Delay Activity of Specific Prefrontal Interneuron Subtypes Modulates Memory-Guided Behavior

Memory-guided behavior requires maintenance of task-relevant information without sensory input, but the underlying circuit mechanism remains unclear. Calcium imaging in mice performing a delayed Go/No-Go task revealed robust delay activity in dorsomedial prefrontal cortex (dmPFC), with different pyramidal neurons signaling Go and No-Go action plans. Inhibiting pyramidal neurons by optogenetically activating somatostatin (SST)- or parvalbumin (PV)-positive interneurons, even transiently during an early delay period, impaired task performance primarily by increasing inappropriate Go responses. In contrast, activating vasoactive intestinal peptide (VIP)-positive interneurons enhanced the behavioral performance and neuronal representation of action plans. Furthermore, while the natural activity of SST and PV neurons was strongly biased toward Go trials, VIP neurons were similarly active in Go and No-Go trials. SST/VIP neuron activation also impaired/enhanced performance of a delayed two-alternative forced choice task. Thus, dmPFC is a crucial component of the short-term memory network, and activation of its VIP neurons improves memory retention.