2. Academic Validation
  3. SARS-CoV-2 infection is associated with hypothalamic orexin suppression and persistent cortical NeuN attenuation

SARS-CoV-2 infection is associated with hypothalamic orexin suppression and persistent cortical NeuN attenuation

  • J Neuroinflammation. 2026 May 5;23(1):216. doi: 10.1186/s12974-026-03842-y.
Gun Young Yoon # 1,  Young Cheul Chung # 2 3,  Ji Hyun Choi 1,  Yun Ha 4,  Se Yeon Seo 4,  Keun Bon Ku 1,  Do Yeon Kim 1 5,  Woo Yeon Hwang 1 5,  Gi Uk Jeong 1 6,  Dae-Gyun Ahn 1,  Kyun-Do Kim 1,  Je-Keun Rhee 4 7,  Won-Ho Shin 8 9,  Young-Chan Kwon 10 11
Affiliations

Affiliations

  • 1 Center for Infectious Diseases Vaccine and Diagnosis Innovation (CEVI), Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
  • 2 Division of Advanced Predictive Research, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
  • 3 Human and Environmental Toxicology, University of Science and Technology (UST), Daejeon, 34114, Republic of Korea.
  • 4 Department of Bioinformatics & Life Science, Soongsil University, Seoul, 06978, Republic of Korea.
  • 5 College of Pharmacy, Korea University, Sejong, 30019, Republic of Korea.
  • 6 Department of Microbiology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
  • 7 AI-Bio Convergence Research Institute, Soongsil University, Seoul, 06978, Republic of Korea.
  • 8 Division of Advanced Predictive Research, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea. [email protected].
  • 9 Human and Environmental Toxicology, University of Science and Technology (UST), Daejeon, 34114, Republic of Korea. [email protected].
  • 10 Center for Infectious Diseases Vaccine and Diagnosis Innovation (CEVI), Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea. [email protected].
  • 11 Medical Chemistry and Pharmacology, University of Science and Technology (UST), Daejeon, 34114, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 42087199 DOI: 10.1186/s12974-026-03842-y
Abstract

Long COVID frequently presents with persistent neurological symptoms, including cognitive impairment, fatigue, and sleep disturbances; however, 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 persisted in the brain and coincided with focal loss of Neuronal Nuclei (NeuN)-positive cortical neurons beyond acute Infection. SARS-CoV-2, but not the influenza A virus, triggered rapid and sustained suppression of hypothalamic orexin expression, defining a virus-specific neuropathological signature. Considering the downregulation of orexin and focal cortical NeuN attenuation, we found that exogenous orexin-A/B supplementation increased NeuN abundance in vitro and in vivo under the tested conditions. Overall, these findings identify the orexin system as a candidate neural vulnerability to SARS-CoV-2 and suggest that orexinergic dysfunction may contribute to the neurological manifestations of Long COVID.

Keywords

Hcrt (Orexin); Long COVID; NeuN; Neurological pathogenesis; SARS-CoV-2.

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