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Mechanistic study of declining hippocampal neurogenesis in the aging brain

衰老大脑海马神经发生下降的机制研究

基本信息

批准号：
10334527
负责人：
Shaoyu Ge
金额：
$ 32.7万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10334527
关键词：
Activities of Daily Living Address Adult Age Aging Alzheimer&apos s Disease Animals Area Biological Assay Blood Brain Cell Culture Techniques Cell Cycle Cells Clinical Cognitive Development Disease Elderly Exhibits Functional Regeneration Generations Hippocampus (Brain)Homeostasis Hyperemia In Situ Individual Interneurons Learning Life Mediating Metabolic Methods Nerve Degeneration Nerve Regeneration Nerve Tissue Nervous system structure Neuronal Plasticity Neurons Patients Persons Pilot Projects Play Prevalence Process Proliferating Public Health Rattus Receptor Activation Regulation Research Proposals Rodent Role Signal Transduction Sphingolipids Structure of germinal center of lymph node Testing Tissues United States age related cognitive disorder aged aging brain aging population base brain cell dentate gyrus environmental enrichment for laboratory animals experience human old age (65+)inorganic phosphate insight lipidomics member metabolomics nerve stem cell neural circuit neural network neurogenesis neurotrophic factor neurovascular neurovascular coupling newborn neuron normal aging novel strategies novel therapeutics optogenetics pathological aging receptor repaired screening stem cell biology stem cell niche young adult

项目摘要

With an ever-aging population and an estimated prevalence of Alzheimer disease of 5.7 million people in the United States alone, the impetus for more targeted treatments for age-related cognitive disorders is greater now than ever. Neuroplasticity, the ability of neural networks to adapt and remodel given experience, dwindles with age, providing possible mechanistic insights into this decline. An important layer of neuroplasticity, unique to a couple of discrete areas of the adult mammalian brain, is the addition of newly-generated neurons into existing circuits, a process known as neurogenesis. While the existence and importance of adult hippocampal neurogenesis in young adults has been well-established, we know very little about hippocampal neurogenesis in aging brains. Importantly, hippocampal neurogenesis continues into old age although there is a substantial decline in the number of newborn neurons. For example, in 26-month-old rodents, ~1000 proliferating cells could be detected per day, although only half that detected in 5-month-old adult rats. A recent study demonstrated that thousands of new neurons could be detected in the aged adult human dentate gyrus, and further, that in patients with Alzheimer disease, newborn neurons were fewer in number and exhibited delayed maturation. As a starting point, we ask why neurogenesis declines in the aging brain. Based on our preliminary studies, we found that biased circuit activity may regulate hippocampal neurogenesis in the aging brain. During screening of potential molecules biasing circuit activity, we found that one sphingolipid signaling is active in interneurons and becomes less active in the aging brain. We propose to genetically intervene this signaling to study its role in regulating neurogenesis in the aging brain. Lastly, we determine how biased circuit activity regulates hippocampal neurogenesis. Our results will not only provide mechanistic insights into the understanding of neurogenesis in the aging brain it also provides a possible strategy to intervene aging circuit activity to regulate neurogenesis.

随着人口的不断老龄化和阿尔茨海默病的估计患病率为570万人仅在美国，对年龄相关认知障碍进行更有针对性的治疗的动力就更大比以往任何时候都要好神经可塑性，即神经网络适应和重塑给定经验的能力，随着年龄的增长，为这种下降提供了可能的机械见解。神经可塑性的一个重要层面，成年哺乳动物大脑的几个离散区域，是新产生的神经元加入到这是一个被称为神经发生的过程。虽然成年海马的存在和重要性虽然年轻人的神经发生已经得到了很好的证实，但我们对海马神经发生知之甚少在老化的大脑中。重要的是，海马神经发生持续到老年，尽管有大量的新生神经元数量的下降。例如，在26个月大的啮齿动物中，约1000个增殖细胞可以虽然只有5个月大的成年大鼠中检测到的一半。最近的一项研究表明，在老年人齿状回中可以检测到数千个新的神经元，在阿尔茨海默病中，新生神经元数量较少，并表现出延迟成熟。为出发我们要问的是，为什么衰老的大脑中神经发生会下降。根据我们的初步研究，我们发现，偏置回路活动可调节老化脑中海马神经发生。在筛选潜在分子偏置电路活动，我们发现一个鞘脂信号在中间神经元中是活跃的，在老化的大脑中不那么活跃。我们建议从遗传学上干预这种信号传导，以研究其在调节衰老大脑中的神经发生最后，我们确定了偏置电路活动如何调节海马神经发生我们的研究结果不仅为理解神经发生提供了机制性的见解，它还提供了一种干预衰老回路活动以调节神经发生的可能策略。