Bi-directional command of cognitive control by distinct prefrontal cortical output neurons to thalamus and striatum

Abstract

The medial prefrontal cortex (mPFC) steers goal-directed actions and withholds inappropriate behavior. Dorsal and ventral mPFC (dmPFC/vmPFC) circuits have distinct roles in cognitive control, but underlying mechanisms are poorly understood. In this study, we provide anatomical, behavioral, and neurophysiological evidence for distinct roles of four distinct prefrontal projection populations in behavior. We used neuroanatomical tracing techniques, chemogenetics and fiber photometry in freely behaving rats, and in vitro electrophysiology to characterize dmPFC and vmPFC outputs to distinct thalamic and striatal subdomains and show that they have dissociable roles in cognitive control. We identify four spatially segregated projection neuron populations in the mPFC. Chemogenetic silencing shows that dmPFC and vmPFC projections to lateral and medial mediodorsal thalamus subregions oppositely regulate cognitive control. In addition, superficial and deep layer dmPFC neurons projecting to striatum and thalamus divergently regulate cognitive control. Using fiber photometry, we show that these projections distinctly encode behavior. Finally, we show that postsynaptic striatal and thalamic neurons differentially process synaptic inputs from dmPFC and vmPFC, highlighting mechanisms that potentially amplify distinct pathways underlying cognitive control of behavior. Collectively, we show that mPFC output circuits targeting anatomically and functionally distinct striatal and thalamic subregions encode bidirectional command of cognitive control.