Orexin promotes arousal from general anaesthesia, but the mechanisms are unclear. The nucleus accumbens (NAc), a target of orexin neurons, helps regulate consciousness. During isoflurane anaesthesia, orexinergic afferents in the NAc were wake-active. Optogenetic activation of these terminals prolonged induction time, shortened emergence time, and reduced the burst suppression ratio from 67.4% to 14.5% during 1.4 vol% isoflurane anaesthesia. Microinjection of orexin-A into the NAc promoted arousal. Orexin-1 receptors were expressed mainly in NAc D1 receptor-positive neurons. Activation increased D1R+ neuron firing from 0.77 to 2.53 spikes per second and restored NAc-to-frontal cortex coherence. Orexin restores communication between the NAc and frontal cortex by upregulating D1R+ neuron activity, thereby promoting arousal from isoflurane anaesthesia.
Early administration of S-Ketamine (on day 1) after trauma significantly improves PTSD symptoms in rodent models, particularly impaired fear extinction, while late administration (day 7) does not. The firing and burst rates of dopamine neurons in the ventral tegmental area (VTA) decrease after PTSD modeling and are restored only by early S-Ketamine. These VTA dopamine neurons respond to conditioned stimuli and help replace aversive memory encoding during fear extinction. Inhibiting the VTA-to-orbitofrontal cortex (OFC) pathway blocks S-Ketamine's therapeutic effect. A non-invasive brain stimulation targeting the OFC sensitizes cortical dopaminergic transmission and extends the effective time window of S-Ketamine for anti-PTSD treatment.