NEURAL MECHANISMS OF SPATIAL WORKING MEMORY

描述（由申请人提供）：该申请涉及广泛的挑战领域（15）：转化科学和特定挑战主题，15- mh -109：前额叶皮层对高级脑功能和复杂行为的调节。本项目的目标是了解工作记忆（WM）中主动维持的神经机制。WM是大多数高级认知领域的核心组成部分，对执行控制至关重要。WM功能障碍被认为在认知障碍中起着重要作用，这些障碍包括多动症、阿尔茨海默病和最突出的精神分裂症。理解正常和病理WM功能背后的神经元机制的进展将构成基础科学的重大进步，并将作为临床人群研究的跳板，例如精神分裂症患者，其中WM功能障碍被认为是更广泛的认知障碍的主要决定因素。我们的方法是在人类和非人类灵长类动物中使用相同的长时间记忆任务进行直接匹配的成像实验，然后在猴子中使用相同的任务再次进行多单元记录。至关重要的是，这些研究将旨在提供有关导致存储信息随时间衰减（即WM延迟）的神经机制的详细信息，以及如何将其转化为行为变化。通过询问哪些神经元、回路和区域的活动与储存的WM内容随时间的正常丢失相关，以及/或与药物干预引起的诱导扰动相关，可以提供对这些问题的利用。我们将测试人类和非人类灵长类动物在这方面是否表现出相似的神经元模式，我们将使用多单元记录来测试来自吸引子网络计算模型的特定假设。我们的多物种、多方法方法将弥合计算模型、非人类灵长类动物单单元记录研究和人类神经成像数据之间的差距。通过建立这个桥梁，我们将大大推进我们对人类认知中工作记忆机制的理解。工作记忆是一种对正常认知功能至关重要的高级功能，在精神疾病中经常受到干扰。我们将使用多种方法研究猴子空间工作记忆的正常和病理功能，然后使用成像实验测试我们在人类中所学到的相关性。研究结果将为精神疾病的药理学和其他治疗方法提供更有原则的方法。

DESCRIPTION (provided by applicant): This application addresses Broad Challenge Area (15): Translational Science and Specific Challenge Topic, 15-MH-109: Prefrontal cortex regulation of higher brain function and complex behaviors. The goal of this project is to understand the neural mechanisms that underlie active maintenance in working memory (WM). WM is a core component of most domains of higher cognition and is critically important for executive control. WM dysfunction is thought to play a major role in the cognitive impairments seen in a wide-range of disorders, including ADHD, Alzheimer's disease, and most prominently, schizophrenia. Progress in understanding the neuronal mechanisms underlying normal and pathological WM function would constitute a major advance in basic science, and will serve as a launch pad for studies in clinical populations, such as patients with schizophrenia, for which WM dysfunction is thought to be a major determinant of more widespread cognitive impairment. Our approach is to conduct directly matched imaging experiments in humans and non-human primates using an identical long-duration memory task in both species, and then to conduct multi-unit recording in monkeys again using the same task. Critically, these studies will be designed to provide detailed information regarding the neural mechanisms that result in the decay of stored information over time (i.e., WM delay), and how this translates into behavioral change. Leverage on these issues will be provided by asking which neurons, circuits, and areas have activity that is correlated with the normal loss of stored WM content over time, and/or correlated with the induced perturbations that result from pharmacologic interventions. We will test whether human and non-human primates show similar neuronal patterns in this regard, and we will use multi-unit recording to test specific hypotheses derived from computational models of attractor networks. Our multi- species, multi-method approach will bridge the gap between computational models, single unit recording studies in non-human primates, and human neuroimaging data. By forming this bridge, we will greatly advance our understanding of the mechanisms of working memory in human cognition. Working memory is a high level function that is absolutely critical to normal cognitive function, and is often disturbed in psychiatric illness. We will investigate the normal and pathological function of spatial working memory in the monkey using a variety of methodologies, and then test the relevance of what we have learned in humans using imaging experiments. The result will be a more principled approach to pharmacologic and other therapies for psychiatric illness.