Entorhinal-hippocampal interactions during progressive memory impairments in mouse models of Alzheimer's disease pathology

项目概要/摘要 阿尔茨海默病（AD）是一种以记忆丧失和进行性认知功能障碍为特征的痴呆症 损伤在过去的十年里，主要的假设都认为这些症状是由于 淀粉样蛋白-β（Aβ）和tau蛋白的积累导致神经变性。然而， 降低Aβ水平在临床试验中基本上是无效的，并且靶向tau的策略已被证明是困难的。 许多失败的药物试验引起了人们的担忧，即减少病理性蛋白质而不预防或 逆转受影响细胞和网络的功能变化可能不足以治疗。这凸显 需要研究AD病理学如何影响重要的大脑区域，连接和活动模式 为了记忆通过研究已知在疾病进展早期易受攻击的特定回路， 可以获得有价值的洞察力，以初步网络的变化，潜在的进行性认知衰退，并确定 早期治疗干预的可能目标。鉴于海马神经元功能障碍的有力证据 在AD中的处理和空间记忆，关键是要了解这些变化是否是由异常的 输入或局部海马变化。内侧内嗅皮层（MEC）为大脑提供重要的空间输入。 海马体及其在早期AD中的脆弱性是公认的。因此，本提案将检验假设 MEC功能的变化出现在认知能力下降和海马处理缺陷之前， 一种早期的电路功能障碍，可能会导致记忆障碍的发展。在目标1中，我们首先 使用体外电生理学来表征MEC和CA 1中不同细胞类型的内在特性如何 在记忆受损的过程中发生了改变在目标2中，我们将使用硅探针同时 从整个MEC和海马的512个通道记录，以确定如何以及何时同步单个 在AD病理学模型中，区域内和区域间的单位和局部场电位（LFP）分解。在Aim中 3，我们将使用微型显微镜进行体内钙成像，以跟踪空间编码的发展 当小鼠在线性轨道上奔跑并探索开放的 领域专门的病毒靶向工具将使我们能够分离特定的MEC亚群并验证假设 MECII星状细胞在CA 1缺陷之前表现出改变的空间编码。这些实验将使用3种不同的 AD病理学和神经变性的小鼠模型，包括Aβ（APP-KI）、tau（P301 S）和组合 （3x-Tg）转基因以鉴定跨模型的回路功能障碍的会聚机制。所有这些 aims将在AD病理学小鼠模型中分离出导致记忆缺陷的特定回路。

Project Summary/Abstract Alzheimer's disease (AD) is a form of dementia characterized by memory loss and progressive cognitive impairments. The leading hypotheses over the past decade have assumed that these symptoms are due to accumulation of amyloid-beta (Aβ) and tau proteins that lead to neurodegeneration. However, treatments that reduce Aβ levels have largely been ineffective in clinical trials and strategies to target tau have proven difficult. Numerous failed drug trials have raised concerns that reducing pathological proteins without preventing or reversing functional changes in the affected cells and networks may be insufficient for treatment. This highlights a need to examine how AD pathology impacts brain regions, connections, and activity patterns that are important for memory. By investigating specific circuits that are known to be vulnerable early in disease progression, we can gain valuable insight into the initial network changes underlying progressive cognitive decline and identify possible targets for early therapeutic interventions. Given the strong evidence for dysfunction in hippocampal processing and spatial memory in AD, it is critical to understand whether these changes are driven by abnormal inputs or local hippocampal changes. The medial entorhinal cortex (MEC) provides critical spatial inputs to the hippocampus and its vulnerability in early AD is well established. Therefore, this proposal will test the hypothesis that changes in MEC function emerge prior to cognitive decline and hippocampal processing deficits, and provide an early point of circuit dysfunction that could drive development of memory impairments. In Aim 1, we will first use in vitro electrophysiology to characterize how intrinsic properties of distinct cell types in MEC and CA1 are altered during the progression of memory impairments. In Aim 2, we will use silicon probes to simultaneously record from 512 channels throughout MEC and hippocampus to determine how and when synchrony of single units and local field potentials (LFPs) within and across regions breaks down in models of AD pathology. In Aim 3, we will use in vivo calcium imaging with miniature microscopes to track the development of spatial coding deficits across months in MECII, MECIII, and CA1 neurons as mice run on a linear track and explore an open field. Specialized viral targeting tools will allow us to isolate specific MEC subpopulations and test the hypothesis that MECII stellate cells exhibit altered spatial coding prior to deficits in CA1. These experiments will use 3 distinct mouse models of AD pathology and neurodegeneration covering Aβ (APP-KI), tau (P301S), and combinatorial (3x-Tg) transgenes to identify convergent mechanisms of circuit dysfunction across models. Together, these aims will isolate specific circuits that break down to produce memory deficits in mouse models of AD pathology.