Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
Proc Natl Acad Sci U S A. 2019 Jul 2;116(27):13621-13630. doi: 10.1073/pnas.1811825116. Epub 2019 Jun 13.
Stroke is the leading cause of adult disability. Neurogenesis after stroke is associated with repair; however, the mechanisms regulating poststroke neurogenesis and its functional effect remain unclear. Here, we investigate multiple mechanistic routes of induced neurogenesis in the poststroke brain, using both a forelimb overuse manipulation that models a clinical neurorehabilitation paradigm, as well as local manipulation of cellular activity in the peri-infarct cortex. Increased activity in the forelimb peri-infarct cortex via either modulation drives increased subventricular zone (SVZ) progenitor proliferation, migration, and neuronal maturation in peri-infarct cortex. This effect is sensitive to competition from neighboring brain regions. By using orthogonal tract tracing and rabies virus approaches in transgenic SVZ-lineage-tracing mice, SVZ-derived neurons synaptically integrate into the peri-infarct cortex; these effects are enhanced with forelimb overuse. Synaptic transmission from these newborn SVZ-derived neurons is critical for spontaneous recovery after stroke, as tetanus neurotoxin silencing specifically of the SVZ-derived neurons disrupts the formation of these synaptic connections and hinders functional recovery after stroke. SVZ-derived neurogenesis after stroke is activity-dependent, region-specific, and sensitive to modulation, and the synaptic connections formed by these newborn cells are functionally critical for poststroke recovery.
中风是成年人残疾的主要原因。中风后神经发生与修复有关;然而,调节中风后神经发生及其功能效应的机制仍不清楚。在这里,我们通过使用一种模拟临床神经康复范例的前肢过度使用操作,以及在梗死周围皮层中局部操纵细胞活性,研究了中风后大脑中诱导的神经发生的多种机制途径。前肢梗死周围皮层中活性的增加,无论是通过调制驱动,都可以增加侧脑室下区(SVZ)祖细胞在梗死周围皮层中的增殖、迁移和神经元成熟。这种效应对来自邻近脑区的竞争很敏感。通过在转基因 SVZ 谱系追踪小鼠中使用正交轨迹追踪和狂犬病毒方法,SVZ 衍生的神经元在梗死周围皮层中形成突触连接;前肢过度使用会增强这些效应。这些新生 SVZ 衍生神经元的突触传递对于中风后的自发恢复至关重要,因为破伤风神经毒素特异性沉默 SVZ 衍生神经元会破坏这些突触连接的形成,并阻碍中风后的功能恢复。中风后 SVZ 源性神经发生是活性依赖性的、区域特异性的,对调制敏感,这些新生细胞形成的突触连接对于中风后的恢复具有功能上的关键作用。