In vertebrates, the adult neural stem cell population is largely maintained in a state of quiescence, a reversible state of cell cycle arrest. Quiescence is a transcriptionally heterogeneous cell state. Recent work from our lab using the zebrafish telencephalon as a model system has shown that this heterogeneity reflects, in part, cells differing in quiescence depth, or resistance to activation, with cells are positioned along a transcriptional continuum of substates differing in their proximity to proliferation. With increased chronological age, proliferation by neural stem cells decreases, resulting in a decrease in the production of adult-born neurons through the differentiation of resulting progenitors cells, a process known as adult neurogenesis. Decreased neural stem cell proliferation with increased chronological age, and the subsequent impact on neurogenesis, has been attributed to an increase in neural stem cell quiescence depth over time, however the molecular mechanisms underlying this over time change remain unknown.
To determine whether decreased neurogenesis by adult neural stem cells is a consequence of increased quiescence depth with chronological aging, and identify possible mechanisms underlying this change, we will compare the transcriptional identities of NSCs isolated from aged zebrafish to those in young adults. Further, we will associate transcriptional changes over the lifespan with differences in chromatin accessibility within the same single-cells to identify changes to the chromatin landscape that may lead to any transcriptional differences. With this approach, we will determine whether changes in proliferation frequency and neurogenic capacity over time result from an increase in quiescence depth among vertebrate neural stem cells over the lifespan, as defined by transcriptional identity, and elucidate possible molecular mechanisms associated with these changes.
