Brain region CREB1 gene Cells Circadian Dysregulation Circadian Rhythms Cognition Complex Consensus Cues Data Data Set Eels Epilepsy Event Gene Expression Gene Expression Profile Generations Genes Goals Hip region structure Hippocampus (Brain)Hour Human Ions Knockout Mice Label Lead Learning MAP Kinase Gene Memory Methods MicroRNAs Molecular Mood Disorders Moods Morphology Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuronal Plasticity Neurons Pathway interactions Phase Phosphotransferases Physiological Physiological Processes Physiology Play Population Population Heterogeneity Process Property Prosencephalon RNA Reporter Reporting Research Role Shapes Signal Pathway Signal Transduction Sleep Sleep Wake Cycle Syndrome System Technology Testing Time Transgenic Mice Transgenic Organisms Vertebral column Work base behavior influence body system circadian pacemaker cognitive capacity cognitive process density excitatory neuron executive function hippocampal pyramidal neuron in vivo innovation insight interdisciplinary approach model design mouse model neural circuit novel public health relevance research study suprachiasmatic nucleus

项目摘要

DESCRIPTION (provided by applicant): Human physiology is modulated by an inherent 24-hr (circadian) clock. Central to this time-keeping process is the master circadian pacemaker located within the suprachiasmatic nucleus (SCN). This relatively small brain region provides a daily timing cue that orchestrates ancillary clock timing systems found in all organ systems of the body. Of note, within the central nervous system (CNS), the SCN appears to function in coordination with forebrain oscillators to modulate an array of complex cognitive processes, and the disruption of clock physiology as a result of the aging process, neurodegeneration or photic desynchrony has profound effects on mood, memory and executive function. These observations raise questions about the functional features of forebrain cellular oscillators, clock gated synaptic circuitry and rhythmic gene expression patterns. In this application we propose to employ a wide array of innovative interdisciplinary approaches to determine the functional significance and mechanistic underpinnings of clock physiology in the forebrain. This application is predicated on the central hypothesis that forebrain circadian clocks function in coordination with the SCN to modulate cellular plasticity as a function of the time-of-day. To maintain focus, our analysis of forebrain oscillatory activity will be centered on the pyramidal neurons of the hippocampal CA1 cell layer. In Aim 1, we propose to perform a cellular-level analysis of clock timing. For these studies, we will use a combination of innovative transgenic reporter mouse models to address the following questions: 1) does the CA1 cell layer consist of a homogenous or heterogeneous population of oscillators, and 2) is there a relationship between forebrain clock cell phase and the responsiveness of signaling pathways that contribute to neuronal plasticity. In Aim 2, we propose to test the role that forebrain clocks play in the generation of molecular rhythms. Although rhythmic activity has been reported in the forebrain, we do not know what role these forebrain oscillators play in driving these rhythms. Here, we propose to use a conditional knockout mouse line, where the circadian clock is deleted in forebrain excitatory neurons to assess how forebrain timing shapes kinase rhythms. Further, to assess how the forebrain clock shapes the transcriptional profile of the CA1 cell layer, we propose to employ an array-based transcriptome profiling approaches in combination with a newly developed in vivo RNA labeling and isolation approach which will allow us to selectively profile gene expression from discrete cell populations. In Aim 3 we will examine whether microRNA132 functions as a clock-gated regulator of cellular plasticity and cognition. For this study, we propose a novel set of transgenic and knockout mouse models designed to 'lock' microR132 to stable physiological levels across the circadian cycle. The combined use of these approaches will provide an unparalleled level of insight into the role that forebrain clock timing plays in shaping forebrain functionality from the molecular to the behavioral level.

描述（由申请人提供）：人类生理学由固有的24小时（昼夜节律）时钟调节。该时间保存过程的核心是位于上核（SCN）内的昼夜节律起搏器。这个相对较小的大脑区域提供了每日的时序提示，该提示精心策划了人体所有器官系统中发现的辅助时钟正时系统。值得注意的是，在中枢神经系统（CNS）内，SCN似乎与前脑振荡器协调起作用，以调节一系列复杂的认知过程，并且由于衰老过程，神经退行性或光学的DESynchrony对时钟生理的破坏对情绪，记忆和执行功能具有深远的影响。这些观察结果提出了有关前脑细胞振荡器的功能特征的问题门控突触回路和节奏基因表达模式。在此应用中，我们建议采用各种创新的跨学科方法来确定前脑时钟生理学的功能意义和机械基础。该应用是基于中心假设，即前脑昼夜节律与SCN协调起作用，以调节细胞可塑性，这是当天时间的函数。为了保持焦点，我们对前脑振荡活性的分析将集中在海马CA1细胞层的锥体神经元上。在AIM 1中，我们建议对时钟正时进行细胞级分析。在这些研究中，我们将使用创新的转基因记者小鼠模型的组合来解决以下问题：1）CA1细胞层是否由振荡器的同质或异质群组成，而2）在前脑时钟细胞相和信号通路的响应能力之间存在关系，从而有助于神经元可塑性。在AIM 2中，我们建议测试前脑时钟在分子节律产生中所起的作用。尽管在前脑中已经报道了节奏活动，但我们不知道这些前脑振荡器在推动这些节奏中起着什么作用。在这里，我们建议使用条件敲除小鼠线，其中昼夜节律时钟在前脑兴奋性神经元中被删除，以评估前脑的定时如何塑造激酶的节奏。此外，为了评估前脑时钟如何塑造CA1细胞层的转录曲线，我们建议采用基于阵列的转录组分析方法与新开发的体内RNA标记和隔离方法结合使用，这将使我们能够从离散细胞群中选择性地概述基因表达。在AIM 3中，我们将检查MicroRNA132是否充当细胞塑性和认知的时钟门控调节剂。在这项研究中，我们提出了一组新型的转基因和基因敲除小鼠模型，该模型旨在将MicroR132“锁定”到整个昼夜节律的稳定生理水平。这些方法的合并使用将提供无与伦比的洞察力，以了解前脑时钟正时在将前脑功能从分子到行为水平塑造前脑功能中所起的作用。