Disruption of the hypothalamic orexin system links SARS-CoV-2 infection to persistent cortical neuronal pathology
Long COVID frequently presents with persistent neurological symptoms, including cognitive impairment, fatigue, and sleep disturbances, yet its underlying mechanisms remain unclear. Here, we show that SARS-CoV-2 infection induces lasting cortical neuronal injury and hypothalamic orexin (hypocretin) dysfunction in vivo. In K18-hACE2 and wild-type BALB/c mice, viral RNA persists in the brain and coincides with focal loss of NeuN-positive cortical neurons beyond the acute infection. SARS-CoV-2, but not influenza A virus, triggers rapid and sustained suppression of hypothalamic orexin expression, defining a virus-specific neuropathological signature. Given the observed downregulation of orexin and focal cortical NeuN expression, we show that augmenting orexin signaling with recombinant orexin-A/B restores NeuN expression in vitro and in vivo. These findings identify the orexin system as a selective neural vulnerability of SARS-CoV-2 and define orexinergic circuit disruption as a mechanistic axis underlying the neurological manifestations of Long COVID.