Microvascular Function and Neuroplasticity after Stroke

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The brain initiates an exquisite process of repair after a stroke, involving rewiring of neuronal connections and reorganization of surviving tissue around the stroke. As with neurons, the vasculature also undergoes dramatic reorganization. Mechanisms such as angiogenesis are postulated to improve blood flow while co-existing mechanisms such as inflammatory cell adhesion and chronic constriction can impede flow. It is unknown how these mechanisms interplay to affect peri-infarct perfusion in the chronic stages of stroke, and how they might influence the remapping of brain function during recovery. Our long-term goal is to determine key factors that influence the rewiring and remapping of surviving neurons in peri-infarct areas, and to modulate them in a way that enhances the recovery process. The focus of this project, toward the achievement of this goal, is to understand how microvascular changes after stroke influence the plasticity of neuronal connections. As a model, we will create photothrombotic strokes in the mouse vibrissa system to mimic small, survivable strokes often seen in humans. Components of the neurovascular unit, including pre- and postsynaptic neuronal structures and microvessels, will be tracked dynamically over weeks of functional recovery using in vivo twophoton laser-scanning microscopy. We will use a novel thinned-skull cranial window that avoids the spurious effects of surgically induced inflammation, thus enabling the observation of brain remodeling in a natural intracranial environment. Our central hypothesis is that anomalies in microvascular blood flow can negatively influence neuronal rewiring in chronic stages of stroke. We further hypothesize that rehabilitative paradigms to enhance functional recovery alleviate microvascular dysfunction and improve neuronal remodeling. These hypotheses will be tested through three specific aims. In Aim 1, we plan to determine whether existing benchmarks of neuronal plasticity, i.e., dendritic spine and axon bouton number, are influenced by chronic, stroke-induced changes in microvascular density and perfusion. In Aims 2 and 3, we plan to determine how rehabilitative training by repetitive use and cortical electrical stimulation impacts these indices. We expect that this work will provide insight on the role of chronic microvascular changes in stroke recovery. It will further develop a novel imaging-based experimental framework for future mechanistic studies.