Losing specificity: the role of the locus coeruleus in age-related distractibility

项目总结 越来越多的研究强调了额叶区域的重要性，在 功能和结构水平，与年龄相关的注意力和认知加工能力下降。 然而，大脑中潜在的神经生物学病理生理变化 这些下降的原因在很大程度上仍然不清楚。这项建议的目标是研究神经细胞 与年龄相关的注意力分散的机制，重点是从 蓝斑(LC)。在目前的方案中，我们将测试神经的假设 LC与突显网络(SN)的连接障碍导致老年人忽略干扰物失败 成年人。为此，我们将同时检查人类和动物的大脑 人脑成像与动物神经回路相结合的综合方法 2)等同的研究设计，包括兼容的注意任务范式； 类比神经网络分析，以及人与动物之间的救援策略。vbl.使用 我们新的体外和体内单向电路特异性基因操作方法，我们将 直接损伤和挽救动物的LC-SN电路，并检查电路操作如何 在动物模型中，在分心因素存在的情况下，注意力表现会发生变化。对于人类来说 ，我们将研究LC-SN连接如何与选择性注意相关联 性能，以及如何通过认知培训计划改善LC-SN连接 提高注意力的表现。为了提高LC信号估计的保真度，我们将 在结构和功能层面利用两种先进的成像方法，即 神经黑色素加权结构磁共振成像和物理噪声校正。最后，我们将包括一个 测量阿尔茨海默病家族史(一级亲属)作为潜在变量 对探索性分析感兴趣。拟议的项目将提供一个重要的跳板，以 今后的工作是查明和预防与年龄有关的注意力下降，包括 阿尔茨海默病的高危人群。

PROJECT SUMMARY A growing body of research has highlighted the importance of frontal regions, at both the functional and structural levels, in age-related declines in attentional and cognitive processing. However, the underlying neurobiological pathophysiological changes in the brain that contribute to these declines are still largely unclear. The objective of this proposal is to investigate neural mechanisms of age-related attentional distractibility, focusing on the neural circuit initiated from the locus coeruleus (LC). In the current proposal, we will test the hypothesis that the neural dysconnectivity of LC with the salience network (SN) drives failures of ignoring distractors in older adults. To this end, we will examine humans’ and animals’ brains simultaneously through 1) an integrative approach combining human brain imaging and animal-based neural circuit manipulation and 2) equivalent research designs, including compatible attention task paradigms, analogous neural network analyses, and rescue strategies between human and animal. Using our novel unidirectional circuit-specific gene manipulation approach in vitro and in vivo, we will directly impair and rescue the LC-SN circuit in animals and examine how the circuit manipulation changes attention performance in the presence of distractors in the animal model. For human older adults, we will examine how LC-SN connectivity is associated with selective attention performance, and how improved LC-SN connectivity through a cognitive training program may lead to improved attentional performance. To increase fidelity in LC signal estimation, we will utilize two advanced imaging approaches at both the structural and functional level, namely neuromelanin-weighted structural MRI and physio-noise correction. Finally, we will include a measure of family history of Alzheimer’s disease (first degree relative) as variable of potential interest for exploratory analyses. The proposed project will provide an essential springboard to future work to identify and protect against age-related declines in attention, including among individuals at-risk for Alzheimer’s disease.