After stroke, many survivors undergo a period of neural repair and spontaneous recovery of function. However, this process is usually incomplete and fails to avert chronic disability. The underlying mechanisms of repair after injury are poorly understood, and there is insufficient medical therapy available to stimulate the process. Previous work has demonstrated that successful recovery is associated with neuroplasticity at the molecular, cellular, and network level, and shares features with other forms of activity-dependent plasticity, like learning. The objective this proposal is to understand the cellular basis of plasticity after stroke, how it contributes to recovery of network connectivity and behavioral function, and how it might be targeted therapeutically. Specifically, this proposal will explore the role of a specific class of neurons ? parvalbumin inhibitory interneurons ? in modulating plastic remodeling of neural networks after stroke. Parvalbumin interneurons have been shown to gate plasticity in learning, development, and other activity-dependent plasticity paradigms, but have never been studied in the setting of stroke recovery. We will assess how pharmacogenetic manipulation of parvalbumin interneuron firing rates alters healthy activity-dependent plasticity (whisker sensory deprivation), as well as plasticity after focal ischemic injury (photothrombosis) in the somatosensory cortex of adult mice. Using these plasticity models, we will assess microscopic structural rewiring with histology, network connectivity with a cutting-edge in vivo optical neuroimaging platform, and functional recovery with behavioral phenotyping. This integrated approach will allow us to demonstrate if parvalbumin inhibitory circuits are a key mediator of post-stroke plasticity and a potential therapeutic target to promote functional recovery in stroke survivors. This proposal will thus focus on two specific aims:
Aim 1 : To determine the role of parvalbumin interneurons in activity-dependent plasticity in the adult mouse somatosensory cortex.
Aim 2 : To determine the role of parvalbumin interneurons in cortical remapping, functional connectivity and behavioral recovery following focal ischemia.

Public Health Relevance

Stroke is the leading cause of chronic disability in the United States, and improving patient recovery with medical therapy will remain a significant challenge until we understand the basic mechanisms of repair after brain injury. This project will help explain the cellular basis of network plasticity phenomena (i.e. peri-lesional remapping and recovery of global functional connectivity) that is associated with functional recovery, and may lead to novel neurorehabilitative therapies for stroke patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS103275-01
Application #
9394111
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chen, Daofen
Project Start
2017-07-01
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Washington University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130