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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' 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

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 蓝斑中的去甲肾上腺素能神经元是晚期阿尔茨海默病 (AD) 的一个关键标志。损失 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先于晚期投射丧失 神经元并导致早期认知症状。然而，尽管有大量的解剖学证据， 关于跨病理阶段的神经调节信号传导的功能数据很少。此外，技术 局限性阻碍了对遗传模型中神经调节信号的纵向测量 疾病。为了解决这一差距，我们建议结合新颖的成像方法，包括宽视场 清醒状态下整个皮层的 ACh 和 NE 信号传导以及神经元活动的“介观”成像 行为动物。使用 AD 的两种遗传模型，我们将检验以下假设：（1）初始 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 病理导致神经调节剂和皮质活动之间的耦合逐渐丧失， 位于ACh和NE之间。重要的是，我们将纵向跟踪每只动物随时间的变化，并且 跨模型进行比较，以确定与疾病相关的失调的趋同特征。我们的结果将 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了一个新的框架 接近。