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

大脑的前额叶皮层控制着人们如何在大约几秒钟的短时间内记住事物的大小，比如许多物品或声音的音高。这种能力被称为参数化工作记忆（PWM），它帮助人们理解他们的世界，做出决定，以及采取行动或表现。PWM功能障碍可能与许多脑部疾病有关，包括阿尔茨海默病、精神分裂症、注意缺陷多动障碍和双相情感障碍。这些疾病影响到全世界2亿多人。通过这个研究项目，研究人员将更多地了解前额皮质如何控制健康和患病大脑中的脉宽调制。有了这些新信息，他们可能能够为许多患有脑部疾病的人创造新的治疗方法。脉宽调制依赖于前额皮质神经元的持续活动。这种持续的活动是分级的，以至于神经元的放电率与要记住的事物的数量相关，这可以从与局部微电路的网络相互作用中产生。然而，为了稳定地显示分级的持续活动，这些网络必须包含具有双稳定性的神经元，这样在它们的输入范围内稳定的静止和活动共存。前额叶皮层的神经元可以显示双稳定性，这取决于由钙激活的非选择性阳离子（can）电流。然而，前额叶皮层的细胞双稳定性发生在刺激和神经调节的非常特定的实验条件下。研究人员的总体目标是确定前额叶皮层中can介导的条件双稳定性是否是神经元的真正生理特性，以及它是否支持局部循环网络中的分级持久活动。他们将开发一个计算和实验分析的多学科研究计划，以研究从分子相互作用到神经网络行为的性质。通过分子、细胞和网络水平的理论建模、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介导PWM的神经基质。通过这种方式，他们将了解前额叶皮层PWM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。这些努力将有助于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和病理，并推进神经科学基本特性的理论。法国国家研究机构（ANR）正在资助一个伙伴项目。

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).