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 preferentially active under anesthesia while most neurons are suppressed. Chemogenetic activation of these excitatory neurons enhances anesthetic potency and deepens NREM sleep, whereas their inhibition blunts anesthetic effects. We identify these NREM and Anesthesia Promoting (NAP) neurons as PFC Layer 5 extratelencephalic (L5 ET) neurons. Remarkably, NAPs have sparse cortical projections and predominately communicate with subcortical nuclei including anterior and reticular thalamic nuclei, hypothalamus, and claustrum. We identify a transgenic mouse line that labels L5 ET neurons and verify that PFC L5 ET neurons are uniquely activated under anesthesia. Furthermore, we show that activation of PFC L5 ET neurons promotes deep NREM sleep. These findings identify a unique excitatory PFC circuit that promotes both naturally-occurring and drug-induced unconsciousness, with implications for both sleep regulation and anesthetic action.