The burden of neurological disorders has increased substantially over the past 25 years because of an expanding aging population. Several lines of evidence indicate that a decline in adult stem cell function can drive age- related disease, whereas enhanced tissue regeneration by adult stem cells can delay aging. Radial glial neural stem cells (NSCs) generate newborn neurons and astrocytes (neurogenesis) to modify existing hippocampal circuits. These newborn cells play an essential role in learning, memory, and cognition. Yet, neuronal production declines with age, coincident with initial functional decline. We reasoned that cellular heterogeneity within the NSC pool has masked the ability to uncover the origins of neurogenesis decline. In previous research, we have resolved NSC heterogeneity into two radial glia-like cell subpopulations. In doing so, we identified a NSC sub- population that is homeostatic in the young brain, as it balances stem cell loss with NSC expansion (self- renewal), but transitions out of homeostasis in the mature brain. This finding indicates a new way to pinpoint when, why, and how NSCs lose homeostasis and the commensurate ability to generate new cells. We propose to utilize this precise platform to define cellular, molecular, and state-specific mechanisms underlying NSC homeostasis. Our developing conceptual framework of NSC homeostasis can be applied to aging of other tissues and cell types. We hypothesize that NSCs undergo a reversible cellular aging program in the mature brain, which lengthens quiescence and leads to a loss of NSCs and neuron production. We will test this theory with three specific aims: 1. Uncover whether the age-related decrease in neurogenesis results from a smaller number of NSCs, or their reduced capacity to generate progeny. 2. Identify the underlying gene networks that control NSC homeostasis and its age-dependent decline, thus providing new molecular targets for drug development aimed at maintaining the NSC pool. 3. Determine how exercise selects for specific NSCs to boost the stem cell pool and enhance neurogenesis. Augmenting NSC function to repair the aging brain could serve as a catalyst for cognitive rejuvenation for patients ranging from the mildly impaired to those with Alzheimer?s disease.
The research described in this proposal will address early cellular origins of cognitive dysfunction. The study seeks to define when, why and how NSCs functionally decline and lose the ability to modulate hippocampus circuitry. The results obtained here will have the potential to stall age-related cognitive decline for patients ranging from the mildly impaired to those with Alzheimer's disease.
