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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：
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.

随着人口不断老龄化，阿尔茨海默病的患病率估计为570万人