Prefrontal cortical neural processes supporting working memory: differential roles of distinct neuronal subtypes and modulation by dopamine

Abstract

The prefrontal cortex plays a crucial role in working memory, which is the system responsible for temporarily maintaining and manipulating information. The prefrontal cortex contains a complex network of interconnected excitatory and inhibitory neurons, but the specific roles of different neuron subtypes in supporting working memory are not yet fully understood. In this study, I examined the functions of three distinct subtypes of prefrontal cortical neurons in working memory and their modulation by dopamine. Firstly, I compared two major types of cortical projection neurons, intratelencephalic (IT) and pyramidal tract (PT) neurons, in the deep layer. I found that IT neurons convey stronger working memory signals than PT neurons, while PT neurons carry more temporal information during the delay period. These findings suggest that IT and PT neurons have different roles in the maintenance of working memory and tracking the passage of time, respectively. Secondly, I investigated the role of vasoactive intestinal polypeptide (VIP)-expressing neurons in working memory. I discovered that VIP neurons convey strong working memory signals and that VIP neuronal inactivation strongly impairs behavioral performance. This highlights the critical role of VIP neurons in working memory. Lastly, I explored the mPFC neural processes mediating dopamine effects on working memory. I discovered that selective knockdown of dopamine D1 receptors (D1R) in VIP neurons impairs behavioral performance, suggesting that VIP neurons are a critical mediator of dopamine effects on working memory. Additionally, dopamine release during the delay period was higher in contralateral-choice trials, and optogenetic stimulation of mPFC dopaminergic terminals increased the animal's contralateral choices. Furthermore, optogenetic dopaminergic stimulation disproportionately increased the contralateral-choice-related activity of VIP neurons. These findings suggest that dopamine might modulate working memory by altering the laterality of mPFC neuronal delay-period activity. Overall, this study reveals the cell type-specific neural processes that support working memory in the mPFC and how dopamine modulates these processes. As working memory is critical for many prefrontal cortical cognitive functions, these findings have broad implications for prefrontal cortical functions and malfunctions.