Neurogenesis and Memory Network Dynamics during Normal Aging

正常衰老过程中的神经发生和记忆网络动态

• 批准号: 8970277
• 负责人: SARA N BURKE
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970277
• 关键词: Activities of Daily Living; Adult; Age; Aging; American; Animals; Area; Behavior; Behavior Therapy; Behavioral; Biological Neural Networks; Biomedical Engineering; Brain; Brain region; Bromodeoxyuridine; Cells; Censuses; Characteristics; Clinical Treatment; Cognitive; Cognitive aging; Cognitive deficits; Complex; Data; Designer Drugs; Discrimination; Elderly; Electrodes; Environment; Etiology; Exhibits; FOS gene; Functional disorder; Goals; Hippocampus (Brain); Immediate-Early Genes; Impaired cognition; Implant; Individual; Knowledge; Label; Lead; Life; Link; Location; Long-Term Care; Longevity; Measures; Memory; Memory Loss; Memory impairment; Methods; Monitor; Neurodegenerative Disorders; Neurons; Newborn Infant; Outcome; Patient Self-Report; Pattern; Performance; Pharmaceutical Preparations; Physiological; Primates; Process; Production; Public Health; Rattus; Reporting; Research; Rodent; Role; Spatial Distribution; Structure; Testing; Therapeutic Intervention; United States National Institutes of Health; Update; age related; aged; behavioral outcome; dentate gyrus; design; experience; granule cell; improved; in vivo; innovation; neural circuit; neurogenesis; neuropathology; neurophysiology; newborn neuron; normal aging; novel; place fields; programs; public health relevance; receptive field; receptor; relating to nervous system; research study; therapeutic target

 DESCRIPTION (provided by applicant): By the year 2020 the number of Americans over the age of 65 is projected to reach 55 million. It is therefore imperative that the ability of these individuals to live independently is preserved for reasons of personal dignity as well as the financial and public-health consequences that result from the necessity of long-term care. Unfortunately, even in the absence of significant neuropathology, a large proportion of elderly people will experience memory decline that will interfere with their instrumental activities of daiy living. The hippocampus is critical for memory and is subject to dysfunction during aging. Importantly, the dentate gyrus subregion of the hippocampus is one of only two brain regions in which new neurons are born and integrated into existing neural circuits; a process referred to as neurogenesis. Neurogenesis declines with age, but it is not known how this contributes to cognitive impairments. Although neurogenesis could have vital functions for normal memory, there is a fundamental gap in our knowledge of how this process impacts neuronal networks both within the dentate gyrus as well as in the brain regions that receive direct input from this structure. Moreover, to date, there is not a single report of the in vivo physiological characteristics of dentate gyrus neurons in aged animals. The long-term goal of the proposed research plan is to pinpoint disruptions in the neural circuits of old animals that can then be restored through therapeutic or behavioral interventions to reduce cognitive impairments in the elderly. The objective in this particular application is to determine how neurogenesis levels impact hippocampal-dependent behaviors and the dynamics of neural networks within the dentate gyrus and its primary efferent target, CA3. The central hypothesis is that the integration of newborn neurons is critical for dynamic hippocampal representations needed to support complex behaviors. The rationale for the proposed research is that understanding the functional importance of neurogenesis and how dentate gyrus and CA3 cellular activity dynamics are impacted by lower numbers of newborn neurons could direct clinical treatments for cognitive deficits associated with aging that are going to become more prevalent as the number of elderly people in the U.S. continues to grow. The hypothesis will be tested with 2 specific aims: 1) identify how age- related neurogenesis decline impact dentate gyrus circuit dynamics, and 2) quantify the impact of age- associated functional changes in the dentate gyrus on CA3. These aims will be achieved through the use of high-channel count neural recordings that allow single-cell activity to be monitored from up to hundreds of neurons across multiple brain regions simultaneously in behaving rats. This is an innovative approach that optimizes power for detecting neural-behavioral relationships.

 描述（由申请人提供）：到2020年，65岁以上的美国人预计将达到5500万。因此，出于个人尊严以及长期护理的必要性所造成的经济和公共卫生后果的原因，必须保护这些人独立生活的能力。不幸的是，即使没有明显的神经病理学，很大一部分老年人也会经历记忆力下降，这将干扰他们日常生活的工具性活动。海马体对记忆至关重要，在衰老过程中会出现功能障碍。重要的是，海马的齿状回亚区是仅有的两个大脑区域之一，在这两个区域中，新的神经元诞生并整合到现有的神经回路中;这一过程被称为神经发生。神经发生随着年龄的增长而下降，但尚不清楚这如何导致认知障碍。虽然神经发生对正常记忆具有重要功能，但我们对这一过程如何影响齿状回内的神经元网络以及接受该结构直接输入的大脑区域的知识存在根本性的空白。此外，迄今为止，还没有关于老年动物齿状回神经元在体生理特性的报道。拟议研究计划的长期目标是查明老年动物神经回路的中断，然后通过治疗或行为干预来恢复，以减少老年人的认知障碍。在这个特定的应用程序的目的是确定神经发生水平如何影响海马依赖的行为和神经网络的动态齿状回及其主要传出目标，CA3。核心假设是新生神经元的整合对于支持复杂行为所需的动态海马表征至关重要。这项研究的基本原理是，了解神经发生的功能重要性以及齿状回和CA3细胞活动动力学如何受到新生神经元数量减少的影响，可以指导与衰老相关的认知缺陷的临床治疗，随着美国老年人数量的增加，这种认知缺陷将变得更加普遍。该假设将通过2个特定目的进行检验：1）确定年龄相关的神经发生衰退如何影响齿状回回路动力学，以及2）量化齿状回中年龄相关的功能变化对CA 3的影响。这些目标将通过使用高通道计数神经记录来实现，该记录允许在行为大鼠的多个大脑区域中同时监测多达数百个神经元的单细胞活动。这是一种创新的方法，可以优化检测神经行为关系的能力。