Abstract
Stroke induces network-wide changes in the brain, affecting the excitability in both nearby and remotely connected regions. Brain stimulation is a promising neurorestorative technique that has been shown to improve stroke recovery by altering neuronal activity of the target area. However, it is unclear whether the beneficial effect of stimulation is a result of neuronal or non-neuronal activation, as existing stimulation techniques nonspecifically activate/inhibit all cell types (neurons, glia, endothelial cells, oligodendrocytes) in the stimulated area. Furthermore, which brain circuit is efficacious for brain stimulation is unknown. Here we use the optogenetics approach to selectively stimulate neurons in the lateral cerebellar nucleus (LCN), a deep cerebellar nucleus that sends major excitatory output to multiple motor and sensory areas in the forebrain. Repeated LCN stimulations resulted in a robust and persistent recovery on the rotating beam test, even after cessation of stimulations for 2 weeks. Furthermore, western blot analysis demonstrated that LCN stimulations significantly increased the axonal growth protein GAP43 in the ipsilesional somatosensory cortex. Our results demonstrate that pan-neuronal stimulations of the LCN is sufficient to promote robust and persistent recovery after stroke, and thus is a promising target for brain stimulation.
Highlights
Balance, coordination, movement planning and visuospatial function[26–28] (Fig. 1)
In this study we demonstrate that selective neuronal stimulations in the contralesional LCN (cLCN) can promote robust recovery after stroke (Fig. 3), and more importantly, the effect of the cLCN stimulations is persistent, as stimulated mice maintained their recovery state for 2 weeks after the stimulations were stopped (Fig. 5)
CLCN-stimulated mice exhibited increased GAP43 expression in the ipsilesional S1 and this GAP43 increase was positively correlated with recovery (Fig. 4), suggesting that cLCN stimulations may enhance structural plasticity such as axonal sprouting
Summary
Balance, coordination, movement planning and visuospatial function[26–28] (Fig. 1). Previous studies have demonstrated that lesioning of the dentato-thalamo-cortical pathway reduced excitability in the contralateral cortex, while stimulations of the dentato-thalamo-cortical pathway enhanced contralateral cortical excitability[29]. Studies have shown that chronic electrical stimulation in the LCN after stroke can enhance stroke recovery[30,31]. It is unclear whether the stimulation effect is due to direct neuronal activation, and whether the pro-recovery effect is persistent. In this study we used optogenetics to selectively stimulate only neurons of the contralesional LCN (cLCN) after stroke and examined its effects on functional recovery. We addressed whether the effects of cLCN stimulation are transient or persistent. As increasing neuronal activity leads to activity-dependent processes such as axonal sprouting, we hypothesized that LCN stimulations would have a positive effect on GAP43 expression
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