How LC Integrity in Older Adults Mediates Perceptual and Memory Processes

项目摘要 本提案的总体目标是了解结构和 蓝斑基因（LC）的功能在老年人群体中的中度感知和记忆。有 LC回路在认知过程和LC中的神经元损失中起核心作用的实质性证据是 已知在神经退行性疾病如ADRD和PD中发生。假设LC神经元的完整性 在正常衰老过程中也能调节认知能力的保持。然而，到目前为止， 缺乏研究，无论是表征LC完整性的差异效应或LC之间的关系细节 完整性和认知功能。更一般地说，LC活动和认知之间的联系 这些过程在人类中还没有得到很好的表征。历史原因是，立法会一直很难 由于其体积小，因此大多数人类研究都是通过使用瞳孔来推断LC功能 膨胀作为替代测量。为了克服该领域现有的局限性，我们提出了一系列详细的 在老年人中进行的心理物理学和基于MRI的研究旨在表征LC的结构和功能 调节行为，反过来又如何通过已知的中间大脑区域的活动来介导， 参与感知和记忆过程。我们进一步提出了计算方法来表征 LC电路完整性与不同认知表现模式之间的个体差异 任务和先进的神经影像学方法来定位和成像LC，这是我们的 组使用基于MRI的方法，我们将使用高分辨率神经黑色素敏感的 结构成像、纤维束成像和功能连接。这种方法将使我们能够确定候选人 LC回路完整性的生物标志物。我们将使用一系列的受试者内设计，我们操纵LC活动 并研究LC和行为之间的关系以及被认为介导这些行为的大脑区域， 行为在不同知觉模态和记忆任务之间是一致的或不一致的。总的来说，这项研究 将提供一个重要的和急需的了解如何LC完整性的基础认知下降， 老年人通过结合先进的神经成像，良好控制的行为评估， 分析，我们希望发现以前无法在体内LC调制机制，并产生一个新的研究。 独特的数据集，以解决LC完整性如何调节认知的基本机制问题， 这在老年人中各不相同，LC和认知之间的关系在多大程度上是广义的 或者个性化到特定领域。由此产生的对LC电路的理解有助于解释 功能失调的调节回路可能会导致认知能力下降，或者与正常的衰老和年龄有关， 相关病症，如阿尔茨海默氏症和阿尔茨海默氏症相关病症。这反过来又有可能支持 用于诊断与LC衰退相关的病理学和开发新治疗的非侵入性方法。

Project Summary The overarching goal of the present proposal is to understand how individual differences in the structure and function of Locus Coeruleus (LC) moderate perception and memory in an older adult population. There is substantial evidence that the LC circuit plays a central role in cognitive processes and neuronal loss in LC is known to occur in neurodegenerative disorders such as ADRD and PD. Integrity of LC neurons is hypothesized to mediate the preservation of cognitive abilities during normal aging as well. To date, however, there exists a dearth of research that either characterizes differential effects of LC integrity or details relationships between LC integrity and cognitive function in older adult humans. More generally, the link between LC activity and cognitive processes has not been well characterized in humans. Historical reasons for this is that the LC has been difficult to image due to its small size and thus most human research makes inferences about LC function by using pupil dilation as a surrogate measure. To overcome existing limitations in the field, we propose a series of detailed psychophysical and MRI-based studies in older adults aimed to characterize how LC structure and function moderates behavior and in turn how this is mediated by activity in intermediate brain regions known to be involved in perceptual and memory processes. We further propose computational approaches to characterize individual differences in how LC circuit integrity relates to different patterns of cognitive performance across tasks, and advanced neuroimaging methods to localize and image the LC, which have been pioneered by our group. Using MRI-based methods, we will examine LC integrity using high-resolution neuromelanin-sensitive structural imaging, tractography and functional connectivity. This approach will allow us to identify candidate biomarkers of LC circuit integrity. We will use a series of within-subject designs where we manipulate LC activity and examine whether relationships between LC and behavior and brain regions thought to mediate those behaviors are consistent or not between different perceptual modalities and memory tasks. Overall this study will provide an important and much needed understanding of how LC integrity underlies cognitive declines in older adults. By combining advanced neuroimaging, well-controlled behavioral assessment, and computational analysis, we expect to uncover previously inaccessible in vivo mechanisms of LC modulation and generate a unique dataset to address fundamental mechanistic questions of how the LC integrity moderates cognition, how this varies across older adults and the extent to which relationships between LC and cognition are generalized or individualized to particular domains. The resulting understanding of LC circuit can help explain how dysfunctional modulatory circuits may generate cognitive declines or be implicated in normal aging and age- related disorders such as Alzheimer's and Alzheimer's related disorders. This, in turn, has potential to support non-invasive methods for diagnosing pathologies associated with LC decline and developing new treatments.