Circadian changes in network excitability and Alzheimer disease pathogenesis

网络兴奋性的昼夜变化与阿尔茨海默病发病机制

• 批准号: 10306153
• 负责人: Karen L Gamble
• 金额: $ 76.09万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10306153
• 关键词: Ablation; Address; Affect; Affinity Chromatography; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Animal Model; Area; Behavioral; Bioinformatics; Cell physiology; Cells; Circadian Dysregulation; Circadian Rhythms; Clinical; Data; Development; Disease; Diurnal Rhythm; Electrophysiology (science); Epilepsy; Event; Exhibits; Family; Functional disorder; Gene Expression; Genes; Genetic Transcription; Healthcare; Healthcare Systems; Hippocampus (Brain); Human; Impaired cognition; Impairment; Interneurons; Intervention; Investigation; Knock-in; Knowledge Portal; Ligands; Mediating; Membrane; Molecular; Mus; Neurons; Parvalbumins; Pathogenesis; Pathology; Patients; Pattern; Periodicity; Pharmacology; Phase; Physiology; Predisposition; Prevention strategy; Property; Prosencephalon; Regulation; Research; Ribosomes; Seizures; Slice; Testing; Time; Translating; Variant; Wild Type Mouse; bioinformatics pipeline; circadian; circadian pacemaker; circadian regulation; comparison group; dentate gyrus; design; designer receptors exclusively activated by designer drugs; excitatory neuron; experimental study; fight against; human model; inhibitory neuron; innovation; insight; molecular clock; mouse model; neuroimaging; neuronal excitability; neurophysiology; patch clamp; postsynaptic; programs; relating to nervous system; response; single molecule; tau Proteins; tool; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Converging evidence indicates that neuronal and network hyperexcitability is an important early event in Alzheimer’s disease (AD) patients. The cellular and molecular basis of this hyperexcitability is a critical area of investigation and the presence of similar hyperexcitability in animal models enables studies to dissect underlying mechanisms. A key insight is that hyperexcitability in both AD patients and mouse models has a strong diurnal rhythm. Emerging data also indicate that neural excitability in the forebrain is normally under control of the circadian clock, which regulates seizure thresholds and susceptibility to epileptiform activity. Circadian variation in cellular function is driven by transcriptional molecular clocks expressed in most cells, and molecular clock ablation increases AD pathology. We have compelling preliminary evidence for rhythmic variation in neuronal excitability that is at least partly due to circadian regulation of the membrane properties of inhibitory interneurons, especially fast-spiking cells expressing parvalbumin (PV). Given that PV+ interneurons in the cortex and dentate gyrus are strongly implicated in AD, and that circadian rhythms are disrupted in AD patients and AD mouse models, we propose rigorous experiments to test the hypothesis that dysregulation of the molecular clock and resulting changes in PV+ interneuron gene expression and activity contribute to AD- related neuronal hyperexcitability. Specifically, we will evaluate the differences in circadian clock and clock- controlled gene expression in PV+ interneurons vs. excitatory neurons in the mouse models of AD, using a combination of RNA sequencing, state-of-the-art bioinformatics, and recently developed tools to evaluate molecular clock rhythmicity and transcription in a cell-specific manner (Aim 1). We will record from inhibitory and excitatory neurons in the dentate gyrus and cortex to determine if clock-driven changes in PV+ inhibitory neuron activity are disrupted in AD models and contribute to overall hyperexcitability (Aim 2). Finally, we will utilize an innovative chemogenetic chronotherapeutic approach to manipulate PV+ interneuron physiology to determine whether reinstating the normal circadian patterns of PV+ interneuron activity in AD mice protects against hyperexcitability, cognitive impairment, and pathology (Aim 3). The proposed studies led by a strong interdisciplinary team use powerful approaches to determine how disruption of circadian rhythms facilitates neuronal hyperexcitability that contributes to early stages of AD. Understanding these mechanisms may catalyze development of behavioral or pharmacologic interventions.

项目总结 越来越多的证据表明，神经元和网络的过度兴奋性是一种重要的早期事件。 阿尔茨海默病(AD)患者。这种过度兴奋的细胞和分子基础是 动物模型中类似的过度兴奋性的研究和存在使研究能够剖析 潜在的机制。一个关键的见解是，AD患者和小鼠模型中的过度兴奋都有 强烈的昼夜节律。新出现的数据还表明，前脑中的神经兴奋性通常低于 控制生物钟，它调节癫痫阈值和癫痫样活动的敏感性。 细胞功能的昼夜变化是由大多数细胞中表达的转录分子时钟驱动的，并且 分子时钟消融增加了AD的病理改变。我们有令人信服的初步证据证明 神经元兴奋性的变化，至少部分是由于神经细胞膜特性的昼夜调节 抑制性中间神经元，尤其是表达小白蛋白(PV)的快速刺激性细胞。鉴于PV+中间神经元 大脑皮质和齿状回与阿尔茨海默病密切相关，在阿尔茨海默病中昼夜节律被打乱 在患者和AD小鼠模型中，我们提出了严格的实验来检验以下假设 分子时钟和由此引起的PV+中间神经元基因表达和活性的变化参与了AD- 相关的神经元过度兴奋性。具体地说，我们将评估生物钟和生物钟的差异- 在AD小鼠模型中，控制PV+中间神经元和兴奋性神经元的基因表达 结合RNA测序、最先进的生物信息学和最近开发的工具来评估 分子时钟节律性和细胞特有的转录(目标1)。我们将从抑制录制 以及齿状回和皮质中的兴奋性神经元，以确定时钟驱动的PV+抑制变化 在AD模型中，神经元活动被破坏，并导致整体的过度兴奋性(目标2)。最后，我们会 利用创新的化学发生计时治疗方法操纵PV+神经元间生理学 确定恢复AD小鼠PV+中间神经元活动的正常昼夜节律模式是否具有保护作用 对抗过度兴奋、认知障碍和病理(目标3)。拟议中的研究由一位强大的 跨学科团队使用强大的方法来确定昼夜节律的中断如何促进 阿尔茨海默病早期的神经元过度兴奋性。了解这些机制可能会 促进行为或药物干预措施的发展。