Limited restoration of motor function occurs spontaneously during a plastic time window after stroke. A deeper understanding of post-stroke plasticity is critical to devise more effective pharmacological and rehabilitative treatments. Here, I have characterized the spontaneous evolution after a photothrombotic lesion in mice, both in terms of motor deficit and plasticity in the perilesional cortex. In generalized motor tasks such as the Gridwalk and Schallert Cylinder test, motor deficits were stable for at least 30 days after photothrombotic stroke in the Caudal Forelimb Area (CFA). The skilled reaching test, performed once a week, showed a trend for spontaneous improvement over time in the number of correct graspings. However, kinematic analysis, evaluated by means of an innovative semi-automated tool, revealed a persistent alterations in grasping movements, pointing to the development of compensatory strategies. The perilesional cortex has been proposed as the area mediating functional recovery. I found a reorganization of the motor maps in sensorimotor cortex around to the lesion. Particularly, I observed a significant shrinkage of the forelimb area, in favour of hindlimb representation using Intracortical Microstimulation (ICMS). Moreover, neuroanatomical markers, previously characterized in the literature as “neuroplasticity brakes” (i.e. Perineuronal nets, Parvalbumin- and Somatostatin-positive cells) spontaneously decrease after stroke, suggesting an enhancement of the potential for plastic rearrangements. Altogether these results, suggest a spontaneous attempt to reopen a critical period characterized by sprouting and plasticity phenomena, that needs to be amplified and properly guided for maximizing recovery. The GABAergic system is one of the key modulators of plasticity in the brain, and its role has been amply studied in relation to opening and closure of the “critical period” in sensory cortices during development. To test whether reductions in GABAergic signalling were causally involved in motor improvements, we treated animals during an early post-stroke period with a benzodiazepine inverse agonist, which impairs GABAA receptor function. We found that hampering GABAA signalling led to significant restoration of function in general motor tests such as the gridwalk and the pellet reaching tasks, with no significant impact on the kinematics of reaching movements. Improvements were persistent as they remained detectable about three weeks after treatment. Using electrophysiological recordings I found an electrical imbalance between the two hemispheres. In particular, contralesional motor cortex was found to exert an enhanced transcallosal inhibition over the spared, perilesional tissue. Silencing the healthy hemisphere using cortical infusion of Botulinum Neurotoxin E, partially improved motor recovery in the gridwalk test. We then established a rehabilitation protocol that combined intensive and highly repeatable exercise of the mouse forelimb with a robotic platform with reversible inactivation of the healthy, contralesional motor cortex. We found that such treatment promoted recovery in both Gridwalk and Schallert Cylinder tests and in end point measures during Skilled reaching test. Remarkably, the combined therapy also restores pre-lesion movement patterns during reaching movement, as evaluated by kinematic analysis. Furthermore, such rehabilitated animals showed a more plastic perilesional cortex, with an additional significant decrease in plasticity brakes.

Studying and modulating post-stroke neuroplasticity to improve motor recovery / Alia, Claudia; relatore: Caleo, Matteo; Scuola Normale Superiore, 21-Nov-2016.

Studying and modulating post-stroke neuroplasticity to improve motor recovery

Alia, Claudia
2016

Abstract

Limited restoration of motor function occurs spontaneously during a plastic time window after stroke. A deeper understanding of post-stroke plasticity is critical to devise more effective pharmacological and rehabilitative treatments. Here, I have characterized the spontaneous evolution after a photothrombotic lesion in mice, both in terms of motor deficit and plasticity in the perilesional cortex. In generalized motor tasks such as the Gridwalk and Schallert Cylinder test, motor deficits were stable for at least 30 days after photothrombotic stroke in the Caudal Forelimb Area (CFA). The skilled reaching test, performed once a week, showed a trend for spontaneous improvement over time in the number of correct graspings. However, kinematic analysis, evaluated by means of an innovative semi-automated tool, revealed a persistent alterations in grasping movements, pointing to the development of compensatory strategies. The perilesional cortex has been proposed as the area mediating functional recovery. I found a reorganization of the motor maps in sensorimotor cortex around to the lesion. Particularly, I observed a significant shrinkage of the forelimb area, in favour of hindlimb representation using Intracortical Microstimulation (ICMS). Moreover, neuroanatomical markers, previously characterized in the literature as “neuroplasticity brakes” (i.e. Perineuronal nets, Parvalbumin- and Somatostatin-positive cells) spontaneously decrease after stroke, suggesting an enhancement of the potential for plastic rearrangements. Altogether these results, suggest a spontaneous attempt to reopen a critical period characterized by sprouting and plasticity phenomena, that needs to be amplified and properly guided for maximizing recovery. The GABAergic system is one of the key modulators of plasticity in the brain, and its role has been amply studied in relation to opening and closure of the “critical period” in sensory cortices during development. To test whether reductions in GABAergic signalling were causally involved in motor improvements, we treated animals during an early post-stroke period with a benzodiazepine inverse agonist, which impairs GABAA receptor function. We found that hampering GABAA signalling led to significant restoration of function in general motor tests such as the gridwalk and the pellet reaching tasks, with no significant impact on the kinematics of reaching movements. Improvements were persistent as they remained detectable about three weeks after treatment. Using electrophysiological recordings I found an electrical imbalance between the two hemispheres. In particular, contralesional motor cortex was found to exert an enhanced transcallosal inhibition over the spared, perilesional tissue. Silencing the healthy hemisphere using cortical infusion of Botulinum Neurotoxin E, partially improved motor recovery in the gridwalk test. We then established a rehabilitation protocol that combined intensive and highly repeatable exercise of the mouse forelimb with a robotic platform with reversible inactivation of the healthy, contralesional motor cortex. We found that such treatment promoted recovery in both Gridwalk and Schallert Cylinder tests and in end point measures during Skilled reaching test. Remarkably, the combined therapy also restores pre-lesion movement patterns during reaching movement, as evaluated by kinematic analysis. Furthermore, such rehabilitated animals showed a more plastic perilesional cortex, with an additional significant decrease in plasticity brakes.
21-nov-2016
BIO/12 BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA
Scienze biologiche
Biology
brain
Caudal Forelimb Area (CFA)
cortex
GABAergic system
Intracortical Microstimulation (ICMS)
neurobiology
neuroplasticity brakes
perilesional cortex plasticity
Scuola Normale Superiore
Caleo, Matteo
Cattaneo, Antonino
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11384/86002
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