Disruption of neuromodulatory signaling in models of Alzheimer's Disease

阿尔茨海默病模型中神经调节信号的破坏

基本信息

批准号：
10391934
负责人：
JESSICA A CARDIN
金额：
$ 44.41万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10391934
关键词：
APP-PS1 Acetylcholine Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Anatomy Animals Arousal Attention Axon Basal Nucleus of Meynert Behavior Behavior monitoring Behavioral Brain Cells Cerebral cortex Cognition Cognitive Coupling Data Disease Disease model Exhibits Future Genetic Models Goals Image Impaired cognition Individual Link Longevity Measurement Memory Modeling Monitor Motor Mus Neocortex Nerve Degeneration Neurobehavioral Manifestations Neurodegenerative Disorders Neuromodulator Neurons Norepinephrine Parkinson Disease Pathologic Pathology Perception Process Regulation Reporter Resolution Role Signal Transduction Structure System Techniques Testing Therapeutic Time Variant Work awake basal forebrain basal forebrain cholinergic neurons cholinergic cholinergic neuron cognitive function cognitive process experimental study human model imaging approach in vivo insight locus ceruleus structure mouse model neuronal patterning neuroregulation noradrenergic novel novel imaging technique prevent receptor relating to nervous system spatiotemporal therapeutic evaluation

项目摘要

PROJECT SUMMARY: Degeneration of neuromodulatory neurons, such as cholinergic neurons in the basal forebrain and noradrenergic neurons in the Locus Coeruleus, is a key hallmark of advanced Alzheimer’s Disease (AD). Loss of neuromodulatory inputs to the cerebral cortex contributes to dysregulation of attention, arousal, and cognition, processes that are robustly modulated by release of acetylcholine (ACh) and norepinephrine (NE). Functional dysregulation of these neuromodulatory systems likely precedes late-stage loss of projection neurons and contributes to early cognitive symptoms. However, despite extensive anatomical evidence, there is little functional data on neuromodulatory signaling across stages of pathology. In addition, technical limitations have precluded longitudinal measurements of neuromodulatory signaling in genetic models of disease. To address this gap, we propose to combine novel imaging approaches, including wide-field ‘mesoscopic’ imaging of ACh and NE signaling and neuronal activity across the entire cortex in awake behaving animals. Using two genetic models of AD, we will test the following hypotheses: (1) The initial consequence of pathology is early loss of state-dependent spatiotemporal dynamics of ACh and NE signaling. (2) AD pathology causes a progressive loss of coupling between neuromodulators and cortical activity and between ACh and NE. Importantly, we will longitudinally track changes over time within each animal and also compare across models to identify convergent signatures of disease-related dysregulation. Our results will provide an unprecedented level of insight into the disruption of key neuromodulatory systems throughout the lifetime in models of Alzheimer’s Disease and provide a novel framework for future evaluation of therapeutic approaches.

项目概要：神经调节神经元的退化，例如基底前脑的胆碱能神经元和蓝斑中去甲肾上腺素能神经元的缺失是晚期阿尔茨海默病 (AD) 的一个重要标志。大脑皮层的神经调节输入会导致注意力、唤醒和注意力的失调认知过程受到乙酰胆碱 (ACh) 和去甲肾上腺素 (NE) 释放的强烈调节。这些神经调节系统的功能失调可能会导致晚期投射丧失然而，尽管有大量的解剖学证据，但仍然存在这种现象。此外，关于跨病理阶段的神经调节信号传导的功能数据很少。局限性阻碍了对遗传模型中神经调节信号的纵向测量为了解决这一差距，我们建议结合新的成像方法，包括宽视野。清醒状态下整个皮层的 ACh 和 NE 信号传导以及神经活动的“介观”成像使用两种 AD 遗传模型，我们将测试以下假设：（1）初始假设病理学的后果是 ACh 和 NE 信号传导的状态依赖性时空动态的早期丧失。 (2) AD 病理学导致神经调节剂和皮质活动之间的耦合逐渐丧失，重要的是，我们将纵向跟踪每只动物随时间的变化。跨模型进行比较，以确定与疾病相关的失调的趋同特征。对整个过程中关键神经调节系统的破坏提供了前所未有的洞察力阿尔茨海默病模型的寿命，并为未来的治疗评估提供一个新的框架接近。