The Dynamic Neuromodulome in Alzheimer's Disease and Aging

阿尔茨海默病和衰老中的动态神经模块

• 批准号: 10901011
• 负责人: JEANNIE CHIN
• 金额: $ 63.51万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901011
• 关键词: AD transgenic mice; Acetylcholine; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Anatomy; Animals; Area; Arousal; Atlases; Attention; Axon; Behavior; Behavioral; Behavioral Assay; Benchmarking; Biological Assay; Brain; Cell Death; Cell Nucleus; Cognition; Competence; Control Animal; Critical Pathways; Data; Data Set; Development; Diagnostic; Disease; Disease Marker; Disease Progression; Disease model; Dopamine; Exhibits; Functional disorder; Future; Goals; Histologic; Human; Impaired cognition; Individual; Longevity; Measurement; Measures; Memory; Memory Loss; Mental Depression; Modeling; Motivation; Multiplexed Analysis of Projections by Sequencing; Mus; Mydriasis; Neuromodulator; Neurons; Norepinephrine; Pathologic; Pathology; Patients; Pattern; Perception; Phenotype; Physiological; Physiology; Play; Predisposition; Pupil; Resolution; Role; Sensory; Serotonin; Shapes; Structure; Substantia nigra structure; System; Techniques; Testing; Therapeutic; Time; Translations; Work; awake; basal forebrain; cellular pathology; cohort; diagnostic tool; disorder risk; human data; in vivo; juvenile animal; locus ceruleus structure; luminance; model building; mouse model; multimodality; nerve supply; neuropsychiatric symptom; nonhuman primate; noninvasive diagnosis; normal aging; novel; optogenetics; postsynaptic; predictive modeling; presynaptic; raphe nuclei; response; sensory stimulus; stem; temporal measurement; transcriptomics

PROJECT SUMMARY Neuromodulators such as dopamine, serotonin, acetylcholine, and norepinephrine play important roles in shaping perception, cognition, and behavior. Evidence suggests that these systems may be particularly susceptible to dysfunction in Alzheimer’s disease (AD). This dysfunction can lead to neuropsychiatric symptoms that can appear early in disease progression, before the profound decline in cellular integrity and associated deficits in memory and cognition that are hallmarks of AD. These neuromodulators vary quickly from moment to moment, but it’s not clear how these dynamics vary across aging, and when they diverge from normal aging over the progression of AD. Understanding when these changes occur relative to well-described anatomical and behavioral benchmarks of AD disease progression would reveal the “critical path” of neuromodulator pathology in AD that distinguishes it from normal aging, and could suggest potential targets for treatment or diagnosis of AD prior to the onset of memory loss and cognitive decline. The overall goals of this project are to understand how fast activity these ascending systems change during the progression of AD, and to enable the development of diagnostic tools for non-invasive assessment of disease risk. We will perform systematic measurements of neuromodulator release at multiple ages in two different Alzheimer’s disease mouse lines and control animals using a novel combination of techniques developed by our team. We will combine these in vivo functional measurements with anatomical data in the same mice that includes markers of cellular pathology, axonal integrity, and transcriptomics, as well as behavioral assays, in order to produce a multimodal atlas of disease progression bridging structure and function in the brain’s major modulatory systems. Finally, building on our previous finding that spontaneous fluctuations in pupil size are correlated with specific patterns of neuromodulator release in the brain, we will attempt to build models that allow us to infer neuromodulator levels from pupillometric measurements, and we will validate the translation relevance of these models in a unique human data set. In summary, this project will provide the clearest view to date of pathological changes in neuromodulator dynamics with AD, where they diverge from normal changes during aging, and their relationship to underlying anatomical changes throughout the brain.

项目摘要 多巴胺、血清素、乙酰胆碱和去甲肾上腺素等神经调节剂起着重要作用 在塑造感知、认知和行为中的作用。有证据表明，这些系统可能 在阿尔茨海默病（AD）中特别容易发生功能障碍。这种功能障碍会导致 神经精神症状，可以出现在疾病进展的早期，在深刻的 细胞完整性下降以及相关的记忆和认知缺陷，这些都是 AD.这些神经调质每时每刻都在迅速变化，但目前还不清楚这些神经调质是如何变化的。 随着年龄的增长，动态变化，当它们在衰老的过程中偏离正常衰老时， AD.了解这些变化何时发生，相对于描述良好的解剖学和 AD疾病进展的行为基准将揭示AD的“关键路径”， AD中的神经调质病理学将其与正常衰老区分开来，并可能表明 在记忆丧失和认知功能丧失发作之前治疗或诊断AD的潜在靶点 下降这个项目的总体目标是了解这些提升的活动有多快 系统在AD进展过程中发生变化，并使诊断工具的开发成为可能 用于疾病风险的非侵入性评估。我们将进行系统的测量， 在两种不同的阿尔茨海默病小鼠系中在多个年龄的神经调节剂释放， 使用我们团队开发的新技术组合来控制动物。我们将联合收割机 这些体内功能测量与相同小鼠的解剖数据，包括 细胞病理学、轴突完整性和转录组学的标志物，以及行为测定， 为了产生疾病进展桥接结构和功能的多模式图谱， 大脑的主要调节系统最后，基于我们之前的发现， 瞳孔大小的波动与脑中神经调节剂释放的特定模式相关。 大脑，我们将尝试建立模型，使我们能够推断神经调质水平， 瞳孔测量，我们将验证这些模型的翻译相关性， 独一无二的人类数据集总之，该项目将提供迄今为止最清晰的视图， AD患者神经调质动力学的病理变化，与正常情况不同 衰老过程中的变化，以及它们与整个衰老过程中潜在的解剖学变化的关系。 个脑袋