The entorhinal cortex and aerobic exercise in aging

 描述(由申请人提供)：这个项目的总体目标是调查在最初身体不活跃的健康老年人中，内嗅觉-海马体记忆系统对有氧运动训练的反应。内嗅觉-海马体沟通是成功导航和上下文相关记忆形成的关键。这一区域显示了阿尔茨海默病的深刻病理。在认知正常的老年人中，内嗅觉和海马体萎缩率随着年龄的增长而加快，他们还表现出导航功能受损，在向外定位导航时，海马区和海马区的活动减少。分心导航是一种灵活的导航形式，它依赖于对环境中地标之间的关系进行成功编码。体育锻炼一直是减缓阿尔茨海默病认知衰退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。内嗅觉皮质直接投射到齿状回，齿状回是海马体的神经起源区域，众所周知，在动物模型中，齿状回对运动反应强烈。环境的丰富不仅促进了海马区的完整性，而且增加了啮齿动物内嗅皮层的皮质厚度。 动物研究表明，体育锻炼是环境丰富引起的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，以及有氧运动是否对内嗅觉完整性和内嗅觉-海马体通信产生影响。填补这一知识缺口是至关重要的，因为内嗅觉皮质位于海马体输入的震中，是皮质-海马体交流的门户。我们假设内嗅觉皮质和内嗅觉-海马区通讯是有氧运动的主要功能/解剖靶点。在两个特定目标中，我们试图检验这样一个假设，即在最初身体不活跃的老年人进行运动训练后，在记忆任务执行(特定目标1)和在虚拟环境中的向心导航(特定目标2)过程中，内嗅觉功能完整性和内嗅觉-海马体功能连通性得到增强，并且这种增强与认知变化呈正相关。我们还将调查特定的参与者亚组，例如那些在空间推理测试中表现不佳的人，或者那些有更严重的内嗅觉萎缩的人，是否可能对有氧运动更敏感。为了研究这些目的，我们将使用一项随机对照临床试验 运动训练，使用高分辨率功能和结构磁共振技术，对认知任务中的行为表现进行基线和后续评估，包括内嗅觉和海马体完整性、有氧健身和脑功能，这些技术针对检查内嗅觉-海马体记忆系统进行了优化。拟议的项目与国家老龄研究所的使命直接相关，其重点是了解衰老过程的神经生物学基础，目的是通过改变生活方式促进健康的认知和大脑衰老。

 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.