Regulation of working memory switches from striatal dopamine D2-receptor to D1-receptor neurons under high cognitive load

Working memory (WM) is a fundamental cognitive function crucial adaptive behavior. The intricate interplay between the frontal cortex and striatum in governing WM maintenance and updating remains a central question. In this study, we employed optogenetics to demonstrate that inhibiting both dorsomedial striatum (DMS) D1R- and D2R-neurons enhances WM, while their activation impairs it across T-maze and operant-based delayed-non-match-to-place (DNMTP) paradigms in mice. Notably, these neurons selectively modulate WM maintenance and retrieval, with no impact on encoding. Analysis through signal detection theory (SDT) revealed specific regulation of WM signal detection sensitivity, with no alterations in motivational or motor states during the operant DNMTP task. Interestingly, DMS D2R-neurons govern WM regulation under low cognitive load, switching to D1R-neurons as cognitive load increases. Activation of DMS D1R-neurons during the delay phase severely impairs WM under high cognitive load, a deficit rescued by optogenetic inhibition of dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), or dopaminergic terminals in DMS. Additionally, treatment with the D1R antagonist SCH39166, but not the D2R antagonist Sulpiride mitigates these impairments. Collectively, our findings propose a "relay" model wherein cognitive load-dependent WM control switches from DMS D2R- to D1R-neurons, offering nuanced, complementary, and inhibitory regulation of WM maintenance and retrieval. This study suggests potential strategies to enhance WM by promoting a suppressive state in DMS and to increase WM capacity through specific modulation of DMS D1R-neurons.