Hippocampal Cellular Rhythms

海马细胞节律

• 批准号: 9270610
• 负责人: KARL H OBRIETAN
• 金额: $ 41.82万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/9270610
• 关键词: Address; Aging-Related Process; Alzheimer' s Disease; Automobile Driving; Behavioral; Biochemical Process; Birds; 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; Genetic Transcription; 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; Periodicity; Phase; Phosphotransferases; Physiological; Physiological Processes; Physiology; Play; Population; Population Heterogeneity; Process; Property; Prosencephalon; RNA; Reporter; Reporting; Research; Role; Shapes; Signal Pathway; Signal Transduction; Sleep Wake Cycle; 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; experimental study; hippocampal pyramidal neuron; in vivo; innovation; insight; interdisciplinary approach; model design; mouse model; neural circuit; novel; public health relevance; sleep syndrome; suprachiasmatic nucleus; transcriptome

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(申请人提供)：人体生理学由固有的24小时(昼夜节律)时钟调节。这种计时过程的中心是位于视交叉上核(SCN)内的主昼夜节律起搏器。这个相对较小的大脑区域提供每天的计时线索，协调在身体所有器官系统中发现的辅助时钟计时系统。值得注意的是，在中枢神经系统(CNS)中，SCN似乎与前脑振荡器协同工作，调节一系列复杂的认知过程，而由于衰老、神经退行性或光去同步性导致的时钟生理中断对情绪、记忆和执行功能有深远的影响。这些观察提出了关于前脑细胞振荡器、时钟的功能特征的问题 门控突触回路和节律性基因表达模式。在这项应用中，我们建议使用一系列创新的跨学科方法来确定前脑中时钟生理学的功能意义和机制基础。这一应用是基于一个中心假设，即前脑昼夜节律时钟与SCN协同工作，作为一天中的时间函数来调节细胞的可塑性。为了保持焦点，我们对前脑振荡活动的分析将集中在海马CA1细胞层的锥体神经元上。在目标1中，我们建议执行时钟计时的细胞级别的分析。在这些研究中，我们将使用一组创新的转基因报告鼠模型来解决以下问题：1)CA1细胞层由同种或不同种类的振荡器组成，以及2)前脑时钟细胞时相与促进神经元可塑性的信号通路的反应性之间是否存在关系。在目标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。尽管前脑有节律活动的报道，但我们不知道这些前脑振荡器在驱动这些节律中扮演了什么角色。在这里，我们建议使用条件基因敲除小鼠品系，其中前脑兴奋性神经元中的昼夜节律时钟被删除，以评估前脑计时如何塑造激酶节律。此外，为了评估前脑时钟如何塑造CA1细胞层的转录图谱，我们建议使用基于阵列的转录组谱方法与新开发的体内RNA标记和分离方法相结合，这将使我们能够选择性地从离散细胞群体中分析基因表达。在目标3中，我们将研究microRNA132是否作为细胞可塑性和认知的时钟门控调节器发挥作用。在这项研究中，我们提出了一套新颖的转基因和基因敲除小鼠模型，旨在将microR132‘锁定’到昼夜节律周期中稳定的生理水平。这些方法的结合使用将提供无与伦比的洞察力，了解前脑时钟计时在塑造从分子到行为层面的前脑功能中所起的作用。