基于高分辨磁共振成像技术的正常老年人海马亚区功能损伤机制研究

海马体作为学习和记忆的重要结构，是受衰老过程影响最为显著的脑区。研究表明，海马体各个亚区在衰老过程中表现出不同程度的易损性，但这种易损性差异是否也表现在海马更广泛的功能连接损伤中，以及其在学习与记忆能力下降过程中的作用机制，目前仍不清楚。最近，申请人采用认知老化大鼠模型，揭示了海马亚区（CA1和CA3）环路连接在老化中的易损性差异，为理解正常老化中海马环路损伤机制提供了重要的动物实验证据。在此基础上，本项目拟利用高分辨功能磁共振成像技术，考察正常老年人海马亚区局部功能活动和环路功能连接的异常变化模式及相互关系，针对海马亚区的功能特异性，探索海马不同亚区易损性差异对学习记忆不同加工过程（长时和短时记忆）的影响机制，深化对正常老化过程中海马亚区功能易损性差异的本质的理解。本项目将为厘清认知老化的发展规律及神经机制提供新的视角，并可能为认知老化的防治提供潜在的干预靶点。

The hippocampus, a structure critical for learning and memory, is among the brain areas most frequently affected in the course of normal aging. Comprised of anatomically distinct, but richly interconnected subfields, substantial evidence suggests the principal cell fields of the hippocampus are differentially vulnerable to aging. However, whether the differential vulnerability of hippocampal subfields is associated with broader disruption in network-level functional interaction, and how it contributes to age-related learning and memory impairment, has been difficult to test. Recently, taking advantage of a well characterized neurocognitive aging rat model, we have revealed that early reduction of CA3 connectivity may give rise to disrupted CA1 connectivity, which in turn underlies age-related decline in episodic learning and memory, providing important animal experimental evidence for differential vulnerability of circuit-level connectivity of hippocampal subregions. By applying high-resolution functional magnetic resonance imaging techniques in elderly human subjects, the current project aims to systematically study how aging affects hippocampal subfields in relation to learning and memory impairment. We will investigate 1) aging-related abnormality in regional activity and circuit-level connectivity of different hippocampal subfields, 2) putative differential vulnerability of hippocampal subfields during aging, and 3) how their differential vulnerability contributes to diverse processes of associative memory (short and long-term learning and memory). This project will not only provide novel insights into the pathophysiological mechanisms of aging, but also offer potential targets for the prevention and intervention of cognitive aging.