Metabolic requirements of adult neural stem cells

描述（由申请人提供）：尽管神经干细胞在成年哺乳动物大脑的几个区域产生新的神经元，但神经发生的速率并不保持不变。衰老导致神经元生成减少，而自愿运动和高脂肪饮食已被证明可以增加成人神经生成的速率。我们提出代谢燃料可用性的变化是这些现象背后的共同机制。通过流动培养室测量多个实时呼吸端点，我们发现年轻和年老的神经干细胞都具有非常高的氧化代谢速率，并且不需要葡萄糖来维持氧气消耗。这些结果表明，神经干细胞依赖于一些新的内源性燃料来维持细胞分裂所需的高水平有氧呼吸。我们假设成体神经干细胞的代谢和有丝分裂活动依赖于脂肪酸或酮体的代谢。在发育过程中，大脑依赖于来自母乳的多不饱和脂肪酸和酮体；在整个生命周期中，神经干细胞对这些燃料的代谢依赖可能是一种保守的能量分布，通过这种能量分布，b -氧化提供了细胞分裂所需的大量ATP。我们还假设，衰老的神经干细胞中较少的线粒体满足了高代谢需求，导致活性氧水平增加，线粒体突变发生率更高。我们建议确定神经干细胞的燃料资源，确定细胞分裂的代谢成本，并研究燃料供应是否影响体内神经发生的速率。在体外和体内操纵神经干细胞可用的燃料可能会揭示一种新的机制，通过这种机制，成年哺乳动物大脑中的生物行为、能量消耗和细胞活动是耦合的。我们希望通过确定行为引起的细胞活动变化的潜在机制来影响公众健康，特别是在成人和衰老的大脑中能够再生的细胞。

DESCRIPTION (provided by applicant): Although neural stem cells give rise to new neurons in several regions of the adult mammalian brain, rates of neurogenesis do not remain constant. Aging leads to decreased neuron production, while voluntary exercise and high-fat diet have been shown to increase rates of adult neurogenesis. We propose changes in availability of metabolic fuels as a common mechanism underlying these phenomena. Using a flow culture chamber fitted to measure multiple real-time respiratory endpoints, we have shown that both young and aged neural stem cells have extraordinarily high rates of oxidative metabolism and do not require glucose to sustain oxygen consumption. These results suggest that neural stem cells are dependent upon some novel endogenous fuel to maintain high levels of aerobic respiration necessary for cellular division. We hypothesize that adult neural stem cells are dependent upon metabolism of fatty acids or ketone bodies for metabolic and mitotic activity. During development, the brain is dependent upon polyunsaturated fatty acids and ketone bodies derived from mothers' milk; metabolic dependence upon these fuels may be a conserved energetic profile in neural stem cells across the lifespan, by which B-oxidation provides large quantities of ATP necessary for cellular division. We also hypothesize that high metabolic demand met by fewer mitochondria in aged neural stem cells leads to increased levels of reactive oxygen species and a higher occurrence of mitochondrial mutations. We propose identifying the fuel resources of neural stem cells, determining the metabolic costs of cellular division, and investigating whether fuel availability affects rates of neurogenesis in vivo. Manipulating the fuels available to neural stem cells in vitro and in vivo may uncover a novel mechanism by which organismal behavior, energy consumption, and cellular activity are coupled in the adult mammalian brain. We hope to impact public health by identifying mechanisms underlying behavior-induced changes in cellular activity, especially in cells capable of regeneration within the adult and aging brain.