Interneuron and Network Synchrony in Alzheimer's Disease

项目总结/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AD中的记忆障碍随着年龄的增长而增加，并与过度兴奋、中间神经元过度兴奋和过度兴奋有关。 死亡、回路重塑和受损的中间神经元功能。中间神经元丢失和功能障碍 然而，目前尚不清楚这些解剖学变化如何导致认知缺陷。 中间神经元在使局部网络同步以产生对长时间运动重要的脑节律方面起着关键作用。 术语增强和记忆编码以及中间神经元丢失与振荡减少有关 和记忆障碍的研究。了解海马中间神经元的功能如何改变 在AD中，无论是在学习障碍出现之前还是之后，对于理解这些认知障碍都是至关重要的。 赤字在本研究中，我们将验证AD患者海马中间神经元同步性改变的假设 模型小鼠，以及年轻的网络功能障碍，症状前小鼠可以预测记忆障碍。 为了研究中间神经元活动和局部网络之间的关系，我们将使用硅探针， 同时记录局部场电位和单个单位在整个CA 1和齿状回（DG）的 3xTg-AD和野生型小鼠在虚拟现实中运行。我们将首先研究在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AD中的中间神经元 模型小鼠将具有相对于网络振荡的异常放电模式， CA 1和DG的中间神经元。接下来，我们将使用记忆障碍之前的年轻3xTg-AD小鼠， 为了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（如中间神经元锁相、振荡功率或相干性）将预测 在稍后的时间点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AD记忆障碍进展的新见解。 描述AD患者海马结构的特征及其如何导致认知缺陷将是研究AD的关键。 开发AD的靶向治疗，特别是在症状前阶段的预防性干预 最有可能成功的地方

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.