Hypothalamic spatial transcriptomics and connectomics in a mouse model of Alzheimers disease

阿尔茨海默病小鼠模型中的下丘脑空间转录组学和连接组学

• 批准号: 10288595
• 负责人: Alexander Choi Jackson
• 金额: $ 42.06万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-20 至 2022-09-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288595
• 关键词: Address; Affect; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Anatomy; Arousal; Autopsy; Axon; Behavioral; Bioinformatics; Biological Markers; Biology; Body Weight; Brain; Brain region; Cells; Censuses; Clinical; Collaborations; Collection; Data; Data Set; Development; Disease; Disease Progression; Dissection; Early identification; Electrophysiology (science); Exhibits; Functional disorder; Funding; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genomics; Goals; Hand; Health; Histamine; Hypothalamic dysfunction; Hypothalamic structure; Immunohistochemistry; Impaired cognition; Knowledge; Laboratories; Lateral Hypothalamic Area; Lead; Memory; Memory Loss; Metabolic; Methods; Molecular; Molecular Analysis; Molecular Target; Mus; National Institute of Mental Health; Nerve Degeneration; Neuroanatomy; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Neurosecretory Systems; Neurotensin; Parents; Pathogenesis; Pathologic; Pathology; Pattern; Population; Positioning Attribute; Posterior Hypothalamus; Resolution; Risk; Role; Site; Sleep; Slice; Structure; Symptoms; Synapses; System; Taxonomy; Techniques; Therapeutic Intervention; United States National Institutes of Health; Viral; Wakefulness; Work; aged; cell type; cognitive development; feeding; hypocretin; innovation; melanin-concentrating hormone; memory process; motivated behavior; mouse model; neuropathology; new technology; optogenetics; patch clamp; pre-clinical; sex; single molecule; single-cell RNA sequencing; tool; transcriptome; transcriptomics

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to elucidate the role of lateroposterior hypothalamic (LPH) neuronal cells and circuits in the pathogenesis of Alzheimer’s disease (AD) using cutting-edge transcriptomic and connectomic analyses. The LPH comprises a collection of interrelated structures, including the lateral hypothalamic area (LHA) and ventral posterior hypothalamus (VPH) that are key modulators of behavioral state, orchestrating sleep and wakefulness, motivated behavior, neuroendocrine function and memory processing. Mounting pathological evidence suggests that cell types in this region are vulnerable to degeneration in AD. For example, examination of post-mortem brains from AD patients shows a dramatic loss of key sleep-wake- regulating cell populations in the LPH. In more posterior regions of the LPH, both clinical and preclinical evidence suggests that the mammillarybodies (MB), an important node in a brain-wide memorysystem,has also emerged as a site of early vulnerability in AD pathogenesis. Clinically, non-cognitive and metabolic disruptions have been shown to precede the onset of memory loss and cognitive decline. This collective evidence points to the LPH as a potential early indicator of risk/propensity to develop neuropathology that leads to AD. However, underlying the diverse functions of the LPH is a highly heterogenous and poorly characterized population of neurons, subsets of which may exhibit distinct molecular alterations and/or contribute to specific circuit-level changes that underpin the early AD-associated pathology within this region. Resolving these alterations in a cell-type-specific and circuit-specific manner is thus the crucial step towards a mechanistic understanding of the LPH’s role in early AD pathogenesis and the identification of early-stage biomarkers. The present supplement builds upon the parent R01 (MH112739) through a systematic molecular, cellular and connectivity analysis of the LPH to specifically address the cell type-specific and circuit-level alterations associated with AD. We will approach this through a combination of cutting-edge techniques including single-cell transcriptomics, spatial transcriptomics, and connectomic circuit mapping, in a mouse model of AD (5XFAD). In Aim 1, we will systematically collect single-cell and spatial transcriptomic profiles from young and aged mouse LPH, to identify the changes in transcriptome profiles associated with AD in an anatomically resolved manner. In Aim 2, we will quantitatively assess the long-range axonal projections of key populations of neurons that exhibit pathological alterations and will examine functional synaptic connectivity using viral tracing, patch-clamp electrophysiology and optogenetics. The work proposed here will yield a valuable cell type census and connectomic analysis of the molecular and cellular changes occurring within the LPH during the progression of AD neurodegeneration, and will form the basis for future NIA applications focused on the role of specific hypothalamic cells and circuits in AD pathogenesis.

项目总结/文摘