ABSTRACT
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.
