US-French Research Proposal: Experimental and Theoretical Investigation of the Multi-Scale Emergence of Parametric Working Memory in Prefrontal Cortex Recurrent Networks

美法研究提案：前额皮质循环网络中参数工作记忆多尺度出现的实验和理论研究

• 批准号: 1608236
• 负责人: Jeanne Paz
• 金额: $ 61万
• 依托单位: The J. David Gladstone Institutes
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1608236&HistoricalAwards=false
• 关键词: US; French; Research; Proposal; Experimental

The prefrontal cortex of the brain controls how people remember sizes of things, such as a number of items or the pitch of a sound, within a short time frame of about a few seconds. This ability, called parametric working memory (PWM), helps people to interpret their world, make decisions, and act or behave. Dysfunction in PWM may be involved in many brain diseases, including Alzheimer's disease, schizophrenia, attention deficit hyperactivity disorder, and bipolar disorders. These diseases affect more than 200 million people worldwide. Through this research project, researchers will learn more about how the prefrontal cortex controls PWM in healthy and diseased brains. With this new information, they may be able to create new treatments for many people suffering from brain diseases.PWM relies on the persistent activity of neurons in the prefrontal cortex. This persistent activity is graded such that the firing rate of neurons correlates with the quantity of things to be remembered, which can emerge from network interactions with the local microcircuitry. Yet, to robustly display graded persistent activity, these networks must incorporate neurons with bistability, such that stable quiescence and activity coexist in their range of input. Neurons in the prefrontal cortex can display bistability that depends on non-selective cationic (CAN) currents activated by calcium. However, cellular bistability in the prefrontal cortex occurs under very specific experimental conditions of stimulation and neuromodulation. The researchers' overall goal is to determine whether CAN-mediated conditional bistability in the prefrontal cortex is a genuine physiological property of neurons and whether it supports graded persistent activities within local recurrent networks. They will develop a multidisciplinary research program of computational and experimental analysis to study properties ranging from molecular interactions to the behavior of neural networks. With theoretical modeling at the molecular, cellular, and network levels, extensive numerical simulations, intracellular recordings, and optogenetics, the researchers will identify and control neural substrates that mediate PWM. In this way, they will learn the causal mechanisms and dynamic principles of PWM in the prefrontal cortex, including the multi-stability that characterizes its graded persistent activity. These efforts will help researchers to better understand higher cognitive and behavioral functions and pathologies related to PWM, and also advance theories of fundamental properties in neuroscience. A companion project is being funded by the French National Research Agency (ANR).

大脑的前额叶皮质控制着人们如何在几秒钟的短时间内记住事物的大小，比如一些物品或声音的音调。这种能力被称为参数工作记忆(PWM)，帮助人们解释他们的世界，做出决定，以及行动或行为。脉宽调制功能障碍可能与许多大脑疾病有关，包括阿尔茨海默病、精神分裂症、注意力缺陷多动障碍和双相情感障碍。这些疾病影响着全球2亿多人。通过这项研究项目，研究人员将更多地了解前额叶皮质如何控制健康和患病大脑的脉宽调制。有了这一新信息，他们可能能够为许多患有脑病的人创造新的治疗方法。脉宽调制依赖于前额叶皮质神经元的持续活动。这种持续的活动是分级的，因此神经元的放电率与要记住的东西的数量相关，这些东西可以通过与局部微电路的网络相互作用而出现。然而，为了稳健地显示分级的持续活动，这些网络必须包括具有双稳态的神经元，以便在它们的输入范围内稳定的静止和活动共存。前额叶皮质的神经元可以表现出依赖于钙激活的非选择性阳离子(CaN)电流的双稳态。然而，前额叶皮质的细胞双稳态发生在非常特殊的刺激和神经调节的实验条件下。研究人员的总体目标是确定前额叶皮质中CaN介导的条件性双稳态是否是神经元的真正生理属性，以及它是否支持局部递归网络中的分级持续活动。他们将开发一个计算和实验分析的多学科研究计划，研究从分子相互作用到神经网络行为的各种性质。通过分子、细胞和网络层面的理论建模、广泛的数值模拟、细胞内记录和光遗传学，研究人员将识别和控制调节脉宽调制的神经底物。通过这种方式，他们将了解前额叶皮质脉宽调制的因果机制和动态原理，包括其分级持续活动的多重稳定性。这些努力将帮助研究人员更好地理解与脉宽调制相关的高级认知和行为功能以及病理学，并推进神经科学的基本性质理论。法国国家研究机构(ANR)正在资助一个配套项目。