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Alteration of sleep and cortical parvalbumin interneurons in mouse model of Alzheimers disease

阿尔茨海默病小鼠模型中睡眠和皮质小白蛋白中间神经元的改变

基本信息

批准号：
10557189
负责人：
Fumi Katsuki
金额：
$ 12.14万
依托单位：
HARVARD MEDICAL SCHOOL
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：
2021-05-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557189
关键词：
APP-PS1 Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer’s disease biomarker Amyloid beta-Protein Animals Area Award Behavior Biological Assay Biological Markers Boston Brain Characteristics Clinical Cognition Coupling Data Dementia Development Disease Disease Progression Early Intervention Early identification Educational workshop Faculty Family Fiber Foundations Functional disorder Generations Genetic Genetic Models Goals Hippocampus Human Impaired cognition In Vitro Interneurons Intervention Learning Link Literature Long-Term Effects Massachusetts Medial Memory Memory impairment Mentorship Methods Mus Myoepithelial cell Neuroanatomy Neurons Parvalbumins Pathogenesis Pathology Patients Photometry Play Polysomnography Populations at Risk Prefrontal Cortex Public Health Reporting Research Research Personnel Role Sleep Sleep disturbances Solid Symptoms Techniques Testing Therapeutic Training Universities Work abeta accumulation abeta deposition age related amyloid pathology cell cortex cell type conditioned fear density experimental study genetic manipulation hippocampal pyramidal neuron in vivo longitudinal design medical schools mouse genetics mouse model network dysfunction neural neuronal excitability non rapid eye movement novel pre-clinical prevent signal processing skills sleep abnormalities sleep spindle

项目摘要

Alzheimer's disease (AD) is a highly prevalent form of dementia and one of the largest public health challenges worldwide. Thus, developing early interventions to prevent or delay AD progression is vital. Neuronal network dysfunction is an early characteristic of AD, observed in people at risk of developing this disorder, and has been linked to abnormal activity of cortical parvalbumin (PV) containing interneurons. Another early characteristic of AD is sleep abnormalities, observed years before the onset of cognitive impairment. While both these issues develop during early stages of AD and are potential factors that exacerbate subsequent AD pathogenesis, the relationship between abnormal PV neuron activity and sleep impairment has not been investigated. The overarching hypothesis here is that abnormal excitability of PV neurons during the early stage of AD is responsible for impaired sleep oscillations, further accumulation of amyloid-β (Aβ), and impaired cognition. Thus, early interventions, correcting PV abnormalities could prevent sleep disturbances, slow down Aβ accumulation, and prevent memory deficits in AD. The proposed experiments utilize well-established AD mouse models (APP/PS1 and 5XFAD) and focus on the medial prefrontal cortex (mPFC), an area critical for generation of non-rapid-eye-movement (NREM) slow waves and one of the earliest regions to accumulate Aβ, and the hippocampus (HPC) which is vital for learning and memory and altered in AD. Previous in vitro studies using these AD mouse models reported findings regarding PV abnormalities which appear to contradict each other. Thus, Aim 1 of this proposal will use the state-of-the-art fiber photometry technique, along with local field potential recordings in vivo to longitudinally characterize how neuronal activity in PV neurons and pyramidal neurons change, and how changes in PV interneurons relate to sleep oscillations across early to later stages of AD in the two mouse models with different timecourses of AD pathology. Aim 2 will assess the therapeutic benefit of sustained manipulation of PV neurons via chemogenetics on sleep oscillation abnormalities, Aβ level, and behavior (HPC-dependent memory). If successful, this work will identify the timing of AD-related disruption of cortical network activity, sleep oscillation biomarkers and inform early intervention strategies to prevent or delay AD progression. The training plan for this award includes mentorship from an expert team of Harvard Medical School/VA Boston faculty specializing in sleep research, cortical oscillations, neuroanatomy, and AD. Faculty investigators from Boston University/VA Boston and the Massachusetts Alzheimer's Disease Research Center will provide comprehensive training on AD research in humans and in mouse models. The proposed technical and conceptual training in fiber photometry and histochemical assay for AD pathology, as well as didactic courses and workshops relevant to AD and professional development will facilitate the applicant's goal of becoming an independent investigator in the AD research field.

阿尔茨海默病（AD）是一种非常普遍的痴呆症，也是最大的公共卫生挑战之一