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OPTOGENETIC MAPPING OF CELL SPECIFIC CONNECTIONS IN THE MOUSE BRAIN AFTER STROKE

中风后小鼠大脑中细胞特异性连接的光遗传学图谱

基本信息

批准号：
10201764
负责人：
ADAM Q BAUER
金额：
$ 41.89万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201764
关键词：
Adult Affect Anatomy Animal Model Area Automobile Driving Axon Behavioral Biological Markers Brain Brain region Cells Complement Contralateral Data Distant Evolution Exhibits Functional Magnetic Resonance Imaging Genes Global Change Goals Growth Associated Protein 43 Growth Cones Image Impairment Incidence Individual Infarction Injury Integral Membrane Protein Ischemia Ischemic Stroke Knockout Mice Knowledge Left Maps Measures Molecular Motor Motor Cortex Mus Neuronal Plasticity Optics Pathway interactions Patients Pattern Physical therapy Population Prevalence Process Proteins Recovery Recovery of Function Rehabilitation therapy Reporting Rest Role Signal Transduction Site Stimulus Stroke Structure Synapses System Technology Testing Time Tissues United States Vertebral column awake axon growth axonal sprouting behavior influence brain repair density disability experience functional restoration human model improved in vivo ischemic lesion knock-down motor recovery neurobehavioral neuroimaging optogenetics overexpression post stroke relating to nervous system repaired restoration stroke recovery stroke survivor therapeutic target transcriptome

项目摘要

PROJECT SUMMARY/ABSTRACT The goal of the current proposal is to determine how molecular- and systems-level mechanisms of brain repair interact to influence behavioral recovery after focal ischemia in mice. Stroke causes direct structural damage to local circuits and indirect functional damage to global networks that can result in behavioral deficits spanning multiple domains. Neuroplasticity after stroke involves molecular changes within perilesional tissue that can be influenced by distant regions spared from injury. At the systems level, functional magnetic resonance imaging has revealed that recovery from stroke is associated with functional reorganization of the brain through the formation of new or alternative circuits. Directly impacted brain regions remap to adjacent tissue in concert with behavioral recovery. More globally, patterns of resting-state functional connectivity gradually normalize in patients experiencing good recovery. While functional neuroimaging studies in humans and animal models consistently demonstrate local and global changes in functional brain organization after stroke, it is unknown how these processes interrelate to support behavioral recovery. Understanding how (or if) remapped brain regions reintegrate into global networks to support recovery after stroke requires more direct examination of evolving local and global connectivity structure. At the molecular level, limited data suggest that new axons appear after stroke in periinfarct cortex and distant, homotopic contralateral cortex. Increased expression of plasticity-associated genes are found in perilesional tissue including those involved in axonal sprouting. Growth Associated Protein 43 (GAP-43) is an integral membrane protein found in axonal growth cones, synapses, and widely induced after focal ischemia. This protein might drive anatomical connections within the periinfarct that support functional restoration after stroke. However, the role of axonal sprouting in functional neuroplasticity following focal ischemia has not been examined. We hypothesize that GAP-43-dependent axonal sprouting is required for local circuit repair and reintegration into global networks, and this evolving process drives the degree of behavioral recovery after stroke. We further hypothesize that axonal sprouting can be modulated by neural activity in excitatory nodes functionally-connected to the site of injury, and these activity-dependent processes depend on GAP-43. Critical barriers to testing this hypothesis in vivo have been the inability to serially examine global network connectivity as it evolves with recovery, and longitudinally examine subunits of remapped circuits as they change over time. We have overcome these barriers by integrating optical intrinsic signal imaging with optogenetics to probe local circuit connectivity more directly. We will use this technology to determine: 1) how the reemergence of local circuits and global networks relate to functional recovery following focal ischemia, 2) if GAP-43-dependent axonal sprouting is required for local and/or global motor network repair and behavioral recovery, and 3) if activity in excitatory motor nodes modulates local/global motor network repair and behavioral recovery, and if these changes rely on GAP-43.

项目总结/文摘