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).
