Cognitive and Molecular Challenges to Statistical Inference Across Healthy Aging.

健康老龄化过程中统计推断的认知和分子挑战。

• 批准号: 10005106
• 负责人: Matthew Nassar
• 金额: $ 24.8万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005106
• 关键词: Address; Affect; Age; Age-associated memory impairment; Aging; Arousal; Award; Bayesian learning; Behavior; Behavioral; Belief; Biological; Biology; Brain; Brain Stem; Cognitive; Cognitive aging; Comparative Study; Data; Decision Making; Diagnostic; Dopamine; Elderly; Electroencephalography; Foundations; Glutamates; Goals; Human; Hybrids; Impairment; Individual Differences; Intervention; Joints; Laboratory Research; Lead; Learning; Life; Link; Longevity; Magnetic Resonance Spectroscopy; Maps; Measurable; Measurement; Measures; Mediating; Mediator of activation protein; Memory; Memory impairment; Molecular; Nature; Neural Network Simulation; Neurodegenerative Disorders; Norepinephrine; Perception; Performance; Phase; Play; Process; Property; Proxy; Psychological Theory; Recording of previous events; Reporting; Research; Research Personnel; Research Support; Risk; Role; Schools; Short-Term Memory; Signal Transduction; Source; Stimulus; System; Task Performances; Techniques; Testing; Time; Training; Uncertainty; Visual; Work; age related; base; behavior measurement; behavioral study; career; cognitive function; comparative; emerging adult; expectation; experimental study; gamma-Aminobutyric Acid; glutamatergic signaling; healthy aging; improved; information processing; lens; neural network; psychobiology; psychologic; relating to nervous system; skills; theories; tool; trend; visual information; young adult

Age-related cognitive decline is a problem of growing importance given the trend toward increased lifespan and the importance of cognitive function in determining risk for neurodegenerative disease. Despite the importance of this problem, the cognitive and molecular changes that mediate it are still poorly understood. While there are competing theories for the mediators of cognitive aging at both psychological and molecular levels, theories on aging and the research supporting them have typically focused on a single level of analysis. As our understanding of the biological basis for behavior grows, this divide becomes less sensible. Instead, psychological theory should be constrained according to its known biology, and biology should in turn inform psychological theory. Here I propose to learn neural network modeling and magnetic resonance spectroscopy (MRS) techniques in order to bridge human psychological theory that has been the focus of my recent work to the molecular level theory that was the focus of my post-baccalaureate training at the NIA. I will build from my recent work that highlights a key statistical problem faced by the brain: how to selectively pool information across relevant sources but partition information across irrelevant ones. I will closely examine the cognitive and molecular mechanisms that allow for efficient pooling and partitioning to test the overarching theory that, due to impaired glutamate and dopamine signaling, older adults develop a selective deficit in pooling relevant sources of information. I will test this theory in two separate paradigms: visual working memory (K99) and learning and perceptual inference (R00). During the K99 phase of the award I will examine how pooling information from visual targets with similar features can 1) improve effective memory capacity, 2) be achieved by a neural network model, and 3) be impaired by simulated molecular deficiencies (glutamate, dopamine, norepinephrine). This bridge between cognitive and molecular levels of analysis will be used to test whether age-related memory deficits are due to inefficient pooling and mediated by molecular deficits in glutamate and dopamine (as measured through MRS and behavioral proxy, respectively). During the R00 phase of the award I will use the training in neural networks and MRS provided in the K99 phase to examine how 1) pooling sequential pieces of information affects learning and perceptual bias, 2) efficient pooling and partitioning can be achieved by a neural network model and 3) these processes are disrupted by specific molecular deficiencies. The established relationships between statistical properties (sequential pooling and partitioning), psychological measurements (learning and perceptual bias) and molecular factors (glutamate, dopamine, and norepinephrine signaling levels) will be used to test whether age-related differences in learning and perceptual bias reflect deficient pooling mediated by local glutamate deficiency (as measured through MRS). Overall, this work will contribute a deeper and more detailed understanding of the psychological and molecular factors that interact to mediate age-related cognitive decline. In addition, the K99 training will provide me the tools necessary to link psychological and molecular levels of analysis and the R00 phase will build the foundations of my independent research laboratory allowing me to develop a successful scientific career driven by experiments that build and refine a unified understanding of cognitive aging.

鉴于寿命延长的趋势以及与年龄相关的认知能力下降是一个日益重要的问题 认知功能在确定神经退行性疾病风险中的重要性。尽管这很重要 对于这个问题，调节它的认知和分子变化仍然知之甚少。虽然有竞争 在心理和分子水平上认知衰老的中介理论、衰老理论和 支持它们的研究通常集中于单一层面的分析。作为我们对生物学基础的理解 随着行为的增长，这种划分变得不那么明智。相反，心理学理论应该根据其理论受到限制。 众所周知的生物学，而生物学又应该为心理学理论提供信息。这里我建议学习神经网络建模 和磁共振波谱（MRS）技术，以架起人类心理学理论的桥梁。 我最近的工作重点是分子水平理论，这是我在 NIA 学士后培训的重点。我 将以我最近的工作为基础，强调大脑面临的一个关键统计问题：如何选择性地汇集 跨相关来源的信息，但跨不相关来源的分区信息。我会仔细检查认知 以及允许有效池化和分区的分子机制来测试总体理论，由于 由于谷氨酸和多巴胺信号传导受损，老年人在汇集相关来源方面出现选择性缺陷 信息。我将在两个不同的范式中测试这个理论：视觉工作记忆（K99）以及学习和知觉 推理（R00）。在奖项的 K99 阶段，我将研究如何将来自视觉目标的信息与 类似的特征可以 1) 提高有效记忆容量，2) 通过神经网络模型实现，3) 被削弱 通过模拟分子缺陷（谷氨酸、多巴胺、去甲肾上腺素）。认知和分子之间的桥梁 分析级别将用于测试与年龄相关的记忆缺陷是否是由于低效的池化造成的，并由以下因素介导： 谷氨酸和多巴胺的分子缺陷（分别通过 MRS 和行为代理测量）。期间 奖励的 R00 阶段我将使用 K99 阶段提供的神经网络和 MRS 训练来检查如何 1) 汇集连续的信息片段会影响学习和感知偏差，2）有效的汇集和划分可以 通过神经网络模型实现，3）这些过程被特定的分子缺陷破坏。这 建立统计特性（顺序合并和分区）、心理测量之间的关系 （学习和知觉偏差）和分子因素（谷氨酸、多巴胺和去甲肾上腺素信号水平）将 用于测试与年龄相关的学习差异和知觉偏差是否反映了局部介导的汇集不足 谷氨酸缺乏症（通过 MRS 测量）。总体而言，这项工作将有助于更深入、更详细地 了解相互作用介导与年龄相关的认知能力下降的心理和分子因素。在 此外，K99 培训将为我提供必要的工具，将心理和分子水平的分析与 R00 阶段将为我的独立研究实验室奠定基础，使我能够开发成功的 科学事业由建立和完善对认知衰老的统一理解的实验驱动。