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

The cortical mechanisms that actively suppress consciousness remain poorly understood. Here, we identify a specific subset of prefrontal cortical (PFC) neurons that are activated under anesthesia while most cortical neurons are suppressed. Chemogenetic activation of these excitatory neurons enhances anesthetic potency and deepens NREM sleep, whereas their inhibition blunts anesthetic effects and disrupts sleep. We designate these cells NREM- and Anesthesia-Promoting (NAP) neurons. NAP neurons correspond to layer 5 extratelencephalic (L5 ET) neurons enriched in hyperpolarization-activated cyclic nucleotide-gated (HCN1) expression and characteristic HCN-mediated electrophysiological properties. Mechanistically distinct anesthetics act directly and specifically on PFC L5-ET neurons to increase their excitability. NAPs have sparse cortical projections and predominately innervate subcortical targets including anterior and reticular thalamic nuclei. Using a transgenic mouse line (Colgalt2-cre), we confirm that PFC L5 ET neurons are preferentially activated under anesthesia and during deep recovery NREM sleep. Finally, we show that activation of thalamic-projecting Colgalt2-expressing PFC neurons is sufficient to promote deep NREM sleep. These findings identify a novel prefrontal corticothalamic circuit that provides a shared cortical substrate for naturally occurring sleep and anesthetic-induced unconsciousness.