The Role of Parvalbumin Interneurons in Cortical Plasticity and Recovery After Stroke

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PROJECT SUMMARY/ABSTRACT 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.