Hippocampal Cellular Rhythms
海马细胞节律
基本信息
- 批准号:8816285
- 负责人:
- 金额:$ 38.43万
- 依托单位:
- 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 2019-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAging-Related ProcessAlzheimer&aposs DiseaseAnimal Mammary GlandsAutomobile DrivingBehavioralBiochemical ProcessBirdsBoxingBrainBrain PathologyBrain regionCREB1 geneCellsCircadian DysregulationCircadian RhythmsCognitionCognitiveComplexConsensusCuesDataData SetEelsEpilepsyEventGene ExpressionGene Expression ProfileGenerationsGenesGoalsHip region structureHippocampus (Brain)HourHumanIonsKnockout MiceLabelLeadLearningMAP Kinase GeneMemoryMethodsMicroRNAsMolecularMood DisordersMoodsMorphologyNerve DegenerationNeuraxisNeurodegenerative DisordersNeuronal PlasticityNeuronsPathway interactionsPhasePhosphotransferasesPhysiologicalPhysiological ProcessesPhysiologyPlayPopulationPopulation HeterogeneityProcessPropertyProsencephalonRNAReporterReportingResearchRoleShapesSignal PathwaySignal TransductionSleepSleep Wake CycleSyndromeSystemTechnologyTestingTimeTransgenic MiceTransgenic OrganismsVertebral columnWorkbasebehavior influencebody systemcircadian pacemakerdensityexcitatory neuronexecutive functionhippocampal pyramidal neuronin vivoinnovationinsightinterdisciplinary approachmodel designmouse modelneural circuitnovelpublic health relevanceresearch studysuprachiasmatic 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):人体生理学由固有的24小时(昼夜节律)时钟调节。这个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了一个日常的时间线索,协调身体所有器官系统中的辅助时钟计时系统。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、神经变性或光退化而导致的时钟生理学的破坏对情绪、记忆和执行功能具有深远的影响。这些观察结果提出了关于前脑细胞振荡器,时钟,
门控突触回路和节律基因表达模式。在这个应用程序中,我们建议采用广泛的创新跨学科的方法来确定功能的意义和机械基础的时钟生理学在前脑。这个应用是基于一个中心假设,即前脑生物钟与SCN协调起作用,以调节细胞可塑性作为一天中的时间的函数。为了保持重点,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,我们建议进行细胞级的时钟时序分析。对于这些研究,我们将使用创新的转基因报告小鼠模型的组合来解决以下问题:1)CA 1细胞层是否由同质或异质的振荡器群体组成,以及2)前脑时钟细胞相位和有助于神经元可塑性的信号通路的响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的作用。虽然有报道称前脑中存在节律性活动,但我们不知道这些前脑振荡器在驱动这些节律中扮演什么角色。在这里,我们建议使用一个条件性基因敲除小鼠线,在那里的昼夜节律钟被删除的前脑兴奋性神经元,以评估如何前脑定时形状激酶的节奏。此外,为了评估前脑时钟如何塑造CA1细胞层的转录谱,我们建议采用基于阵列的转录组分析方法结合新开发的体内RNA标记和分离方法,这将使我们能够选择性地分析离散细胞群的基因表达。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,我们提出了一套新的转基因和基因敲除小鼠模型,旨在“锁定”microR132在整个昼夜节律周期的稳定生理水平。结合使用这些方法将提供一个无与伦比的水平的洞察力的作用,前脑时钟的时间在塑造前脑功能从分子到行为水平。
项目成果
期刊论文数量(0)
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KARL H OBRIETAN其他文献
KARL H OBRIETAN的其他文献
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{{ truncateString('KARL H OBRIETAN', 18)}}的其他基金
MSK, RSK and the regulation of excitotoxic cell death and structural plasticity
MSK、RSK 与兴奋性毒性细胞死亡和结构可塑性的调节
- 批准号:
9245754 - 财政年份:2015
- 资助金额:
$ 38.43万 - 项目类别:
MSK, RSK and the regulation of excitotoxic cell death and structural plasticity
MSK、RSK 与兴奋性毒性细胞死亡和结构可塑性的调节
- 批准号:
9461131 - 财政年份:2015
- 资助金额:
$ 38.43万 - 项目类别:
Mechanisms of hippocampal excitotoxic cell death and structural remodeling
海马兴奋性毒性细胞死亡和结构重塑的机制
- 批准号:
7774848 - 财政年份:2009
- 资助金额:
$ 38.43万 - 项目类别: