Cognitive and Molecular Challenges to Statistical Inference Across Healthy Aging.

与年龄相关的认知衰退是一个日益重要的问题，因为有延长寿命的趋势， 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 尽管如此，调节这个问题的认知和分子变化仍然知之甚少。当有竞争的时候 心理和分子水平上的认知衰老中介理论，衰老理论和 支持它们的研究通常集中在单一层面的分析上。作为我们对生物学基础的理解 随着行为的增长，这种分歧变得不那么明智。取而代之的是，心理学理论应该根据其 已知的生物学，而生物学反过来又应该为心理学理论提供信息。在这里，我建议学习神经网络建模 和磁共振波谱(MRS)技术，以期在人类心理学理论之间架起桥梁 我最近的工作重点是分子水平理论，这是我在NIA毕业后培训的重点。我 我将从我最近的工作中建立起来，该工作突出了大脑面临的一个关键统计问题：如何有选择地汇集 跨相关来源的信息，但跨不相关来源的信息。我将仔细检查认知 以及分子机制，允许有效地汇集和分配，以测试总体理论，由于 谷氨酸和多巴胺信号受损，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)和学习和知觉 推论(R00)。在颁奖的K99阶段，我将研究如何利用 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，以及3)受损 通过模拟分子缺陷(谷氨酸、多巴胺、去甲肾上腺素)。认知和分子之间的这座桥梁 分析水平将被用来测试与年龄相关的记忆缺陷是否是由于低效的池化以及由 谷氨酸和多巴胺的分子缺陷(分别通过MRS和行为代用品测量)。在.期间 R00阶段的奖励我将使用K99阶段提供的神经网络和MRS方面的培训来研究如何1) 汇集连续的信息片段会影响学习和知觉偏差，2)有效的汇集和划分 通过神经网络模型实现，以及3)这些过程被特定的分子缺陷打乱。这个 在统计属性(顺序合并和分区)、心理测量之间建立关系 (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)将是 用来测试与年龄相关的学习差异和知觉偏差是否反映了局部调节的汇集不足 谷氨酸缺乏(通过MRS测量)。总体而言，这项工作将有助于更深入和更详细地 了解交互作用于年龄相关认知衰退的心理和分子因素。在……里面 此外，K99培训将为我提供必要的工具，将心理和分子层面的分析和 R00阶段将为我的独立研究实验室奠定基础，使我能够开发出成功的 由建立和完善对认知老化的统一理解的实验推动的科学事业。

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.