Metabolic requirements of adult neural stem cells

描述(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，但神经发生的比率并不是恒定的。衰老导致神经元生成减少，而自愿锻炼和高脂肪饮食已被证明增加了成人神经发生的比率。我们认为代谢燃料的可获得性变化是导致这些现象的共同机制。使用适合测量多个实时呼吸终点的流动培养箱，我们已经表明，年轻和老年神经干细胞都具有非常高的氧化代谢率，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。我们假设成年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新陈代谢。在发育过程中，大脑依赖于从母乳中提取的多不饱和脂肪酸和酮体；对这些燃料的新陈代谢依赖可能是神经干细胞在整个生命周期中保守的能量分布，通过B-氧化提供大量细胞分裂所需的ATP。我们还假设，老年神经干细胞中较少的线粒体满足高代谢需求会导致活性氧水平增加，线粒体突变的发生率更高。我们建议确定神经干细胞的燃料来源，确定细胞分裂的代谢成本，并调查燃料的可用性是否会影响体内神经形成率。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，成年哺乳动物的大脑中的生物行为、能量消耗和细胞活动是相互耦合的。我们希望通过识别行为引起的细胞活动变化的潜在机制来影响公共健康，特别是在能够在成人和老化的大脑中再生的细胞中。 与公共健康相关：在我们完全了解与年龄相关的疾病的病理方面之前，在分子、细胞和器官水平上描述正常衰老是必要的，例如癌症或神经退化。我们希望通过识别行为引起的细胞活动变化的潜在机制来影响公共健康，特别是在能够在成人和老化的大脑中再生的细胞中。研究新陈代谢和神经干细胞活性之间的联系将有助于表征衰老的细胞机制，并有可能以安全的方式治疗中枢神经系统中与年龄相关的细胞丢失。

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. PUBLIC HEALTH RELEVANCE: A characterization of normal aging on a molecular, cellular and organismal level will be necessary before we can fully understand the pathological aspects of age-related diseases, such as cancer or neurodegeneration. 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. Studying the links between metabolism and neural stem cell activity will be useful both in characterizing the cellular mechanisms of aging and in potentially treating age-related cell loss in the central nervous system in a safe manner.