Developmental ischemic stroke in rat induces maladaptive plasticity in corticospinal system

It is generally considered that brain takes advantage of neural plasticity processes in order to modulate its response to different changes of internal and external environment. These variety of stimuli can induce a relevant shaping and strength of neural connections, influencing in a positive or negative manner the compensative response of the brain itself. The ability of neural networks to modulate their connectivity and functions in response of different stimuli usually decline proportionally to age, so that young neural system is considered more plastic and malleable rather than older ones. Modulation of neural plasticity after a brain insult might be one of the most encouraging research and clinical approach to recover lost functions. For instance, rehabilitation protocols after ischemic stroke lesions are mainly focused on the plastic reorganization of altered connections through their active remodelling. In these cases, however, efficacy of such induced plastic modulation strongly depends upon timing, location, and extension of lesion, and also on both onset and duration of rehabilitative treatments.Moreover, plastic changes induced by brain injuries occurring during the development of a specific cerebral area seems to provoke a counterintuitive worsening of functions due to immaturity of these neural connections. Understanding the structural and molecular mechanisms underlying the "maladaptive" response of brain circuits can help to unveil and develop new therapeutic and rehabilitative targets, in order to promote a significant preservation or recovery of lost functions. A paradigmatic example of developmental injury is the perinatal stroke, that is responsible for more than 70% of moderate-to-severe hemiplegic cerebral palsy in children and occurs during the development of motor system. This process is characterized by an activity-dependent competition between ipsilateral and contralateral corticospinal projections, that evolves with the pruning of ipsilateral fibers and strengthening of contralateral ones. Recent studies have suggested that unilateral ischemic lesion occurring at early age in human favours a “maladaptive” strengthening of ipsilateral projections from the healthy hemisphere (“contralesional reorganization”), causing a worse motor outcome. Investigating the anatomical and molecular underpinnings of ischemic lesion timing effects on motor outcome in well characterized animal models would be useful to understand how plasticity mechanisms can promote or preclude motor recovery in an age-dependent manner. Here I used the unilateral intracortical injection of the potent vasoconstrictor endothelin-1 (ET1) in the left forelimb motor cortex of rat with perinatal (P14) or juvenile (P21) age. These ages were chosen because they represent the higher and the final level, respectively, of developmental corticospinal axons remodelling. In order to assess behavioural long-term motor impairments induced by ischemic lesion, several general and fine motor tests were performed when animals reach adult age. ET1 lesion results in a comparable tissue damage both in P14 and P21 injured animals, but earlier lesioned rats show more prominent long term motor impairments. Taking advantage of well characterized viral vectors acting as anterograde tracers, I analysed, at the level of spinal cord, the anatomical alteration of corticospinal tract components (ipsilateral and contralateral) and plastic remodelling in terms of axonal sprouting from healthy side and their laminar distribution in the denervated side of spinal cord. These data suggest that ET-1 lesion dampens the normal development of corticospinal tract with an age-dependent effect: indeed, the earlier the lesion P14) occurs, the more aberrant is sprouting of contralateral and ipsilateral components of CST onto the denervated spinal cord, with an abnormal targeting of dorsal and ventral laminae of denervated spinal cord. Interestingly, an early skilled training performed one week after lesion is suffcient to modulate this form of maladaptive plasticity, inducing a reduction of aberrant axonal sprouting coincident with a partial amelioration of long-term motor outcome.