This study investigates the long-term neurological consequences of SARS-CoV-2 infection in mice, focusing on the olfactory bulb (OB) and substantia nigra (SN). Despite the absence of infectious virus or viral RNA in the brain, the researchers observed persistent changes in neurotransmitter expression and neuroinflammation. Specifically, they found a significant decrease in tyrosine hydroxylase (TH) expression in the OB and a reduction in TH-positive neurons in the SN, which are key markers of dopaminergic neuron loss. These changes were accompanied by increased levels of proinflammatory cytokines and microglial activation. RNAseq analysis revealed persistent microglial activation and upregulation of genes associated with inflammation and neurodegeneration. Behavioral tests showed altered motor function and anxiety-like behavior in infected mice. Antiviral treatment with nirmatrelvir and molnupiravir reduced virus titers and lung inflammation but did not prevent neurological abnormalities. Similar findings were observed in deceased COVID-19 patients, where TH expression was reduced in the SN. The study suggests that the host immune response, rather than the virus itself, may be a major driver of these neurological sequelae, highlighting the potential for chronic inflammation to contribute to neurodegenerative processes.This study investigates the long-term neurological consequences of SARS-CoV-2 infection in mice, focusing on the olfactory bulb (OB) and substantia nigra (SN). Despite the absence of infectious virus or viral RNA in the brain, the researchers observed persistent changes in neurotransmitter expression and neuroinflammation. Specifically, they found a significant decrease in tyrosine hydroxylase (TH) expression in the OB and a reduction in TH-positive neurons in the SN, which are key markers of dopaminergic neuron loss. These changes were accompanied by increased levels of proinflammatory cytokines and microglial activation. RNAseq analysis revealed persistent microglial activation and upregulation of genes associated with inflammation and neurodegeneration. Behavioral tests showed altered motor function and anxiety-like behavior in infected mice. Antiviral treatment with nirmatrelvir and molnupiravir reduced virus titers and lung inflammation but did not prevent neurological abnormalities. Similar findings were observed in deceased COVID-19 patients, where TH expression was reduced in the SN. The study suggests that the host immune response, rather than the virus itself, may be a major driver of these neurological sequelae, highlighting the potential for chronic inflammation to contribute to neurodegenerative processes.