The entorhinal cortex and aerobic exercise in aging

 描述（由申请人提供）：本项目的总体目标是调查最初身体不活跃的健康老年人的内鼻-海马记忆系统对有氧运动训练的反应。内鼻-海马通讯对于成功的导航和上下文相关记忆的形成至关重要。这个区域显示出阿尔茨海默病的深刻病理学。在认知功能完好的老年人中，内嗅和海马萎缩率随年龄增长而加速，这些老年人在非中心导航期间也表现出导航受损和海马和海马旁区域活动减少。Allocentric导航是一种灵活的导航形式，它依赖于环境中地标之间关系的成功编码。体育锻炼一直是减轻阿尔茨海默病认知能力下降的最有效干预措施之一，并促进健康的认知和大脑老化，包括海马体。内嗅皮层直接投射到海马体的神经原区齿状回，已知齿状回在动物模型中对运动有强烈反应。丰富的环境不仅能促进海马的完整性，而且能增加啮齿动物内嗅皮层的皮层厚度。 动物研究表明，体育锻炼是环境丰富诱导大脑变化的关键变量之一。在人类中，目前尚不清楚这些变化背后的机制，以及有氧运动是否会影响内嗅完整性和内嗅-海马通讯。填补这一知识空白至关重要，因为内嗅皮层位于海马体输入的中心，是皮层-海马体通信的门户。我们假设内嗅皮层和内嗅-海马通讯是有氧运动的主要功能/解剖目标。在两个具体目标，我们试图测试的假设，即在记忆任务的性能（具体目标#1）和在allocentric导航在虚拟环境（具体目标#2）增强运动训练后，最初的身体不活跃的老年人，这种增强是积极相关的认知变化的内嗅功能的完整性和内嗅-海马功能连接。我们还将调查参与者的特定子集，例如那些在空间推理测试中表现不佳或内嗅萎缩更严重的人，是否对有氧运动更敏感。为了研究这些目标，我们将使用一项随机对照临床试验， 运动训练与基线和随访评估行为表现的认知任务的内嗅和海马的完整性，有氧健身，和脑功能，使用高分辨率的功能和结构MRI技术优化检查内嗅-海马记忆系统。拟议的项目与国家老龄问题研究所的使命直接相关，其重点是了解老龄化过程的神经生物学基础，目标是通过改变生活方式促进健康的认知和大脑老化。

 DESCRIPTION (provided by applicant): The overall goal of this project is to investigate the response of the entorhinal-hippocampal memory system to aerobic exercise training in initially physically inactive, healthy seniors. Entorhinal-hippocampal communication is critical for successful navigation and context-dependent memory formation. This region shows profound pathology in Alzheimer's disease. Entorhinal and hippocampal atrophy rates accelerate with age in cognitively intact seniors, who also show impaired navigation and reduced activity in hippocampal and parahippocampal areas during allocentric navigation. Allocentric navigation is a form of flexible navigation that depends on successful encoding of relationships between landmarks in the environment. Physical exercise consistently appears as one of the most effective interventions to attenuate cognitive decline in Alzheimer's disease, and promotes healthy cognitive and brain aging, including the hippocampus. The entorhinal cortex has direct projections to the dentate gyrus, the neurogenic zone of the hippocampus, which is known to respond strongly to exercise in animal models. Environmental enrichment promotes not only hippocampal integrity, but also in- creases cortical thickness in the entorhinal cortex in rodents. Animal research has demonstrated that physical exercise is one of the critical variables for environmental enrichment induced brain changes. In humans, it is currently unknown what mechanisms underlie these changes, and if aerobic exercise has an impact on entorhinal integrity and entorhinal-hippocampal communication. It is fundamentally important to fill this knowledge gap, because the entorhinal cortex sits at the epicenter of inputs to the hippocampus, serving as a gateway for cortical-hippocampal communications. We hypothesize that the entorhinal cortex and entorhinal-hippocampal communication are primary functional/anatomic targets of aerobic exercise. In two Specific Aims we seek to test the hypothesis that entorhinal functional integrity and entorhinal-hippocampal functional connectivity during memory task performance (Specific Aim #1) and during allocentric navigation in a virtual environment (Specific Aim #2) are enhanced following exercise training in initially physically inactive seniors and that this enhancement is positively related to changes in cognition. We will also investigate whether particular subsets of participants, such as those with poor performance on spatial reasoning tests or those with greater entorhinal atrophy, might be more responsive to aerobic exercise. To investigate these aims, we will use a randomized, controlled clinical trial of exercise training with baseline and follow-up assessments of behavioral performance on cognitive tasks of entorhinal and hippocampal integrity, aerobic fitness, and brain function using high-resolution functional and structural MRI techniques optimized for examining the entorhinal-hippocampal memory system. The proposed project is directly relevant to the mission of the National Institute on Aging through its focus on understanding the neurobiological underpinnings of the aging process with the goal to promote healthy cognitive and brain aging through lifestyle changes.