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恒定。衰老导致神经元产生减少，而自愿运动和高脂肪饮食已被证明可以增加成年神经发生的速率。我们提出了变化的可用性的代谢燃料作为一个共同的机制，这些现象的基础。使用适合测量多个实时呼吸终点的流动培养室，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，并且不需要葡萄糖来维持氧消耗。这些结果表明，神经干细胞依赖于一些新的内源性燃料，以维持细胞分裂所必需的高水平的有氧呼吸。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;对这些燃料的代谢依赖可能是整个生命周期中神经干细胞中保守的能量分布，通过B-氧化提供细胞分裂所需的大量ATP。我们还假设，老年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，线粒体突变发生率较高。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，并调查燃料的可用性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，生物体行为，能量消耗和细胞活性在成年哺乳动物大脑中相互作用。我们希望通过确定行为诱导的细胞活动变化的潜在机制来影响公共卫生，特别是在成年和衰老大脑中能够再生的细胞中。 公共卫生相关性：在我们完全理解与年龄相关的疾病（如癌症或神经退行性疾病）的病理学方面之前，有必要在分子、细胞和生物体水平上对正常衰老进行表征。我们希望通过确定行为诱导的细胞活动变化的潜在机制来影响公共卫生，特别是在成年和衰老大脑中能够再生的细胞中。研究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，并以安全的方式潜在地治疗中枢神经系统中与年龄相关的细胞损失。

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.