Inspiring cognitive inference in a cortical network during REM sleep

Sleep has been proposed to facilitate inference, insight, and innovative problem-solving. However, it remains unclear how and when the subconscious brain can create novel ideas. Here, we show that cortical offline, but not online, activity is essential for inference evolution and that activity during rapid-eye movement (REM) sleep is sufficient to inspire inference from inadequate knowledge. In a transitive inference paradigm, mice gained the inference one day, but not shortly, after complete training. Inhibiting the neuronal computations in the anterior cingulate cortex (ACC) during post-learning sleep, but not during wakefulness, disrupted the inference without affecting the original memories. Furthermore, after insufficient learning, artificial activation of medial entorhinal cortex-ACC dialogue during only REM sleep created inferential knowledge. These findings establish causal evidence for the necessity and sufficiency of REM sleep in reorganizing existing knowledge to achieve novel inference, thereby highlighting the power of the idling brain in creativity and cognitive flexibility.