Circuit mechanisms underlying network disruption and temporal processing deficits in Alzheimer's

摘要： 尽管对淀粉样蛋白病理的分子和遗传机制有大量的了解， 关于这些分子机制如何影响神经回路的运行，以及这是如何影响的，我们知之甚少 扰乱神经计算最终导致阿尔茨海默氏症的行为缺陷。在这里，我们试图 了解两种新出现的早期生物标志物的机制-听觉间隙检测缺陷和 大脑皮层网络的功能性断开--以及它们是如何相互联系的。这个 这项建议的目的是确定听觉和其他方面的网络功能何时以及如何中断 皮质区域，以及这如何损害阿尔茨海默病5XFAD小鼠模型中的行为间隙检测。我们的 中心假设是，缝隙检测缺陷是由于 听觉皮质，作为皮质内和皮质间大规模网络破坏的结果。目标 1将确定渐进式网络中断的计算机制。我们的工作 假设网络中断不只是一种全球性的退化，而是具体发生在集线器丢失的情况下 随着时间的推移，神经元会断开模块和皮质区域的连接。目标2将确定网络中断如何 影响前馈和反馈信息在大脑皮层层次中的流动。我们的工作假说 自上而下的反馈预测比前馈预测更早、更严重地受到损害。 目标3将确定网络中断如何损害听觉皮质间隙选择性的计算，以及 这将如何影响缝隙检测行为。我们的工作假设是，缺口选择性是在 表层和影响行为通过第5层的输出。我们将使用 慢性介观双光子GCaMP8f成像、高密度电生理学和 5XFAD小鼠的数量行为。拟议的研究具有创新性，因为它使用了新颖的 成像/电生理学方法解决分子病理如何扰乱神经操作 电路，以及这如何反过来扰乱神经计算，从而产生早发性行为缺陷。这个 拟议的研究具有重要意义，因为它将提供详细的细胞和突触水平的机制 解释阿尔茨海默氏症患者大规模网络中断的性质，并揭示这些中断是如何 影响听觉皮质回路中的特定神经计算，从而产生特定的行为缺陷。这 了解将深化和扩展缺口检测和功能连接的有效性 作为阿尔茨海默氏症的早期生物标记物，并提供对机会之窗性质的洞察 永久性结构损伤前突触网络损伤的潜在治疗干预 发生。

Abstract: Despite substantial knowledge of the molecular and genetic mechanisms contributing to amyloid pathology, very little is known about how these molecular mechanisms affect the operation of neural circuits, and how this disrupts neural computation to ultimately produce behavioral deficits in Alzheimer's. Here we seek to understand the mechanisms underlying two emerging early biomarkers — auditory gap detection deficits and functional disconnection of cortical networks — and how these are mechanistically related to one another. The objective of this proposal is to determine when and how network function is disrupted in auditory and other cortical areas, and how this impairs behavioral gap detection in the 5XFAD mouse model of Alzheimer's. Our central hypothesis is that gap detection deficits result from specific disruption of gap detection circuits in auditory cortex, as a consequence of large-scale network disruption both within and among cortical areas. Aim 1 will determine the computational mechanisms underlying progressive network disruption. Our working hypothesis is that network disruption is not just a global degradation, but occurs specifically as a loss of hub neurons over time, disconnecting modules and cortical areas. Aim 2 will determine how network disruption affects the flow of feedforward and feedback information across the cortical hierarchy. Our working hypothesis is that top-down feedback projections are impaired earlier and more profoundly than feedforward projections. Aim 3 will determine how network disruption impairs the computation of gap selectivity in auditory cortex, and how this impairs gap detection behavior. Our working hypothesis is that gap selectivity is computed in the superficial layers and impacts behavior via output from layer 5. We will test these hypotheses with a combination of chronic mesoscopic 2-photon GCaMP8f imaging, high-density electrophysiology, and quantitative behavior in 5XFAD mice. The proposed research is innovative because it uses novel imaging/electrophysiology approaches to address how molecular pathology disrupts the operation of neural circuits, and how this in turn disrupts neural computation to produce early-onset behavioral deficits. The proposed research is significant because it will provide a detailed cellular- and synaptic-level mechanistic explanation of the nature of large-scale network disruptions in Alzheimer's, and reveal how these disruptions affect specific neural computations in auditory cortical circuits that produce specific behavioral deficits. This understanding will deepen and extend the validity of both gap detection and fMRI functional connectivity measures as early biomarkers for Alzheimer's, and provide insight into the nature of the window of opportunity for potential therapeutic intervention during synaptic network impairment before permanent structural damage occurs.