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

失去特异性：蓝斑在与年龄相关的注意力分散中的作用

• 批准号: 10517713
• 负责人: Benjamin D Katz
• 金额: $ 79.18万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517713
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Animal Model; Animals; Area; Attention; Attentional deficit; Behavior; Behavioral; Brain; Brain imaging; Cognitive; Cognitive aging; Data; Elderly; Exhibits; Failure; Family; Family history of; Financial compensation; First Degree Relative; Functional disorder; Future; Human; Human Characteristics; Image; Imaging Techniques; Impairment; In Vitro; Individual; Knowledge; Laboratories; Lead; Link; Location; Magnetic Resonance Imaging; Measures; Modeling; Molecular; Morphology; Mus; Neurobiology; Neuronal Plasticity; Noise; Parents; Pathologic; Pathway Analysis; Performance; Physiological; Published Comment; Recording of previous events; Research; Research Design; Rest; Role; Siblings; Signal Transduction; Specificity; Symptoms; Testing; Training; Training Programs; Transgenes; Visualization; Work; age effect; age related; aged; base; cognitive training; dementia risk; genetic manipulation; human imaging; human model; imaging approach; improved; in vivo; interest; locus ceruleus structure; mouse model; multimodality; network models; neural circuit; neural network; neuromechanism; neuromelanin; novel; programs; relating to nervous system; response; selective attention; therapeutic target; young adult

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.

项目摘要 越来越多的研究强调了额叶区域的重要性，无论是在大脑还是大脑中， 功能和结构水平，与年龄相关的注意力和认知处理下降。 然而，大脑中潜在的神经生物学病理生理学变化， 这些下降的原因在很大程度上仍不清楚。这项建议的目的是研究神经 与年龄相关的注意力分散的机制，重点是神经回路， 蓝斑（LC）。在目前的提议中，我们将测试神经元 LC与显著性网络（SN）的不连通性导致老年人忽视分心物的失败， 成年人了为此，我们将通过以下方法同时检查人和动物的大脑： 结合人脑成像和动物神经回路的综合方法 操作和2）等效的研究设计，包括兼容的注意任务范式， 类似的神经网络分析，以及人类和动物之间的救援策略。使用 我们新的单向电路特异性基因操作方法在体外和体内，我们将 直接损害和挽救动物的LC-SN回路，并检查回路操纵如何 在动物模型中存在干扰物时改变注意力表现。人类 在老年人中，我们将研究LC-SN连接如何与选择性注意力相关， 性能，以及如何通过认知训练计划改善LC-SN连接， 导致注意力表现改善。为了提高LC信号估计的保真度，我们将 在结构和功能水平上使用两种先进的成像方法，即 神经黑素加权结构MRI和生理噪声校正。最后，我们将包括一个 阿尔茨海默病家族史（一级亲属）作为潜在变量的测量 探索性分析的兴趣。拟议的项目将提供一个重要的跳板， 今后的工作，以确定和防止与年龄有关的注意力下降，包括 有患阿尔茨海默病风险的人。