The Dynamic Neuromodulome in Alzheimer's Disease and Aging

项目总结 神经调节剂如多巴胺、5-羟色胺、乙酰胆碱和去甲肾上腺素起着重要作用。 在塑造感知、认知和行为方面的作用。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。这种功能障碍会导致 到神经精神症状，可以在疾病进展的早期出现，在严重的 细胞完整性下降以及与之相关的记忆和认知缺陷，这是 广告。这些神经调节剂每时每刻变化很快，但还不清楚它们是如何变化的 随着年龄的增长，动态会有所不同，当它们偏离正常衰老的过程时， 广告。了解这些变化发生的时间与描述良好的解剖学和 AD疾病进展的行为基准将揭示出 阿尔茨海默病的神经调节剂病理，将其与正常衰老区分开来，并可能提示 在记忆丧失和认知障碍发作之前治疗或诊断AD的潜在靶点 拒绝。这个项目的总体目标是了解这些活动上升的速度 系统在AD发展过程中发生变化，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 在两个不同的阿尔茨海默病小鼠系和 使用我们团队开发的一种新技术组合来控制动物。我们将联合起来 这些体内功能测量使用的是同一组小鼠的解剖学数据，包括 细胞病理，轴突完整性，转录组，以及行为分析的标记物， 为了制作疾病进展的多模式图谱，桥接结构和功能在 大脑的主要调节系统。最后，基于我们之前的发现，自发的 瞳孔大小的波动与特定的神经调节剂释放模式相关 大脑，我们将尝试建立模型，允许我们从 测量，我们将验证这些模型的平移相关性 唯一的人类数据集。总而言之，这个项目将提供迄今为止最清晰的观点 阿尔茨海默病患者神经调节器动力学的病理变化 衰老过程中的变化，以及它们与整个年龄段潜在解剖变化的关系 大脑。

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.