Stroke is one of the leading cause of long-term disability. However, there is no fundamental treatment for this condition, and current therapies only offer limited benefits. It is necessary to identify and develop better therapeutic strategy. One approach is to understand how animals endogenously recover from experimental stroke models and to leverage these findings to clinical applications. In this vein, much effort has been devoted to the identification of recovery-related genes and proteins. However, to fully understand the role of newly identified molecules, we need to know how these molecules are involved in the dynamics of the neural circuit mechanisms in recovery from stroke. The interruption of blood flow to the brain rapidly induces a cascade of degeneration, inflammation, and reduced neuronal excitability. Therefore, recovery requires the re-normalization of neuronal excitability through the reorganization of surviving neural circuits. However, no clear information on the role of different neuronal types in this neural adaptation after stroke. Therefore, delineating the cell type-specific adaptations is an important first step toward understanding the mechanisms of stroke recovery. In this proposal, we adapted the photothrombotic stroke model aims to induce an ischemic damage in primary motor cortex (MOp), which impairs the forelimb movement. This impaired movement is recovered within 3-4 days after the stroke. Thus, we will study the role of the neural reorganization of nearby circuitry, especially in secondary motor cortex (MOs), in behavioral recovery after the stroke in primary motor cortex (MOp). Interestingly, our preliminary results showed that the inhibition of MOs activity after stroke inhibit the behavioral recovery, suggesting that the neural adaptation in MOs may mediate the recovery from MOp stroke. Using 2-photon microscopic imaging of excitatory and inhibitory MOs neurons before and after the stroke, we will examine the dynamics of different types of neurons in MOs and manipulate the activity of those neurons selectively to examine the cell type specific roles in recovery from stroke. Furthermore, we will also examine the role of individual synapses made by different inputs to different cell types in MOs in recovery from stroke. To achieve this, we adapt the newly developed tool, enhanced green fluorescent protein reconstitution across synaptic partners (eGRASP), to label and monitor synapses between defined pre- and postsynaptic partners using longitudinal 2-photon imaging. Understanding the cell type specific neural adaptation and the dynamics of synaptic inputs to different cell types in MOs after stroke will provide novel insight for the circuit mechanism of the recovery after stroke.
Stroke affects millions of Americans at tremendous cost, and no treatment is considered truly effective. Using newly developed technologies designed to identify neural circuits and their modifications, we propose an exciting new strategy to provide a framework for guiding future studies on stroke as well as developing new strategies to improve patient outcomes.
