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. Using a mouse model of post-acute sequelae of SARS-CoV-2 infection (PASC), we examined neurobiological mechanisms underlying these effects without the confounding influence of contextual factors. RESULTS: SARS-CoV-2 infection induced cognitive, but not anxiety- or depression-like, behavioral deficits. Cognitive impairments correlated with severity of the acute disease. Infected mice showed significant alterations in brain cytokine levels, as well as in kynurenine pathway (KP) metabolites, both of which were associated with acute disease severity. Microbiome taxonomic profiling revealed group-specific differences, indicating that certain bacterial species may contribute to PASC development. CONCLUSIONS: Our findings suggest that SARS-CoV-2 infection causes cognitive deficits in PASC, modulated by acute disease severity, while anxiety- and depression-like behaviors appear unrelated to the viral infection itself. This supports the idea that such psychiatric symptoms may stem from pandemic-related stressors rather than infection. Altered cytokine signaling and KP metabolism may play key roles in the pathophysiology of PASC, identifying potential biomarkers and therapeutic targets.