Preprint Disruption of the hypothalamic orexin system links SARS-CoV-2 infection to persistent cortical neuronal pathology, 2026, Yoon et al.

[SNT Gatchaman]

Disruption of the hypothalamic orexin system links SARS-CoV-2 infection to persistent cortical neuronal pathology

Spoiler: Authors

Gun Young Yoon; Young-Chul Jeong; Ji-Hyun Choi; Yoon Ha; Se Yeon Seo; Keun Bon Ku; Do Yeon Kim; Woo Yeon Hwang; Gi Uk Jeong; Dae-Gyun Ahn; Kyun-Do Kim; Je-Keun Rhee; Won-Ho Shin; Young-Chan Kwon

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 neurones 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 expression, we showed that augmenting orexin signalling using recombinant orexin-A/B restored NeuN expression in vitro and in vivo.

Overall, these findings identify the orexin system as a selective neural vulnerability to SARS-CoV-2 and define orexinergic circuit disruption as a mechanistic axis underlying the neurological manifestations of Long COVID.


Web | DOI | PDF | Preprint: BioRxiv | Open Access

 

[neophyte32]

Ohh... i take Quviviq (Daridorexant), orexin blocker, for 9 months to sleep with a tiny dose of benzo... is that sure ?
I m trying to stop the tiny benzo s dose for sleeping, and now Quviviq ?
What a mess...

 

[DHagen]

Ohh... i take Quviviq (Daridorexant), orexin blocker, for 9 months to sleep with a tiny dose of benzo... is that sure ?
I m trying to stop the tiny benzo s dose for sleeping, and now Quviviq ?
What a mess...

I try very hard not to react too quickly to any new papers before there's been some serious critique and discussion, and even then, remind myself that we've really never seen anything much that's actually actionable, but I still find myself having pretty much the same reaction. "Oh shit - so this means I am doing exactly the wrong thing? Have I made it permanently worse?" Ugh.

But it's mice, so might well have no relevance...

 

[Jaybee00]

Ohh... i take Quviviq (Daridorexant), orexin blocker, for 9 months to sleep with a tiny dose of benzo... is that sure ?
I m trying to stop the tiny benzo s dose for sleeping, and now Quviviq ?
What a mess...

Off topic, but do you feel quiviviq helps with your sleep?

 

[DHagen]

As I wrote above, this is obviously with mice, so who knows the ultimate importance - I am pretty skeptical. But, if this does translate to humans, it seems as though it could be really, really interesting (at least to my non-specialist eyes). I would be very interested to hear from those capable of evaluating it properly. From the start, they do seem to be attempting to address some key issues that receive frequent mention.

p.4

Neurological and neuropsychiatric manifestations—, such as cognitive impairment, sleep disturbance, fatigue, and attention—deficits, represent some of the most debilitating outcomes documented across longitudinal cohorts3-5 . Large-scale neuroimaging studies have revealed that SARS-CoV-2 infection induces long-lasting alterations in cerebral structure and function, including progressive cortical thinning, grey matter loss, and disruption of functional connectivity6-8 . These changes correlate with persistent cognitive symptoms, indicating sustained disruption of neural circuits beyond the acute phase5-7. Several mechanisms have been proposed to explain these effects. Neuropathological studies have revealed viral RNA and proteins in neurones, astrocytes, and microglia, confirming central53
nervous system (CNS) tropism9-11 . Robust systemic immune activation is associated with cognitive symptoms and blood–brain barrier breakdown 9,12 . However, the current neuroinflammatory models do not fully account for these key observations. Neurological sequelae often persist after overt inflammatory signatures wane, and all neurotropic viruses do not produce the same phenotype despite comparable immune activation 13,14. This dissociation suggests that SARS-CoV-2 targets specific neural populations or homeostatic circuits whose dysfunction sustains neurological deficits.

p.5

Beyond regulating arousal, orexin promotes neuronal survival under oxidative stress 20 and limits neuroinflammation 21. However, whether orexin signalling directly regulates cortical neuronal integrity remains unclear. Given the established roles of the orexin system in homeostatic control and neuronal protection 15-17,21,22 , we hypothesised that SARS-CoV-2 infection compromises this critical network, potentially reducing circuit resilience23,24.

 

[V.R.T.]

Possibly relevant discussion

Interesting that Younger should be talking about orexin.

I am more and more thinking that there may be a close analogy between narcolepsy/cataplexy and ME/CFS as immunological processes.

I actually think the cataplexy is almost more interesting - it can make someone completely paralysed in a matter of seconds and then get back to normal in minutes, all as a result of being pleasantly surprised! I think it emphasises just how little we understand about the way the brain controls muscle activity.

 

[neophyte32]

Hors sujet, mais trouvez-vous que Quiviviq vous aide à mieux dormir ?

Off topic, but do you feel quiviviq helps with your sleep?

I don't know. Since I became severely ill (a year ago), my sleep has deteriorated. My nervous system is under strain. Daridorexant alone doesn't help... I also have to take 1.5 mg of bromazepam (but I'm weaning myself off benzodiazepines, which is dangerous because an average dose of benzodiazepines immediately sends me back to almost moderate levels)... I don't know how to manage my sleep anymore; my nervous system is broken. Anyway, end of off topic.