Convergent Control of NREM Sleep and Anesthesia by Prefrontal Layer 5 Extratelencephalic Neurons

The cortical mechanisms governing the transition from consciousness to unconsciousness remain poorly understood. While most cortical neurons are suppressed during NREM sleep and anesthesia, we identify a distinct population of prefrontal cortical (PFC) neurons that are preferentially active in both states. Chemogenetic activation of these excitatory NREM- and Anesthesia-Promoting (NAP) neurons enhances anesthetic potency and deepens NREM sleep, whereas their inhibition blunts anesthetic effects. Anatomical, biophysical, and transcriptomic, biophysical, and anatomical analyses reveal that NAPs are Layer 5 extratelencephalic (L5 ET) neurons that form reciprocal connections with subcortical arousal centers including anterior and reticular thalamic nuclei, hypothalamus, and claustrum. Moreover, L5 ET specific recordings and chemogenetic manipulations reproduced NAP-like activity under anesthesia and its ability to promote NREM sleep. These findings define an excitatory, molecularly and anatomically characterized PFC circuit that contributes to loss of consciousness, consistent with a corticothalamic mechanism of arousal-state transitions in sleep and anesthesia.