Interneuron and Network Synchrony in Alzheimer's Disease

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。阿尔茨海默病患者的记忆障碍随着年龄的增长而增加，并与过度兴奋、中间神经元有关 死亡、电路重塑和神经元间功能受损。神经元间质丢失和功能障碍情况良好 建立于AD，但目前尚不清楚这些解剖变化是如何导致认知缺陷的。 中间神经元在同步局部网络以产生长期重要的大脑节律方面发挥着关键作用。 术语增强、记忆编码和神经元间丢失与减少的振荡有关 以及AD模型中的记忆障碍。了解海马区中间神经元如何发生功能改变 在AD中，无论是在学习障碍出现之前还是之后，都是理解这些认知障碍的关键 赤字。在这项提议中，我们将检验海马区中间神经元同步性在AD中改变的假设 模型小鼠，年轻的、症状前期的小鼠的网络功能障碍可以预测记忆损伤。 为了研究神经元间活动和局部网络之间的关系，我们将使用硅探针来 从CA1和齿状回(DG)的局部场电位和单个单位同时记录 3xTg-AD和野生型小鼠在虚拟现实中运行。我们将首先研究大脑中的中间神经元的放电模式。 6月龄AD模型小鼠，发病后出现记忆障碍。我们假设阿尔茨海默病的中间神经元 模型小鼠会有与网络振荡相关的异常放电模式，这将导致不同步 跨CA1和DG的中间神经元。接下来，我们将使用年轻的3xTg-AD小鼠，在记忆受损之前， 以研究特定的网络变化是否可以预测未来的认知能力下降。我们假设 网络功能的改变(如神经元间相位锁定、振荡功率或一致性)将预测 稍后时间点的记忆损伤的严重程度。这些实验将突出潜在的目标 早期治疗干预，并导致对阿尔茨海默病记忆障碍进展的新见解。 阿尔茨海默病患者海马区去同步化的特征及其对认知功能障碍的影响 为AD制定有针对性的治疗方法，特别是在症状前阶段进行预防性干预 最有可能取得成功的地方。

Project Summary/Abstract Alzheimer's disease (AD) is a form of dementia characterized by memory loss and progressive cognitive impairments. Memory impairments in AD increase with age and are linked to hyperexcitability, interneuron death, circuit remodeling, and impaired interneuron function. Interneuron loss and dysfunction are well established in AD, yet it remains unclear how these anatomical changes contribute to cognitive deficits. Interneurons play a critical role in synchronizing local networks to generate brain rhythms important for long- term potentiation and memory encoding and interneuron loss has been associated with reduced oscillations and memory impairments in AD models. Understanding how hippocampal interneurons are functionally altered in AD, both before and after the emergence of learning impairments, is critical to understanding these cognitive deficits. In this proposal, we will test the hypothesis that hippocampal interneuron synchrony is altered in AD model mice, and that network dysfunction in young, pre-symptomatic mice can predict memory impairments. To examine the relationship between interneuron activity and local networks, we will use silicon probes to record simultaneously from local field potentials and single units throughout CA1 and dentate gyrus (DG) of 3xTg-AD and wild type mice running in virtual reality. We will first examine the firing patterns of interneurons in 6 month old AD model mice, after the onset of memory impairments. We hypothesize that interneurons in AD model mice will have abnormal firing patterns relative to network oscillations, which will desynchronize interneurons across CA1 and DG. Next, we will use young 3xTg-AD mice, prior to memory impairments, in order to investigate whether specific network changes can predict future cognitive decline. We hypothesize that alterations in network function (such as interneuron phase locking, oscillation power or coherence) will predict the severity of memory impairments at a later time point. These experiments will highlight potential targets for early therapeutic interventions and lead to new insights into the progression of memory impairments in AD. Characterizing hippocampal desynchrony in AD and how it contributes to cognitive deficits will be critical in developing targeted treatments for AD, especially preventative intervention during the pre-symptomatic phase where success is most viable.