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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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