Population Network Responses in AD Model Animals

项目摘要 在阿尔茨海默病(AD)中，认知障碍的第一个迹象是在许多年前观察到的 临床诊断为阿尔茨海默病，早在此之前，阿尔茨海默病的突触功能丧失就已经很明显了 任何实质性的神经元损失。β-淀粉样多肽的过度产生或积聚 (Aβ)已被证明通过多种机制对突触活动产生有害影响。 了解早期AD相关突触的细胞和分子机制 功能障碍(在严重学习和记忆障碍的行为表现之前)可能是 对于减缓AD进展的新疗法的开发至关重要。然而， 检测AD相关的皮质回路之间突触功能的变化是技术上的 具有挑战性，特别是如果在AD过程的最早阶段需要它，在 斑块和缠结的形成，当变化很小且难以发现时。确切地说，在哪里，在 应该研究哪一层皮质层，或哪一种突触？目前用于检测的检测方法 AD模型动物的神经回路缺陷是基于传统的电极电生理学 并有几个实际限制，包括：空间分辨率低，细胞类型盲目，以及 实验的劳动密集型性质。新技术带来了更好的时间和空间 同时监测多个神经元的活动的分辨率，从而促进对大脑的研究 神经紊乱中的电路中断。我们建议使用GEVI成像(多细胞光学 使用遗传编码电压指示器对膜电位变化进行成像)。我们的 假说是“突触和神经元功能障碍出现在显著的Aβ沉积和 病理性tau聚集，可以通过负担得起的成像方法常规检测到。一个 简单而灵敏的生理检测方法，用于检测网络生理的变化 学习和学习中淀粉样斑块的大量积累或可复制的行为缺陷 记忆，将加速对最早的细胞和分子变化的研究 在AD病理过程中起着重要作用。了解细胞和分子机制 阿尔茨海默病相关的早期突触功能障碍(学习行为表现前 和记忆缺陷)可能有助于新疗法的开发 AD的进展。

Project Summary In Alzheimer’s disease (AD), the first signs of cognitive impairment are observed many years before a clinical AD diagnosis is established, and the loss of synaptic function in AD is evident long before any substantial loss of neurons. The excessive production or accumulation of β-amyloid peptide (Aβ) has been documented to have deleterious effects on synaptic activity by various mechanisms. Understanding the cellular and molecular mechanisms of the early AD-associated synaptic dysfunction (before the behavioral manifestations of severe learning and memory deficits) may be critical for the development of new therapies for slowing down the progression of AD. However, detection of the AD-associated changes in synaptic function among cortical circuits is technically challenging, especially so if it is needed in the earliest stages of the AD process, before the formation of plaques and tangles, when changes are small and difficult to spot. Where exactly, at which cortical layer, or which synapse, one should investigate? The current assays for detecting neural circuit deficiencies in AD model animals are based on traditional electrode electrophysiology and have several practical limitations including: poor spatial resolution, blindness for cell-types, and a labor intensive nature of experiments. New technologies bring an improved temporal and spatial resolution for monitoring activity in many neurons simultaneously, thus facilitating studies on brain circuitry disruptions in neurological disorders. We propose to use GEVI imaging (multi-cell optical imaging of the membrane potential changes using genetically-encoded voltage indicators). Our hypothesis is that “synaptic and neuronal dysfunctions emerge before significant Aβ deposition and pathological tau aggregation, and can be routinely detected by affordable imaging methods”. A simple and sensitive physiological assay for detecting changes in network physiology, prior to the substantial accumulation of the amyloid plaques or reproducible behavioral deficits in learning and memory, would accelerate the investigations of the earliest cellular and molecular changes mediated by the AD pathological process. Understanding the cellular and molecular mechanisms of the early AD-associated synaptic dysfunction (before the behavioral manifestations of the learning and memory deficits) may help the development of the new therapies for slowing down the progression of the AD.