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.

项目概要 多巴胺、血清素、乙酰胆碱和去甲肾上腺素等神经调节剂发挥着重要作用 塑造知觉、认知和行为的角色。有证据表明这些系统可能 特别容易受到阿尔茨海默病（AD）功能障碍的影响。这种功能障碍可能会导致 神经精神症状可能出现在疾病进展的早期，在深刻的影响之前 细胞完整性下降以及相关的记忆和认知缺陷是 广告。这些神经调节剂每时每刻都在快速变化，但尚不清楚这些神经调节剂是如何变化的 随着年龄的增长，动力学会发生变化，当它们在衰老过程中偏离正常衰老时， 广告。了解这些变化何时发生相对于详细描述的解剖学和 AD 疾病进展的行为基准将揭示 AD 疾病进展的“关键路径” AD 中的神经调节病理学将其与正常衰老区分开来，并可能表明 在记忆丧失和认知能力丧失之前治疗或诊断 AD 的潜在目标 衰退。该项目的总体目标是了解这些上升活动的速度有多快 系统在 AD 进展过程中发生变化，并促进诊断工具的开发 用于疾病风险的非侵入性评估。我们将进行系统的测量 两种不同阿尔茨海默氏病小鼠品系在多个年龄段的神经调节剂释放 使用我们团队开发的新颖技术组合来控制动物。我们将结合 这些体内功能测量与同一小鼠的解剖数据包括 细胞病理学、轴突完整性和转录组学以及行为分析的标记， 为了制作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，即自发的 瞳孔大小的波动与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，使我们能够从 瞳孔测量，我们将验证这些模型的翻译相关性 独特的人类数据集。总之，该项目将提供迄今为止最清晰的视图 AD 神经调节动力学的病理变化，与正常情况不同 衰老过程中的变化，以及它们与整个过程中潜在的解剖变化的关系 脑。