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

描述（由申请人提供）：情节性记忆丧失是衰老的标志之一，也是痴呆症的重要危险因素。鉴于人口老龄化的快速增长和阿尔茨海默病（AD）患病率的增加，了解与年龄相关的记忆力下降的神经基础至关重要。众所周知，记忆的形成主要取决于内侧颞叶（MTL）内的大脑区域。以前的衰老研究主要集中在海马体中与年龄相关的变化，但海马外MTL皮质的变化却很少受到关注。这些皮质似乎是功能分离的，例如，嗅周皮质（PRC）主要负责记忆物品或物体，而海马旁皮质（PHC）则负责记忆空间配置或背景。动物研究进一步表明，这种分工延伸到内嗅皮层（EC），外侧部分（LEC）支持对象记忆，内侧部分（MEC）支持空间记忆。我们设计了一个歧视任务征税对象和空间记忆，并使用高分辨率功能MRI不仅复制PRC和PHC之间的解离，但也严格证明了一个类似的对象/空间之间的分离LEC和MEC在人类的关键证据。与这些进展相关的是，最近的啮齿动物神经认知老化模型已经确定了PRC/LEC通路对与认知下降相关的病理学的选择性脆弱性。LEC/PRC（transentorhinal）区域也是AD小鼠模型中第一个出现存款缠结病理的区域，这也从AD患者的死后组织（即Braak I期）中清楚可见。基于我们高度创新的方法，在功能上分离人类PRC/LEC和PHC/MEC网络，我们提出了一系列新的实验来表征老年人PRC和LEC中最早的行为缺陷和功能畸变。此外，我们打算探测海马齿状回（DG）/CA 3和上游PRC/LEC之间的结构连接的特定中断，该中断通过横向perforant path. We项目到DG/CA 3以前曾报道过使用尖端的高分辨率弥散成像的老年人的perforant路径退化。在此，我们将使用新技术将穿支通路分为内侧和外侧部分，并将检验外侧部分的降解更严重的假设。该项目建立在我们实验室过去五年的工作基础上，该实验室成功地将数十年的动物和计算模型转化为人类衰老条件。我们已经确定了异常条件下的DG/CA 3与年龄相关的记忆丧失使用多模态高分辨率MRI技术。我们的建议在这里扩展了这项工作在一个创新的方向，无论是在方法和假设。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，并可能产生高度选择性的神经靶点用于治疗和干预。

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.