Selective age-related vulnerability in human perirhinal and lateral entorhinal cortices

描述（申请人提供）：情景性记忆丧失是衰老的标志之一，是痴呆的重要危险因素。鉴于老龄化人口的迅速增加和阿尔茨海默病（AD）的患病率增加，了解与年龄相关的记忆衰退的神经基础是至关重要的。记忆的形成主要取决于内侧颞叶（MTL）内的大脑区域。先前的衰老研究主要集中在海马体中与年龄相关的变化，但海马体外MTL皮层的变化却很少得到关注。这些皮层似乎在功能上是分离的，因此，周围皮层（PRC）主要负责记忆物品或物体，而海马体旁皮层（PHC）则负责记忆空间结构或背景。动物研究进一步表明，这种分工延伸到内嗅皮层（EC），其中外侧部分（LEC）支持物体记忆，内侧部分（MEC）支持空间记忆。我们设计了一个物体和空间记忆的区分任务，并使用高分辨率功能性MRI不仅复制了PRC和PHC之间的分离，而且批判性地证明了人类LEC和MEC之间类似的物体/空间分离的关键证据。与这些进展相关的是，最近的啮齿动物神经认知衰老模型已经确定了PRC/LEC通路中与认知衰退相关的病理的选择性脆弱性。LEC/PRC（经鼻区）也是AD小鼠模型中第一个沉积缠结病理的区域，从AD患者的死后组织（即Braak期）中也可以清楚地看到这一点。基于我们在功能上分离人类PRC/LEC和PHC/MEC网络的高度创新方法，我们提出了一系列新的实验来表征老年人PRC和LEC的早期行为缺陷和功能异常。此外，我们打算探索海马齿状体(DG)/CA3和上游PRC/LEC之间结构连接的特定中断，这些结构连接通过外侧射孔通路投射到DG/CA3。我们以前报道过使用尖端超高分辨率扩散成像技术观察老年人射孔路径退化。在这里，我们将使用新技术将射孔路径分割为内侧和外侧部分，并将测试这种退化在外侧部分更严重的假设。这个项目建立在我们实验室过去五年的工作基础上，我们成功地将几十年的动物和计算模型转化为人类的衰老状况。我们使用多模态高分辨率MRI技术确定了DG/CA3中与年龄相关的记忆丧失相关的异常情况。我们在这里的建议在方法和假设方面都将这项工作扩展到一个创新的方向。该项目有望显著提高我们对衰老记忆缺陷的神经生物学基础的理解，并可能为治疗和干预提供高度选择性的神经靶点。

DESCRIPTION (provided by applicant): Episodic memory loss is one of the hallmarks of aging and is an important risk factor for dementia. Given the rapid rise in the aging population and the increased prevalence of Alzheimer's disease (AD), understanding the neural basis of age-related memory decline is of the utmost importance. The formation of memories is known to depend critically on brain regions within the medial temporal lobes (MTL). Prior aging research has focused on age-related changes in the hippocampus, but changes in extrahippocampal MTL cortices have garnered less attention. These cortices appear to be functionally segregated such that the perirhinal cortex (PRC) is primarily engaged by memory for items or objects, whereas the parahippocampal cortex (PHC) is engaged by memory for spatial configurations or contexts. Animal studies have further demonstrated that that this division of labor extends into the entorhinal cortex (EC), with the lateral portion (LEC) supporting object memory and the medial portion (MEC) supporting spatial memory. We designed a discrimination task taxing both object and spatial memory and used high-resolution functional MRI to not only replicate the dissociation between PRC and PHC, but also critically demonstrated key evidence of a similar object/spatial dissociation between LEC and MEC in humans. Related to these advancements, recent rodent models of neurocognitive aging have identified a selective vulnerability in the PRC/LEC pathway to pathology associated with cognitive decline. The LEC/PRC (transentorhinal) region is also the first to deposit tangle pathology in AD mouse models, which is also clear from postmortem tissue from AD patients (i.e. Braak Stage I). Building on our highly innovative approach to functionally segregate the human PRC/LEC and PHC/MEC networks, we propose a novel series of experiments to characterize the earliest behavioral deficits and functional aberrations in the PRC and LEC in older adults. Furthermore, we intend to probe for specific disruptions in structural connectivity between the hippocampal dentate (DG)/CA3 and upstream PRC/LEC, which project to the DG/CA3 via the lateral perforant path. We have previously reported perforant path degradation in older adults using cutting-edge ultrahigh- resolution diffusion imaging. Here, we will use novel techniques to segment the perforant path into medial and lateral portions and will test the hypothesis that this degradation is more severe in the lateral portion. The proposed project builds on the last five years of work from our lab, which successfully translates decades of animal and computational models to the human aging condition. We have identified aberrant conditions in the DG/CA3 associated with age-related memory loss using multimodal high-resolution MRI techniques. Our proposal here extends this work in an innovative direction both in terms of approach and hypothesis. This project is expected to significantly improve our understanding of the neurobiological bases of memory deficits in aging, and may yield highly selective neural targets for treatments and interventions.