Multimodal imaging of prodromal synaptic, circuit, and network-level dysfunction in a murine model of Alzheimer's disease

阿尔茨海默病小鼠模型中前驱期突触、回路和网络水平功能障碍的多模态成像

• 批准号: 10562876
• 负责人: Zhengxin Cai
• 金额: $ 250.3万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562876
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease model; Appearance; Area; Basic Science; Behavioral; Biological; Brain; Calcium; Cells; Cellular Structures; Clinical; Collection; Color; Data; Data Set; Development; Disease; Excitatory Synapse; Experimental Designs; Fluorescence; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Image; Immunohistochemistry; Impaired cognition; Inhibitory Synapse; Interneurons; Knock-in; Knowledge; Label; Lead; Link; Maps; Measures; Modality; Monitor; Multimodal Imaging; Mus; Onset of illness; Parvalbumins; Pathogenesis; Pattern; Positioning Attribute; Positron-Emission Tomography; Preventive treatment; Protein Kinase; Recovery; Shapes; Signal Transduction; Signs and Symptoms; Symptoms; Synapses; Time; Tracer; Translating; Treatment Protocols; Validation; Work; awake; behavior test; blood oxygen level dependent; cell type; clinical translation; density; excitatory neuron; experimental study; in vivo; inhibitor; inhibitory neuron; innovation; insight; mouse model; multidisciplinary; multimodal data; multimodal neuroimaging; multimodality; network architecture; neural circuit; neuroimaging; novel; prevent; prodromal Alzheimer' s disease; response; rho; sex; targeted treatment; treatment effect; treatment response; treatment strategy

PROJECT SUMMARY Alzheimer's disease (AD) disrupts brain organization, which is evident across spatial scales, from synapse loss to whole-brain connectivity, and manifests prior to or at the first sign of symptoms. Many neuroimaging modalities have contributed to our understanding of these changes, yet mechanistic insight into how dysfunction translates across scales, and species, is lacking. In part, these knowledge gaps exist because imaging modes specialize within a finite spatial milieu with access to a limited number of contrasts. To close these gaps, we propose a multimodal approach that leverages the strengths of complementary modes to deepen our understanding of changes in brain organization and inform the development of early-stage and preventative treatment strategies. Fully aligned with PAR-22-059, we propose a multimodal approach to interrogate AD-precipitated brain circuit disturbances and treatment-facilitated recovery. Our approach links excitatory and inhibitory synapse losses (positron emission tomography, PET), cell-type specific circuit-level dysfunction (wide-field calcium, WF-Ca2+, imaging) and brain-wide changes in the blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal in an established murine gene knock-in model of AD. Data will span relevant AD stages and be powered to address sex as a biological variable. Image collection will coincide with behavior testing. Our objective is to leverage the combined strength of complementary imaging modes to identify the synaptic changes that correspond to alterations in circuit and network-level dysfunction in the prodromal and early stages of AD. These data will provide mechanistic insights into the underlying causes of AD-related changes in brain functional organization that are evident in clinically accessible contrasts (PET and BOLD-fMRI). Aim 1. Map excitatory (E) and inhibitory (I) synapse losses. Using three PET tracers, we will map changes in the density of E, I and all synapses. These data will yield a better understanding of how E/I synapses are lost during AD pathogenesis and how these local changes in micro-circuits contribute to more global E/I imbalances. Aim 2. Discover the E/I circuit disruptions that underpin BOLD-fMRI network changes. WF-Ca2+ imaging affords cell-type specific measures of cortex-wide activity. By co-labeling inhibitory and excitatory neurons, we will measure E/I cortical circuit-level activity. Through simultaneous WF-Ca2+ and BOLD-fMRI, we will link cell-type specific E/I activity to brain-wide changes in BOLD-fMRI. Data will be collected from awake unanesthetized mice. Aim 3. Uncover the imaging correlates of treatment-facilitated recovery. Approaches from Aims 1 and 2 will be interleaved. Mice will be given one of two treatments to prevent synapse loss and cognitive decline. Synapse loss (PET), circuit and network function (WF-Ca2+/BOLD-fMRI) will be characterized longitudinally. The innovation of this work lies in the multimodal approach which bridges spatial scales from the synapse to the whole-brain. The significance of this proposal lies in deepening our understand how synaptic, circuit and network-level changes are interwoven and how together they shape AD pathogenesis and treatment response.

项目摘要 阿尔茨海默病（AD）破坏大脑组织，这在空间尺度上是明显的，从突触损失 全脑连接，并在症状出现之前或第一次出现症状时表现出来。许多神经成像方式 有助于我们理解这些变化，但对功能障碍如何转化的机械见解， 跨尺度，跨物种，是缺乏的。在某种程度上，这些知识差距的存在是因为成像模式专门 在有限的空间环境内，可以使用有限数量的对比度。为了缩小这些差距，我们提出了一个 多模式方法，利用互补模式的优势，加深我们对 大脑组织的变化，并为早期和预防性治疗策略的发展提供信息。 与PAR-22 - 059完全一致，我们提出了一种多模态方法来询问AD沉淀的脑回路 干扰和治疗促进的恢复。我们的方法将兴奋性和抑制性突触丢失联系起来 （正电子发射断层扫描，PET），细胞类型特异性回路水平功能障碍（宽场钙，WF-Ca2+， 成像）和血氧水平依赖性（BOLD）功能磁共振的全脑变化 在建立的AD的鼠基因敲入模型中的功能磁共振成像（fMRI）信号。数据将跨越相关的AD阶段 并有能力将性别作为一个生物变量来处理。图像收集将与行为测试一致。 我们的目标是利用互补成像模式的综合优势来识别突触 与前驱期和早期阶段回路和网络水平功能障碍的改变相对应的变化 的AD。这些数据将为AD相关脑变化的根本原因提供机制性见解 在临床上可获得的对比（PET和BOLD-fMRI）中明显的功能组织。 目标1.映射兴奋性（E）和抑制性（I）突触损失。使用三种PET示踪剂，我们将绘制 E、I和所有突触的密度。这些数据将使我们更好地了解E/I突触是如何丢失的 在AD发病过程中，以及微回路中的这些局部变化如何导致更多的整体E/I失衡。 目标二。发现支持BOLD-fMRI网络变化的E/I电路中断。WF-Ca2+成像提供 细胞类型特异性的皮质活动的措施。通过共同标记抑制性和兴奋性神经元，我们将 测量E/I皮质回路水平活动。通过同步WF-Ca2+和BOLD-fMRI，我们将细胞类型 特异性E/I活动对BOLD-fMRI中全脑变化的影响。将从清醒的未麻醉小鼠中收集数据。 目标3.揭示治疗促进恢复的影像学相关性。目标1和2的方法将是 交错的小鼠将接受两种治疗之一，以防止突触丢失和认知能力下降。突触 损失（PET）、电路和网络功能（WF-Ca2 +/BOLD-fMRI）将被纵向表征。 这项工作的创新在于多模态方法，它将空间尺度从突触连接到 整个大脑。这一提议的意义在于加深我们对突触、回路和 网络水平的变化是相互交织的，以及它们如何共同塑造AD发病机制和治疗反应。