The role of proopiomelanocortin neurons in age-related cognitive decline

原阿黑皮素神经元在年龄相关认知衰退中的作用

• 批准号: 10077917
• 负责人: AMANDA L SHARPE
• 金额: $ 28.25万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077917
• 关键词: Age; Age-associated memory impairment; Aging; Alzheimer' s disease model; Anatomy; Applications Grants; Attention; Attenuated; Brain; Brain Stem; Cell Nucleus; Cell physiology; Cognition; Cognitive; Cognitive aging; Cognitive deficits; Data; Elderly; Etiology; Fluorescence-Activated Cell Sorting; Functional disorder; Gene Expression; Genetic; Genetic Models; Geroscience; Glucose; Hippocampus (Brain); Human; Hypothalamic structure; Impaired cognition; Inflammation; Insulin; Intervention; Knowledge; Label; Lead; Leptin; Longevity; Measures; Memory; Mentorship; Molecular; Mus; Neurons; Neurotransmitters; Nucleus solitarius; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Population; Pro-Opiomelanocortin; Quality of life; Research; Research Project Grants; Resource Development; Rodent; Role; Signal Transduction; Sirolimus; Structure of nucleus infundibularis hypothalami; Technology; Testing; Time; Weight Gain; Work; age related; aged; cognitive function; cognitive performance; density; improved; innovation; insight; interest; metabolic rate; mouse genetics; mouse model; novel; paraventricular nucleus; prevent; therapy development; transcriptome; transcriptome sequencing

Cognitive decline is a common sequela of mammalian aging, from rodents to humans. As it often results in the inability to live independently, slowing or preventing the loss of cognition with age would significantly increase the quality of life for older adults. While the etiology of age-related cognitive impairment is unknown, there is increasing evidence that age-related changes in neurotransmitters may play an important role. Neurotransmitters produced from proopiomelanocortin (POMC) are of particular interest because they modulate cognition, metabolic rate and other age-related phenotypes, and their levels are known to decrease with age. Furthermore, when administered systemically, or into the brain, they improve memory, attention, and cognition and delay the decline in cognition in mouse models of Alzheimer’s disease. However, which POMC- producing neurons are responsible for the age-related decline in brain POMC, the mechanism by which this occurs, and its contribution to age-dependent cognitive decline are not known. Our studies will yield insight into mechanisms responsible for age-related changes in POMCHipp neurons and reveal whether interventions that delay aging act, in part, by modulating these neurons. Filling these gaps in knowledge is essential f or development of interventions to reverse cognitive aging. The proposed work is enabled by a novel combination of technology including retrograde labeling of POMCHipp neurons and mouse genetic models that together allow us to specifically target these neurons. This will allow us to analyze age-dependent changes in the number and projection density (Aim 1) and gene expression (Aim 2) of POMCHipp neurons that may provide insight into the decline in cognition with age. We will further determine whether these changes can be reversed by treatment with rapamycin, a drug that increases lifespan in mice while ameliorating age-related declines in cognition, as well the age-related dysfuncton of Arc POMCPVN neurons. Finally, in Aim 3 we will specifically activate or inhibit the function of Arc POMCHipp neurons and measure the impact on cognition. Our approach is highly innovative and will define the role POMCHipp neurons in the mechanisms responsible for cognitive decline with age, and provide a framework for studies to develop interventions to reduce age-related cognitive decline. This JPI project will provide the preliminary data, mentorship, and resources for the development of a competitive, independent research grant proposal in the field of geroscience.

从啮齿动物到人类，认知能力下降是哺乳动物衰老的常见后遗症。因为它经常导致 无法独立生活、减缓或防止随着年龄的增长而丧失认知能力将显着 提高老年人的生活质量。虽然与年龄相关的认知障碍的病因尚不清楚， 越来越多的证据表明，与年龄有关的神经递质变化可能发挥重要作用。 由阿黑皮素原（POMC）产生的神经递质特别令人感兴趣，因为它们 调节认知，代谢率和其他与年龄相关的表型，并且已知它们的水平会降低 随年龄此外，当全身施用或施用到大脑中时，它们改善记忆力、注意力和 认知和延缓阿尔茨海默病小鼠模型认知能力的下降。但是，哪种POMC- 产生神经元负责与年龄相关的大脑POMC下降，这是一种机制， 发生，其对年龄依赖性认知下降的贡献尚不清楚。我们的研究将使我们深入了解 POMCHipp神经元中与年龄相关的变化的机制，并揭示是否干预， 延缓衰老的作用，部分是通过调节这些神经元。填补这些知识空白对于 开发干预措施以逆转认知老化。拟议的工作是通过一种新颖的组合， 包括POMCHipp神经元的逆行标记和小鼠遗传模型， 专门针对这些神经元。这将使我们能够分析年龄相关的变化， POMCHipp神经元的投射密度（Aim 1）和基因表达（Aim 2），这可能有助于了解POMCHipp神经元的功能。 认知能力随年龄增长而下降。我们将进一步确定这些变化是否可以通过治疗逆转 雷帕霉素是一种增加小鼠寿命的药物，同时改善与年龄相关的认知能力下降， Arc POMCPVN神经元的年龄相关性功能障碍。最后，在目标3中，我们将专门激活或抑制 Arc POMCHipp神经元的功能并测量对认知的影响。我们的方法是高度创新的 并将确定POMCHipp神经元在负责认知能力随年龄下降的机制中的作用， 为研究提供框架，以制定干预措施，减少与年龄相关的认知能力下降。这个JPI 该项目将提供初步的数据，指导，和资源的竞争力， 老年科学领域的独立研究补助金提案。