Activation of LH orexin neurons and VTA dopamine neurons is involved in anesthesia/surgery-induced sleep–wake disorders and delirium-like behaviors in mice

Postoperative delirium (POD) and sleep disorders are common surgical complications with a close clinical association, suggesting shared pathophysiological mechanisms mediated by neurotransmitters and neural circuits. Using a mouse model of laparotomy under sevoflurane anesthesia, we assessed delirium-like behaviors (buried food, open field, and Y-maze tests) and sleep alterations (EEG/EMG). Hypothalamic orexin A and midbrain dopamine levels were measured by ELISA. Neural activation was evaluated via c-Fos immunohistochemistry and immunofluorescence staining of lateral hypothalamus (LH) orexin and ventral tegmental area (VTA) dopamine neurons. Tyrosine hydroxylase (TH) expression in the VTA was detected by Western blot. Anesthesia/surgery induced sleep disorders, altered sleep–wake architecture and delirium-like behaviors. Following anesthesia/surgery, c-Fos protein expression was increased in neurons of the LH and ventromedial hypothalamic nucleus (VMH), while it was decreased in sleep-promoting brain regions, including the ventrolateral preoptic area (VLPO) and median preoptic nucleus (MnPO). Additionally, anesthesia/surgery led to increased activation of orexin neurons in the LH and dopamine neurons in the VTA. Hypothalamic orexin A levels and midbrain dopamine concentrations were elevated, along with increased tyrosine hydroxylase (TH) expression in the VTA. Administration of the dual orexin receptor antagonist suvorexant via intraperitoneal injection reduced the activation of VTA dopamine neurons, decreased TH expression, and lowered dopamine levels in these mice. The activation of LH orexin neurons and VTA dopamine neurons is involved in anesthesia/surgery-induced sleep–wake disorders and delirium-like behaviors. The dual orexin receptor antagonist suvorexant ameliorates these abnormalities, highlighting a potential therapeutic target.