Abstract
Motor system development is characterized by an activity-dependent competition between ipsilateral and contralateral corticospinal tracts (CST). Clinical evidence suggests that age is crucial for developmental stroke outcome, with early lesions inducing a “maladaptive” strengthening of ipsilateral projections from the healthy hemisphere and worse motor impairment. Here, we investigated in developing rats the relation between lesion timing, motor outcome and CST remodeling pattern. We induced a focal ischemia into forelimb motor cortex (fM1) at two distinct pre-weaning ages: P14 and P21. We compared long-term motor outcome with changes in axonal sprouting of contralesional CST at red nucleus and spinal cord level using anterograde tracing. We found that P14 stroke caused a more severe long-term motor impairment than at P21, and induced a strong and aberrant contralesional CST sprouting onto denervated spinal cord and red nucleus. The mistargeted sprouting of CST, and the worse motor outcome of the P14 stroke rats were reversed by an early skilled motor training, underscoring the potential of early activity-dependent plasticity in modulating lesion outcome. Thus, changes in the mechanisms controlling CST plasticity occurring during the third postnatal week are associated with age-dependent regulation of the motor outcome after stroke.
Highlights
Developmental stroke represents a rare cerebrovascular disorder and a frequent cause of hemiplegia in children (Kirton, 2013; Kirton and deVeber, 2015)
Lesion timing and characteristics is considered to be a key factor for clinical outcome of developmental stroke (Eyre, 2007; Kirton, 2013; Kirton and deVeber, 2015; Dinomais et al, 2016), no study has investigated the effect of stroke age on motor function and on underlying structural plasticity mechanisms in animal models
We found that a focal cortical stroke occurring at a developmental age (P14) with high sprouting potential of corticospinal tracts (CST) has a dramatically worse long-term behavioral outcome than a stroke performed 1 week later when sprouting potential declines and CST pruning emerges (Hsu et al, 2006; Canty and Murphy, 2008)
Summary
Developmental stroke (perinatal or pediatric) represents a rare cerebrovascular disorder and a frequent cause of hemiplegia in children (Kirton, 2013; Kirton and deVeber, 2015). Strengthening of corticospinal tracts (CST) ipsilateral projections from the healthy hemisphere (otherwise pruned during normal development), and weakening of the contralaterally projecting CST from the affected cortex, have been suggested to be the cornerstone of maladaptive plasticity mechanism after developmental injury (Eyre, 2007; Graziadio et al, 2012). A direct relationship between aberrant rewiring of gross white matter tract and axonal sprouting has not been determined, probably because of the limited resolution power achieved by currently available imaging techniques for human studies (Baek et al, 2013; Raffin and Dyrby, 2013) In this context, studies in animal models that allow detection of axonal sprouting may reveal to which degree injury affects plasticity of axonal terminal fields (Benowitz and Carmichael, 2010), and shed light on the molecular and anatomical basis of the maladaptive phenomenon. Recent findings in adult injured rats highlighted that interventions promoting a widespread and disorganized sprouting are detrimental (Wahl et al, 2014), suggesting that compensatory and adaptive axonal sprouting should follow precise location and branching ‘‘rules’’ to promote functional recovery
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