Abstract
Background.
Brain injury often causes severe motor dysfunction, leading to
difficulties with living a self-reliant social life. Injured neural
circuits must be reconstructed to restore functions, but the adult brain
is limited in its ability to restore neuronal connections. The
combination of molecular targeting, which enhances neural plasticity,
and rehabilitative motor exercise is an important therapeutic approach
to promote neuronal rewiring in the spared circuits and motor recovery.
Objective.
We tested whether genetic reduction of Src homology 2-containing
phosphatase-1 (SHP-1), an inhibitor of brain-derived neurotrophic factor
(BDNF)/tropomyosin receptor kinase B (TrkB) signaling, has synergistic
effects with rehabilitative training to promote reorganization of motor
circuits and functional recovery in a mouse model of brain injury.
Methods.
Rewiring of the corticospinal circuit was examined using neuronal
tracers following unilateral cortical injury in control mice and in Shp-1 mutant mice subjected to voluntary exercise. Recovery of motor functions was assessed using motor behavior tests.
Results.
We found that rehabilitative exercise decreased SHP-1 and increased
BDNF and TrkB expression in the contralesional motor cortex after the
injury. Genetic reduction of SHP-1 and voluntary exercise significantly
increased sprouting of corticospinal tract axons and enhanced motor
recovery in the impaired forelimb.
Conclusions.
Our data
demonstrate that combining voluntary exercise and SHP-1 suppression
promotes motor recovery and neural circuit reorganization after brain
injury.
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