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

项目摘要/摘要 阿尔茨海默病(AD)是一种以记忆丧失和进行性认知为特征的痴呆症 减损。过去十年的主要假说假设这些症状是由于 淀粉样β蛋白(Aβ)和tau蛋白的积聚导致神经变性。然而，治疗方法 降低Aβ水平在临床试验中很大程度上是无效的，针对tau的策略被证明是困难的。 无数失败的药物试验引发了人们的担忧，即在不预防或不预防的情况下减少病理蛋白 逆转受影响细胞和网络的功能变化可能不足以用于治疗。这突出了 需要检查AD病理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发展早期易受攻击的特定回路，我们 可以对进行性认知衰退背后的初始网络变化进行有价值的洞察并识别 早期治疗干预的可能靶点。鉴于有强有力的证据表明海马区功能障碍 在AD的处理和空间记忆中，了解这些变化是否由异常驱动是至关重要的 输入或局部海马区改变。内侧内嗅皮层(MEC)提供关键的空间输入 海马体及其在阿尔茨海默病早期的脆弱性是公认的。因此，这一提议将检验这一假设 MEC功能的变化出现在认知能力下降和海马体处理缺陷之前，并提供 电路功能障碍的早期阶段，可能会导致记忆障碍的发展。在目标1中，我们将首先 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 在记忆受损的过程中发生改变。在目标2中，我们将使用硅探针同时 从整个MEC和海马区的512个通道进行记录，以确定如何以及何时单次同步 在AD病理模型中，区域内和区域之间的单位和局部场电位(LFP)被分解。在AIM 3、我们将使用微型显微镜的活体钙成像来跟踪空间编码的发展 MECII、MECIII和CA1神经元数月来的缺陷，小鼠在直线轨道上运行并探索开放的 菲尔德。专门的病毒靶向工具将使我们能够分离特定的MEC亚群，并检验这一假说 在CA1缺失之前，MECII星状细胞表现出空间编码的改变。这些实验将使用3个不同的 AD病理和神经退行性变小鼠模型包括Aβ(APP-KI)、tau(P301S)和组合 (3x-TG)转基因以确定跨模型的电路功能障碍的收敛机制。加在一起，这些 AIMS将在AD病理的小鼠模型中分离出破坏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.