Neural stem cell mechanisms of resilience across the lifespan

脊椎动物的神经系统包含活跃的干细胞，可以在一生中产生新的神经细胞。创造新的神经细胞是大脑弹性、适应能力和‘可塑性’的核心机制。这些新的神经细胞在一定程度上受到年龄和性别相关因素的调节。然而，年龄和性别如何影响新的神经细胞还不是很清楚。这项研究项目将研究神经干细胞如何在不同的年龄和性激素的反应下发挥作用。这些研究将有助于理解神经干细胞如何有助于神经可塑性，而神经可塑性反过来可以促进终身健康的大脑功能和替换因损伤或疾病而失去的神经细胞。此外，该项目将为不同的本科生和研究生提供培训，项目包括通过大脑巴士计划的移动神经科学部门开展外联活动，该部门服务于亚利桑那州南部K-12学校的学生。该项目还将吸引老年人参与，以提高公众对干细胞和大脑弹性的认识。了解神经可塑性和弹性的机制是神经生物学的中心挑战。本项目研究哺乳动物大脑发育过程中基于神经干细胞的复原力机制的进化动力学。具体地说，以老化的啮齿动物为模型，该项目将：(1)研究神经干细胞如何随着时间的推移在细胞、分子和功能水平上发生变化；以及(2)解决女性性激素雌激素和孕激素在这一过程中的作用。PI之前的工作发现了特定的脆弱关键时期，并确定了NRF2转录因子在调节神经干细胞功能方面随年龄增长的关键作用。目前的项目建立在此基础上，并利用转基因动物、病毒载体、单细胞测序和功能分析来回答以下基本问题：(1)神经干细胞种群如何随着年龄的增长而保持；(2)性激素如何影响神经干细胞；(3)神经干细胞在生命周期中的异质性的性质和后果。总体而言，预期的项目结果将有助于确定这类干细胞的基本属性，并揭示其弹性机制。该项目还将改善科学教育，促进神经科学的多样性，将拟议的研究纳入干细胞和脑弹性研究的不同本科生和研究生群体的培训，并就这一主题教育K-12学生和老年人。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.