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Introduction
In the United States, nearly 800,000 people have a stroke annually, making it the 5th leading cause of death and the leading cause of adult disability (Benjamin et al., 2018). More than half of all stroke survivors experience persistent motor deficits that impair daily function, underscoring the significant need for a better understanding of the mechanisms of injury and repair after stroke (Dobkin, 2005). Spontaneous recovery of function is associated with a higher capacity for neuroplasticity in homologous brain regions after stroke (Brown et al., 2009). These regions, which are both remote and adjacent to the infarcted tissue, undergo changes in order to assume the functions of the lost neuronal networks (Furlan et al., 1996). Preclinical models of stroke have been instrumental in understanding the complexity of post-stroke responses and how they relate to functional recovery (Nudo, 2007). Using these models, plasticity which underlies circuit remodeling has been repeatedly shown to be correlated with improved recovery from stroke (Jones and Adkins, 2015). These forms of circuit plasticity involve recruitment of homologous neuronal pathways, inhibition of aberrant electrical signaling, and formation of new connections through synaptogenesis and axonal sprouting throughout the brain and spinal cord (Murphy and Corbett, 2009). However, in some cases, post-stroke neuroplasticity can impede recovery. The degree of functional recovery is heavily dependent on the regions in which the plasticity occurs (Dancause et al., 2005; Kim et al., 2005), emphasizing the need for pre-clinical studies that investigate changes in axonal connectivity in the whole brain after stroke.
In addition to alterations in brain architecture after stroke, the immune system plays a major role in post-stroke pathology and recovery. In particular, the critical role of the immune system in both the acute and chronic phases of post-stroke recovery is becoming increasingly apparent (Jin et al., 2013). Within hours of the onset of injury, damage-associated molecular patterns (DAMPS) are released from dying neurons, astrocytes, and endothelial cells, recruiting immune cells to the brain (Rubartelli and Lotze, 2007). Blood-brain barrier (BBB) disruption, upregulation of cell adhesion molecules, and activation of resident microglia enhance the post-stroke neuro-immune interactions (Abulrob et al., 2008; Patel et al., 2013). Within 24 h of stroke onset, adaptive immune cells, including T cells, can be detected in the ipsilesional hemisphere (Gelderblom...