The vertebrate nervous system contains active stem cells that generate new nerve cells throughout life. Creating new nerve cells is a core mechanism underlying resilience, adaptive capacity, and ?plasticity? in the brain. These new nerve cells are regulated, in part, by age- and sex-dependent factors. However, how age and sex influence new nerve cells is not well understood. This research project will investigate how neural stem cell function across various ages and in response to sex hormones. These studies will help an understanding of how neural stem cells contribute to neural plasticity which, in turn, can promote lifelong healthy brain function and replacement of neural cells lost to injury or disease. Moreover, this project will provide training of diverse undergraduate and graduate students and the projects include conducting outreach via the Brain Bus program?s mobile neuroscience unit that serves students at K-12 schools in Southern Arizona. The project will also engage senior citizens to enhance public awareness of stem cells and brain resilience. Understanding the mechanisms of neural plasticity and resiliency is a central challenge of neurobiology. This project investigates the evolving dynamics of neural stem cell-based resilience mechanisms across developmental time in the mammalian brain. Specifically, using aging rodents as a model, the project will: (1) study how neural stem cells change, at cellular, molecular and functional levels over time; and (2) address the role of the female sex hormones estrogen and progesterone in this process. The PI?s prior work discovered specific critical periods of vulnerability and identified a vital role for the NRF2 transcription factor in regulating neural stem cell function with age. The current project builds on this foundation, and utilizes transgenic animals, viral vectors, single-cell sequencing, and functional assays, to answer fundamental questions of (1) how neural stem cell populations are maintained with age, (2) how sex hormones affect neural stem cells, and (3) the nature and consequences of neural stem cell heterogeneity during the lifespan. Overall, the expected project outcomes will help define the basic attributes of this class of stem cells and reveal mechanisms underlying their resiliency. The project will also improve science education and promote diversity in neuroscience by incorporating the proposed research into training a diverse population of undergraduate and graduate researchers in stem cell and brain resilience research, and by educating K-12 students and senior citizens on this topic. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.