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.

项目概要 综合证据表明，神经和网络过度兴奋是一个重要的早期事件。 阿尔茨海默病（AD）患者的细胞和分子基础是过度兴奋的一个关键领域。 调查和动物模型中类似的过度兴奋性的存在使研究能够剖析 一个关键的见解是，AD 患者和小鼠模型的过度兴奋性都具有一定的相关性。 新出现的数据还表明，前脑的神经兴奋性通常较低。 生物钟的控制，调节癫痫阈值和癫痫样活动的易感性。 细胞功能的昼夜节律变化是由大多数细胞中表达的转录分子钟驱动的，并且 分子钟消融会增加 AD 病理学，我们有令人信服的初步证据证明节律性。 神经元兴奋性的变化至少部分是由于神经元膜特性的昼夜节律调节所致 抑制性中间神经元，尤其是表达小清蛋白 (PV) 的快速尖峰细胞。 皮质和齿状回中的生物钟与 AD 密切相关，并且 AD 中的昼夜节律被打乱 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： 分子时钟以及由此产生的 PV+ 中间神经元基因表达和活性的变化有助于 AD- 具体来说，我们将评估生物钟和生物钟的差异。 AD 小鼠模型中 PV+ 中间神经元与兴奋性神经元的受控基因表达 RNA测序、最先进的生物信息学和最近开发的评估工具的结合 以细胞特异性方式进行分子钟节律和转录（目标 1）。 以及齿状回和皮质中的兴奋性神经元，以确定 PV+ 抑制中是否存在时钟驱动的变化 AD 模型中的神经元活动受到干扰，导致整体过度兴奋（目标 2）。 一种创新的化学遗传学时间治疗方法来操纵 PV+ 中间神经元生理学 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可以起到保护作用 反对过度兴奋、认知障碍和病理学（目标 3）。 跨学科团队使用强大的方法来确定昼夜节律的破坏如何促进 了解这些机制可能有助于 AD 的早期阶段。 促进行为或药物干预措施的发展。