Circadian Structural Plasticity in Central Pacemakers

中央起搏器的昼夜节律结构可塑性

• 批准号: 10287332
• 负责人: Horacio O De La Iglesia
• 金额: $ 29.19万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10287332
• 关键词: ARNTL gene; Alzheimer' s Disease; Alzheimer' s disease patient; Animals; Astrocytes; Automobile Driving; Award; Axon; Biochemical; Biological Rhythm; Brain; Cells; Characteristics; Circadian Dysregulation; Circadian Rhythms; Coupled; Coupling; Cues; Dendritic Spines; Disease; Elements; Enterobacteria phage P1 Cre recombinase; Environment; Feedback; Fiber; Gene Expression; Genes; Genetic Transcription; Heavy Metals; Homeostasis; Image; Immunohistochemistry; Impairment; Individual; Injections; Investigation; Label; Luciferases; Mammals; Manuals; Mediating; Membrane; Molecular; Monitor; Mus; Nervous system structure; Network-based; Neurons; Pacemakers; Parents; Periodicity; Plant Resins; Positioning Attribute; Process; Property; Reporting; Role; Sampling; Scanning Electron Microscopy; Sleep disturbances; Slice; Stains; Structure; Symptoms; Synapses; Synaptophysin; Testing; Time; Tissues; Translations; Vasoactive Intestinal Peptide; Viral; Virus; Wild Type Mouse; base; circadian; circadian pacemaker; density; ex vivo imaging; experimental study; fascinate; microscopic imaging; millisecond; molecular clock; mouse Cre recombinase; postsynaptic; presynaptic; promoter; receptor; recruit; response; suprachiasmatic nucleus; vector

SUMARY Circadian rhythms depend on the molecular transcription/translation negative feedback loop (TTL) operating in clock neurons, and on the network properties of these neurons. Among the properties that could be recruited by the circadian clock are changes in the identity of pre/post synaptic partners and/or strength of the connectivity between clock neurons, a property collectively termed as circadian structural plasticity. The central hypothesis for our parent Award is that circadian structural plasticity within the central circadian clock of mammals, located within the suprachiasmatic nucleus (SCN), is part of the time-encoding mechanism. An early-stage symptom of Alzheimer’s disease (AD) is the disruption of sleep and circadian rhythms. For this Supplement, we test the hypothesis that these symptoms may result in part from the disruption of circadian structural plasticity within the SCN. Specific aim 2D will assess the effect of AD on the expression of the clock gene PER2 through PER2-LUC reporting in ex vivo SCN slices from either AD or WT mice. This experiment will determine the effect of AD on the amplitude of the rhythm of clock gene expression and on the synchrony between cells within the SCN neuronal network. Specific aim 2E will examine the effect of AD on circadian structural remodeling in SCN VIPergic neurons, which are an essential component of the timekeeping mechanism, through virally mediated labeling of VIP neurons with synaptophysin-mCherry followed by ex vivo fluorescent reporting of circadian rhythms of retraction/extension of presynaptic fibers. Specific aims 2F and 2G will use serial blockface scanning electron microscopy to examine circadian plasticity at the ultrastructural level by examining synaptic structural changes (2F) and changes in astrocytic processes that ensheath neurons (2G). Our experiments test predictions of the hypothesis that disruptions of sleep and circadian rhythms that are characteristic of early stages of AD may emerge from the effect of the disease on key circadian plasticity changes within the master circadian clock. Elucidating the potential mechanisms behind these early symptoms of AD could open new opportunities to treat sleep and circadian disruptions in AD patients.

汇总表 昼夜节律取决于分子转录/翻译负反馈环(TTL)在体内的作用 时钟神经元，以及这些神经元的网络特性。在可以招募的房产中 生物钟是突触前/突触后伙伴身份和/或突触强度的变化 时钟神经元之间的连通性，这一特性统称为昼夜结构可塑性。中环 我们父母奖的假设是昼夜节律结构可塑性在中央昼夜节律时钟 哺乳动物位于视交叉上核(SCN)，是时间编码机制的一部分。一个 阿尔茨海默病(AD)的早期症状是睡眠和昼夜节律的中断。为了这个 作为补充，我们检验了这些症状可能部分是由于昼夜节律紊乱造成的假设 SCN内的结构可塑性。 特定目的2D将评估AD通过PER2-Luc对时钟基因PER2表达的影响 报道了来自AD或WT小鼠的体外SCN切片。本实验将确定AD对心脏功能的影响。 SCN内Clock基因表达节律的幅度和细胞间的同步性 神经网络。 具体目标2E将研究AD对SCN VIperable神经元昼夜节律结构重构的影响， 它们是计时机制的重要组成部分，通过病毒介导的VIP标记 突触素-mCherry标记的神经元在体外的昼夜节律的荧光报告 突触前纤维的回缩/伸展。 特定的AIMS 2F和2G将使用连续的块面扫描电子显微镜来检查昼夜节律可塑性 在超微结构水平上，通过检查突触结构变化(2F)和星形胶质细胞突起的变化 这套神经元(2G)。 我们的实验测试了以下假设的预测：睡眠中断和昼夜节律 阿尔茨海默病早期的特征可能来自疾病对关键昼夜节律可塑性的影响 主生物钟内的变化。阐明这些早期症状背后的潜在机制 阿尔茨海默病的治疗可能为治疗阿尔茨海默病患者的睡眠和昼夜节律紊乱提供新的机会。