Abstract Background Survivors of COVID-19 frequently report psychiatric and cognitive sequelae. The origin of such sequelae has not been determined, as it has been a challenge to resolve whether these symptoms have a viral origin or are related to the contextual stressors associated with the pandemic. In the current study, we used a mouse model of post-acute sequelae of SARS-CoV-2 infection (PASC) to evaluate the neurobiological nature of the sequelae without the interference of the contextual effects on behavior following SARS-CoV-2 infection. Results SARS-CoV-2 infection resulted in behavioral deficits related to cognition but not anxiety- or depression-like behavior. The cognitive deficits were affected by the severity of the acute disease. Cytokine and chemokine levels as well as kynurenine pathway metabolites were significantly altered in the brains of infected mice. Both cytokine/chemokine levels and kynurenine pathway metabolites correlated with the severity of the acute disease. Microbiome taxonomic profiling revealed significant differences between groups, suggesting that specific bacterial species may be associated with the development of PASC. Conclusions These results suggest that SARS-CoV-2 infection leads to cognitive deficits in PASC, influenced by the severity of the acute disease. In contrast, PASC anxiety- and depression-like behavior was not related to the viral infection itself. This could indicate that PASC anxiety and depression is more linked to contextual stressors related to the pandemic, rather than the viral infection per se. Additionally, our results points to a role of cytokines and in particular metabolites of the kynurenine pathway in PASC, suggesting their potential as biomarkers and targets for pharmacological treatment.
Santi et al. (2025) studied this question.