Functional Imaging of Hippocampal Subfields in Healthy Aging

描述（由申请人提供）：有大量证据表明，在健康衰老过程中，记忆功能会发生变化。最近对老年大鼠的研究表明，衰老与模式分离或从相似输入产生不同表征的过程受损有关。其他证据也表明，这种损伤可能与CA3海马神经元的过度活跃有关。功能性MRI已被广泛用于研究记忆随年龄变化的变化，但由于该方法的分辨率较低，以类似于动物研究的方式研究海马亚区水平的激活提出了相当大的挑战。然而，最近的技术进步使我们能够克服这一限制，使我们有可能评估功能的细微变化和神经计算的相应变化。当前提案的目的是使用高分辨率（1.5毫米）fMRI结合复杂的对齐技术来研究这些变化，这些技术在海马子区水平上尊重个体的解剖结构，并设计用于测试海马子区特定计算的任务。我们建议使用连续配对联想学习任务和附带编码任务来测试年轻健康人和老年健康人，这两个任务都以不同的方式操纵模式分离的需求。我们假设，随着模式分离需求的增加，各组之间的行为和神经差异将更加明显，并且最早的神经变化将在CA3区域被检测到。如果成功，这项研究将为健康衰老过程中记忆计算变化的确切位置和性质提供清晰的图像。这将帮助我们在动物和人类研究之间建立关键的联系，增强我们对衰老作为痴呆症的主要危险因素的理解，并为确定临床前标记物和开发治疗方法铺平道路，以减缓痴呆症的进展。公共卫生相关性：拟议的研究调查了与年龄相关的记忆衰退（最常见的与衰老相关的认知疾病）的神经基础的详细方面。如果成功，这项研究将为健康衰老过程中记忆计算变化的确切位置和性质提供清晰的图像。这将帮助我们在动物和人类研究之间建立关键的联系，增强我们对衰老是痴呆症的主要危险因素的理解，并为确定轻度认知障碍和阿尔茨海默病等疾病的临床前标记铺平道路。

DESCRIPTION (provided by applicant): There is substantial evidence that changes in memory function occur during healthy aging. Recent findings with aged rats suggest that aging is associated with impairment in pattern separation or the process of creating different representations from similar inputs. Additional evidence also suggests that this impairment may be linked to hyperactivity in CA3 hippocampal neurons. Functional MRI has been used extensively to study memory changes with aging, but due to the method's coarse resolution, studying activation at the level of hippocampal subfields in a manner similar to the animal studies has posed quite a challenge. However, recent technological advances have allowed us to overcome this limitation giving us the potential to assess subtle changes in function and corresponding changes in neural computations. The aim of the current proposal is to study these changes using high-resolution (1.5 mm) fMRI coupled with sophisticated alignment techniques that respect individuals' anatomy at the level of hippocampal subfields, and tasks designed to test computations specific to hippocampal subfields. We propose to test young healthy and aged healthy individuals using two tasks: a continuous paired-associate learning task and a incidental encoding task, both of which manipulate demand on pattern separation in different ways. We hypothesize that as pattern separation demands increase, behavioral and neural differences between groups will be more pronounced, and that the earliest neural changes will be detected in the CA3 region. If successful, this study will provide a clear picture of the exact locus and nature of the changes in memory computations with healthy aging. This will help us make the critical link between animal and human studies, enhance our understanding of aging as the primary risk factor for dementia, and pave the way to identifying pre-clinical markers and developing therapies to decelerate progression to dementia. PUBLIC HEALTH RELEVANCE: The proposed research examines detailed aspects about the neural bases of age-related memory decline (the most common cognitive complaint associated with aging). If successful, this study will provide a clear picture of the exact locus and nature of the changes in memory computations with healthy aging. This will help us make the critical link between animal and human studies, enhance our understanding of aging as the primary risk factor for dementia, and pave the way to identifying pre-clinical markers for disorders such as Mild Cognitive Impairment and Alzheimer's disease.