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.

Public Health Relevance

Stroke is the leading cause of adult disability in the US, with an annual incidence of approximately 800,000 strokes and a prevalence of over 6.6 million stroke survivors. It is clear that strokes disrupt brain function and result in behavioral deficits; however, many stroke survivors exhibit some level of recovery, even in the absence of directed therapy or rehabilitation. In this R01, we will examine how molecular- and systems-level mechanisms of brain repair interact to influence functional recovery after ischemic stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS102870-03
Application #
9961675
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Chen, Daofen
Project Start
2018-09-30
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Snyder, Abraham Z; Bauer, Adam Q (2018) Mapping Structure-Function Relationships in the Brain. Biol Psychiatry Cogn Neurosci Neuroimaging :