Degree: Master of Science Abstract: Myelin is an essential component of nervous system functioning: it supports axonal metabolism, enables saltatory conduction to allow for precise timing across cortical networks to regulate information processing and is increasingly recognized as an integral type of adult experience-dependent structural plasticity. As such, myelin’s role is aiding the neuroplastic reorganization of the brain after stroke has recently received considerable attention, but significant gaps in knowledge remain, chief amongst them the widely differing timecourse and spatial distribution of myelination changes reported across various studies. To help characterize these post-stroke changes in myelin, particularly in the immediate vicinity of the primary site of injury, we investigated the utility of a novel label-free in vivo imaging technique called Spectral Confocal Reflectance Microscopy (SCORE) capable of stably tracking individual superficial cortical myelinated fibers over a period of weeks. We concurrently tracked changes in the integrity and density of axons projecting to or passing through the same peri-lesional areas originating in the contralesional homotopic regions and simultaneously monitored meso-scale functional activation of the cortex in response to somatosensory stimuli of the fore- and hindlimb to gauge the extent of functional recovery occurring in somatosensory processing, given that the stroke model used specifically targeted the forelimb somatosensory representation. The pole test and the cylinder test were also utilized as an indices of behavioral recovery. Furthermore, we administered the atypical antipsychotic quetiapine - a known pro-myelinating agent - to see whether its myelin boosting effect was observable following an ischemic injury as well and to further help evaluate the functional significance of post-stroke myelin densities in aiding functional recovery. We showed longitudinal imaging of both GFP-expressing contralateral crossing fibers and SCORE-imaged myelinated fibers are stable and powerful techniques for evaluating the changing architecture of the post-stroke brain: though a severe deficit in both types of fiber densities are evident immediately in the days following stroke, robust recovery to baseline levels particularly in the density of contralaterally projecting crossing fibers was apparent within 2 weeks after the initial injury. Myelin density, however, particularly in regions close to the stroke core, remained persistently decreased even at 4 weeks post-stroke. Quetiapine treatment increased the density of intact contralateral crossing fibers, but more dramatically helped partially alleviate the chronic myelin deficit observed surrounding the infarct core. Despite these effects, however, quetiapine did not significantly boost the timecourse or extent of the functional recovery of somatosensory processing or behavioral recovery. Nevertheless, myelin density was still shown to be a significant predictor of the size of both forelimb and hindlimb stimulation activated cortical responses, indicating that though myelination appears to play some role in contributing to functional recovery, it does so in concert with other, potentially more influential mechanisms of recovery. Alternatively, functional patterns of cortical activity dictated by rehabilitative training may be necessary to induce more functional patterns of myelination across the recovering cortical networks than was observed in our model of quetiapine administration with no directed sensorimotor rehabilitation.