Cheng Michelle Y, Wang Eric H, Woodson Wyatt J, Wang Stephanie, Sun Guohua, Lee Alex G, Arac Ahmet, Fenno Lief E, Deisseroth Karl, Steinberg Gary K
Departments of Neurosurgery, Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA 94305
Departments of Neurosurgery, Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):12913-8. doi: 10.1073/pnas.1404109111. Epub 2014 Aug 18.
Clinical and research efforts have focused on promoting functional recovery after stroke. Brain stimulation strategies are particularly promising because they allow direct manipulation of the target area's excitability. However, elucidating the cell type and mechanisms mediating recovery has been difficult because existing stimulation techniques nonspecifically target all cell types near the stimulated site. To circumvent these barriers, we used optogenetics to selectively activate neurons that express channelrhodopsin 2 and demonstrated that selective neuronal stimulations in the ipsilesional primary motor cortex (iM1) can promote functional recovery. Stroke mice that received repeated neuronal stimulations exhibited significant improvement in cerebral blood flow and the neurovascular coupling response, as well as increased expression of activity-dependent neurotrophins in the contralesional cortex, including brain-derived neurotrophic factor, nerve growth factor, and neurotrophin 3. Western analysis also indicated that stimulated mice exhibited a significant increase in the expression of a plasticity marker growth-associated protein 43. Moreover, iM1 neuronal stimulations promoted functional recovery, as stimulated stroke mice showed faster weight gain and performed significantly better in sensory-motor behavior tests. Interestingly, stimulations in normal nonstroke mice did not alter motor behavior or neurotrophin expression, suggesting that the prorecovery effect of selective neuronal stimulations is dependent on the poststroke environment. These results demonstrate that stimulation of neurons in the stroke hemisphere is sufficient to promote recovery.
临床和研究工作一直专注于促进中风后的功能恢复。脑刺激策略尤其具有前景，因为它们能够直接操控目标区域的兴奋性。然而，由于现有的刺激技术会非特异性地靶向受刺激部位附近的所有细胞类型，所以阐明介导恢复的细胞类型和机制一直颇具难度。为了克服这些障碍，我们利用光遗传学选择性地激活表达通道视紫红质2的神经元，并证明在患侧初级运动皮层（iM1）进行选择性神经元刺激能够促进功能恢复。接受反复神经元刺激的中风小鼠在脑血流量和神经血管耦合反应方面有显著改善，对侧皮层中包括脑源性神经营养因子、神经生长因子和神经营养因子3在内的活性依赖性神经营养因子的表达也有所增加。蛋白质免疫印迹分析还表明，受刺激的小鼠中可塑性标记物生长相关蛋白43的表达显著增加。此外，iM1神经元刺激促进了功能恢复，因为受刺激的中风小鼠体重增加更快，并且在感觉运动行为测试中的表现明显更好。有趣的是，对正常未中风小鼠的刺激并未改变运动行为或神经营养因子表达，这表明选择性神经元刺激的促恢复作用依赖于中风后的环境。这些结果表明，刺激中风半球的神经元足以促进恢复。
