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.

项目摘要：神经调节性神经元的变性，例如基本前脑中的胆碱能神经元，基因座层中的去肾上腺素能神经元是晚期阿尔茨海默氏病（AD）的关键标志。损失大脑皮质的神经调节输入的影响导致注意力失调，唤醒和认知，通过乙酰胆碱（ACH）和去甲肾上腺素（NE）释放来牢固调节的过程。这些神经调节系统的功能失调可能先于投影晚期丧失神经元并导致早期认知症状。但是，dospite广泛的解剖学证据是跨病理阶段的神经调节信号传导的功能数据。另外，技术局限性排除了神经调节信号传导的纵向测量疾病。为了解决这一差距，我们建议结合新的成像方法，包括广阔的场 ACH和NE信号传导和神经元活性的“介观”成像行为动物。使用两个AD遗传模型，我们将测试以下假设：（1）初始假设病理的结果是ACH和NE信号传导的状态依赖性时空动力学的早期丧失。（2）AD病理学导致神经调节剂与皮质活性和皮质活性和在ACH和NE之间。重要的是，我们将在每只动物中随着时间的流逝而纵向改变轨道比较跨模型，以识别与疾病相关失调的收敛信号。我们的结果将会对整个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氏病模型的寿命，并为将来的治疗评估提供了新的框架方法。