Millions of people have or have had Long COVID. It is a disease whose exact mechanisms are unknown and for which many patients are unable to find medical help. Long COVID is defined as respiratory or extra-respiratory symptoms that appear or persist for several months after infection with SARS-CoV-2. We are particularly interested in neurological or neuropsychiatric symptoms such as anxiety, depression, and memory impairment. We have previously shown that SARS-CoV-2 is neuroinvasive, capable of infecting neurons and being transported along axons. Now, using the golden hamster model for long Covid that we developed, we show that the virus can persist in the brain for more than 80 days after the infection. This persistent infection is accompanied by dysregulation of several immuno-metabolic pathways in the brainstem, such as the dopaminergic and glutamatergic signaling, and energetic metabolism. Remarkably, using a set of different behavioral tests, we also demonstrate that the infected hamsters exhibit persistent or late-onset signs of anxiety, depression and memory impairment, reproducing some features of long Covid in humans.

Immuno-metabolic alterations and the viral persistence in the brain may partly explain the persistence or appearance of cognitive or neuropsychiatric symptoms. Our model enables a comprehensive virological, metabolic and behavioral study of a disease for which there are currently only symptomatic treatments. Identifying these fundamental mechanisms could be of great interest in understanding the cognitive and/or neuropsychiatric alterations observed with other neuroinvasive pathogens.