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

阿尔茨海默氏症网络中断和时间处理缺陷背后的电路机制

• 批准号: 10448151
• 负责人: Michael Wehr
• 金额: $ 65.97万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448151
• 关键词: Address; Affect; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Appearance; Area; Auditory; Auditory area; Auditory system; Behavior; Behavioral; Biological; Biological Markers; Brain region; Cell Death; Chronic; Cognitive deficits; Consensus; Data; Detection; Development; Disease; Disease Progression; Early Diagnosis; Electrophysiology (science); Failure; Feedback; Functional Magnetic Resonance Imaging; Goals; Image; Impairment; Investigation; Knowledge; Measures; Memory impairment; Molecular; Molecular Genetics; Motor; Mus; Nature; Neurobiology; Neurons; Output; Research; Resolution; Rest; Senile Plaques; Sensory; Synapses; Testing; Therapeutic Intervention; Time; amyloid pathology; base; behavioral impairment; density; early detection biomarkers; early onset; functional disability; hippocampal pyramidal neuron; innovation; insight; molecular pathology; mouse model; neural circuit; novel; novel therapeutic intervention; operation; potential biomarker; relating to nervous system; two-photon

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.

摘要： 尽管对淀粉样蛋白病理学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作，以及这是如何发生的，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，我们寻求 了解两个新兴的早期生物标志物的机制-听觉间隙检测缺陷和 皮质网络的功能性断开-以及这些网络如何在机械上相互关联。的 这项建议的目的是确定何时以及如何在听觉和其他神经网络功能中断， 皮质区，以及这如何损害阿尔茨海默氏症的5XFAD小鼠模型中的行为间隙检测。我们 中心假设是，间隙检测缺陷是由特定的间隙检测电路的中断引起的， 听觉皮层，这是皮层区域内部和之间大规模网络中断的结果。目的 1将确定渐进式网络中断的计算机制。我们的工作 一种假设是，网络中断不仅仅是一种全球性的退化，而是具体表现为集线器的丢失 神经元随着时间的推移，断开模块和皮层区域。目标2将确定网络中断 影响前馈和反馈信息在皮层层次中的流动。我们的工作假设 自上而下的反馈投射比前馈投射受损更早更深。 目标3将确定网络中断如何损害听觉皮层中间隙选择性的计算， 这如何损害间隙检测行为。我们的工作假设是，间隙选择性是在 表面层并通过来自层5的输出影响行为。我们将测试这些假设与 慢性介观双光子GCaMP 8 f成像、高密度电生理学和 5XFAD小鼠的定量行为。这项研究是创新的，因为它使用了新的 成像/电生理学方法来解决分子病理学如何破坏神经系统的运作， 电路，以及这反过来如何破坏神经计算，产生早发性行为缺陷。的 拟议的研究很重要，因为它将提供详细的细胞和突触水平机制 解释阿尔茨海默氏症中大规模网络中断的性质，并揭示这些中断是如何发生的。 影响听觉皮层回路中产生特定行为缺陷的特定神经计算。这 理解将加深和扩展缺口检测和功能磁共振成像功能连接的有效性 作为阿尔茨海默病的早期生物标志物进行测量，并提供对机会之窗性质的洞察 在永久性结构损伤之前的突触网络损伤期间进行潜在的治疗干预 发生。