Chromatin accessibility dynamics of neurogenic niche cells reveal a reversible decline in neural stem cell migration during aging

Aging is accompanied by a deterioration in the regenerative and repair potential of stem cell regions in the brain. However, the mechanisms underlying this decline are largely unknown. Here we profile the chromatin landscape of five different cell types freshly isolated from the subventricular zone neurogenic niche of young and old mice. We find that chromatin states exhibit distinct changes with aging in different cell types. Notably, the chromatin of quiescent neural stem cells (NSCs) becomes more repressed with age whereas that of proliferative, activated NSCs becomes more open. Surprisingly, these opposing age-related chromatin changes involve cell adhesion and migration pathways. We experimentally validate that quiescent and activated NSCs exhibit opposite migratory deficits during aging. Quiescent NSCs become more migratory during aging, whereas activated NSCs and progeny become less migratory and less able to mobilize out of the niche in vivo during aging. The cellular mechanism by which aging impairs the migration of activated NSCs and progeny involves increased occurrence of force-producing focal adhesions. Inhibiting the cytoskeletal-regulating kinase ROCK in old activated NSCs and progenitors eliminates cell adhesive forces and boosts migration speed, reverting these cells to a more youthful migratory state. Our work has important implications for restoring the migratory potential of NSCs during aging and brain injury. ### Competing Interest Statement The authors have declared no competing interest.