Cellular interactions during neural repair



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Injury to the central nervous system induces a limited neural repair response that is causally linked to recovery of function. The goal of this dissertation is to better understand neural repair responses, including how different cell types respond to injury and how cellular interactions shape repair. I investigate repair processes in a mouse model of cortical stroke by applying behavioral, imaging, and genetic techniques. In Chapter 2, I characterize the spatiotemporal dynamics of vascular plasticity following stroke, and its association with restoration of blood flow and behavioral function. I find that stroke instigates a short time window during which vascular plasticity unfolds. This window of vascular plasticity is underpinned by transient activation of pro-angiogenic gene expression programs. The formation of new vessels is associated with the restoration of blood flow to peri-infarct regions, which is in turn associated with behavioral improvement. In Chapter 3, I examine reactive astrocyte responses after stroke and their interaction with vascular plasticity. I find that stroke triggers gene expression and functional changes in reactive astrocytes that enable them to support vascular remodeling and repair. Astrocytes orchestrate multiple aspects of vascular repair, including reorganization of extracellular matrix and pericyte attachment to vessels. Ablating reactive astrocytes results in reduced angiogenesis, prolonged blood flow deficits, increased vascular permeability, and worse functional recovery. In Chapter 4 I investigate the subventricular zone (SVZ) cytogenic response to stroke. I find that cells arising from the SVZ after stroke are predominantly undifferentiated precursors and astrocytes. Arrest of cytogenesis by ablation of neural stem cells or aging reduces behavioral recovery. SVZ cytogenesis provides trophic support via vascular endothelial growth factor (VEGF) that drives effective synaptic and vascular plasticity to improve recovery. Replacement of VEGF in peri-infarct cortex of mice lacking cytogenesis is sufficient to increase dendritic spine and vascular density and enhance recovery. Together, these studies refine our understanding of how different cell types response to injury and how cellular interactions coordinate neural repair.



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