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：
10577735
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/10577735
关键词：
Activities of Daily Living Adult Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease patient Animals Area Biological Assay Brain Cell Culture Techniques Cell Cycle Cell Proliferation Cells Clinical Cognitive Development Disease Elderly Exhibits Functional Regeneration Generations Hippocampus Homeostasis Hyperemia In Situ Individual Interneurons Learning Life Mediating Metabolic Methods Nerve Degeneration Nerve Regeneration Nerve Tissue Nervous System Neuronal Plasticity Neurons Persons Pilot Projects Play Prevalence Process 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 brain cell dentate gyrus environmental enrichment for laboratory animals experience genetic manipulation 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.

人口不断增加，阿尔茨海默氏病的估计患病率是570万人仅在美国，针对年龄相关的认知障碍的更多针对性治疗的动力就更大现在比以往。神经可塑性，神经网络适应和改造的能力给定经验，减少随着年龄的增长，为这种下降提供了可能的机械见解。神经塑性的重要层，独特在成年哺乳动物大脑的几个离散区域中，将新生成的神经元添加到现有电路，这一过程称为神经发生。而成人海马的存在和重要性年轻人的神经发生已经建立了良好，我们对海马神经发生知之甚少在衰老的大脑中。重要的是，尽管存在很大的新生神经元的数量减少。例如，在26个月大的啮齿动物中，约有1000个增殖细胞可以每天被检测到，尽管只有一半在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人类齿状回中可以检测到成千上万的新神经元，进一步在患者中随着阿尔茨海默氏病，新生儿神经元的数量较少，并且表现出延迟的成熟。作为开始点，我们问为什么神经发生在衰老的大脑中会下降。根据我们的初步研究，我们发现偏见的电路活性可能调节衰老大脑的海马神经发生。在筛选潜力期间分子偏置电路活性，我们发现一种鞘脂信号在中间神经元中活跃，并变为在衰老的大脑中活跃。我们建议从基因干预此信号以研究其在调节中的作用衰老大脑的神经发生。最后，我们确定如何调节海马的偏置电路活动神经发生。我们的结果不仅将提供有关对神经发生的理解的机械见解衰老的大脑还提供了一种可能干预衰老电路活性以调节神经发生的策略。