Region-specific and activity-dependent regulation of SVZ neurogenesis and recovery after stroke

Abstract

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.

Cranial irradiation at early postnatal age impairs stroke-induced neural stem/progenitor cell response in the adult brain

“…Whole brain irradiation decreases NSPC proliferation and diminishes neurogenesis, not only in the hippocampus but also in the subventricular zone 32 – 35 . It is also established in rodents that NSPCs respond to damage, such as stroke, and contribute to the repair process that is critical for post-stroke functional recovery 36 . We have previously shown 33 , 34 that the response to postnatal irradiation is niche-dependent, i.e.…”

IGF-1 Protects Neurons in the Cortex and Subventricular Zone in a Periventricular Leucomalacia Model

“…Neuronal and glial progenitor cells, which are the sources of neurogenesis, were abundant in the SVZ (25). Especially, in the ischemic brain, these cells have been reported as important self-renewing sources for neurons and glial cells (23).…”

Intracerebroventricular Administration of hNSCs Improves Neurological Recovery after Cardiac Arrest in Rats

“…For ependymal cells (E cells), studies have shown that they do not divide in the adult [51], and recent studies working on single-cell transcriptomic and lineage analysis have proven that E cells have no progenitor properties or function as NSCs [52]. Based on SVZ cell characteristics, using Ki67 or BrdU to label neurogenesis in the SVZ is a wildly accepted method [13,35]. Microtubulebinding protein Dcx, which is transiently expressed in proliferating progenitor cells and newly generated neuroblasts, serves as a marker of migration [53].…”

“…Evidence in the ischemic stroke model showed that SVZ cells contributed to repair after regional ischemia injury [13]. However, different from regional ischemic injury of stroke, global ischemic injury after CA may have a negative impact on SVZ cells.…”