Some of the sensory, motor and cognitive impairments caused by stroke eventually improve, suggesting that the brain has the ability to repair itself and restore lost functionalities. But large knowledge gaps still exist regarding the mechanisms of structural rewiring and functional remapping after stroke. Much of this brain plasticity takes place in the tissue surrounding the core of the ischemic lesion, known as the peri-infarct cortex, but when exactly these changes occur and which cells participate is not clear. In addition, the extent to which circuit remodeling correlates with functional improvement is not known. Recent in vivo imaging developments could help overcome previous limitations in experimental techniques used to record changes in neuronal structure and functional remapping. In particular, research on stroke plasticity and its role in functional recovery would benefit from the use of longitudinal in vivo imaging approaches that allow the investigator to track the dynamics of neuronal structure and function with exquisite spatial and temporal resolution, in the same neurons or circuits before and after stroke. We propose to use an innovative approach and cutting edge imaging techniques, including chronic in vivo two-photon microscopy, to monitor axonal/dendritic structure and record the remapping of lost functionalities, as well as optogenetics and pharmacological manipulations to perturb such remapping. We want to test the hypothesis that synaptic remodeling in pyramidal cell axons or GABAergic interneurons, also plays a role in brain repair. We want to test four hypotheses: 1) that pyramidal cell axons and dendrites of GABAergic interneurons in peri-infarct cortex also play a role in neural repair after stroke;2) that the degree of structural plasticity correlates wth functional recovery;3) that lost functionalities are consistently remapped according to pre-established circuits after stroke;and 4) that blocking tonic inhibition or using constraint therap improve recovery by enhancing plasticity. Our studies will focus on the clinically relevant middle cerebral artery occlusion model of stroke in adult mice and will directly examine the related issues of hemodynamics, collateral blood flow, and circuit plasticity. Our proposed work is intended to generate new knowledge about cortical circuit plasticity after stroke and other types of brain injury, with the hope that this will lead to better strategies for rehabilitation that enhnce functional recovery.

Public Health Relevance

The proposed studies will investigate how circuits of nerve cells in the cerebral cortex adapt to brain injury after stroke and compensate for the loss of sensory or motor functions. The experiments are designed to generate new ideas about how brain plasticity contributes to recovery of function and how to exploit that knowledge to improve rehabilitative therapies for patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS076942-01A1
Application #
8500712
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$336,875
Indirect Cost
$118,125
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095