Top-down modulation of sensory processing allows the animal to select inputs most relevant to current tasks. We found that the cingulate (Cg) region of mouse frontal cortex powerfully influences sensory processing in primary visual cortex (V1) through long-range projections that activate local GABAergic circuits. Optogenetic activation of Cg neurons enhanced V1 neuron responses and improved visual discrimination. Focal activation of Cg axons in V1 caused a response increase at the activation site but decrease at nearby locations (center-surround modulation). While somatostatin-positive GABAergic interneurons contributed preferentially to surround suppression, vasoactive intestinal peptide-positive interneurons were crucial for center facilitation. Long-range cortico-cortical projections thus act through local microcircuits to exert spatially specific top-down modulation of sensory processing.

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.

When faced with problems, we can flexibly change our ways of thinking or our point of view. Our cognitive flexibility arises from this ability of shifting cognitive sets. To elucidate how this dynamic process is implemented in the primate brain, single-unit activity was recorded from the posterior parietal cortex (PPC) of two monkeys performing analogs of the Wisconsin Card Sorting Test, which is most commonly used to test cognitive flexibility in humans. We successfully trained the monkeys to promptly perform set shifting, mostly within a single trial, and found shift-related activity: PPC neurons were transiently activated when the monkeys shifted from one cognitive set to another, but not when they shifted in the opposite direction. This shift-related activity emerged about 4 s before the actual behavioral responses, and it well predicted whether the cognitive set would be successfully shifted. These results provide insights into single-unit level mechanisms of cognitive flexibility.