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) 是一种痴呆症，其特征是记忆丧失和进行性认知能力下降 损伤。过去十年的主要假设假设这些症状是由于 β 淀粉样蛋白 (Aβ) 和 tau 蛋白的积累会导致神经退行性变。然而，治疗 降低 Aβ 水平在临床试验中基本上无效，并且针对 tau 蛋白的策略已被证明很困难。 许多失败的药物试验引起了人们的担忧，即减少病理蛋白而不预防或 逆转受影响细胞和网络的功能变化可能不足以治疗。这凸显了 需要检查 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，我们 可以获得对渐进性认知衰退背后的初始网络变化的宝贵见解，并识别 早期治疗干预的可能目标。鉴于海马功能障碍的有力证据 AD 中的处理和空间记忆，了解这些变化是否是由异常驱动的至关重要 输入或局部海马变化。内侧内嗅皮层 (MEC) 为大脑提供关键的空间输入 海马体及其在 AD 早期的脆弱性是众所周知的。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，并提供 电路功能障碍的早期点，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 CA1 中不同细胞类型的内在特性 在记忆障碍的进展过程中发生改变。在目标 2 中，我们将使用硅探针同时 从整个 MEC 和海马体的 512 个通道进行记录，以确定单个信号同步的方式和时间 AD 病理模型中区域内和区域间的单位和局部场电位 (LFP) 被分解。瞄准 3、我们将利用微型显微镜进行体内钙成像来追踪空间编码的发展 当小鼠在线性轨道上奔跑并探索开放空间时，MECII、MECIII 和 CA1 神经元在几个月内出现缺陷 场。专门的病毒靶向工具将使我们能够分离特定的 MEC 亚群并检验假设 MECII 星状细胞在 CA1 缺陷之前表现出空间编码的改变。这些实验将使用 3 个不同的 AD 病理学和神经变性小鼠模型，涵盖 Aβ (APP-KI)、tau (P301S) 和组合 (3x-Tg) 转基因可识别跨模型的电路功能障碍的收敛机制。在一起，这些 目标是在 AD 病理学小鼠模型中分离出因故障而产生记忆缺陷的特定电路。

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.