COVID-19 induces CNS cytokine expression and loss of hippocampal neurogenesis

Abstract

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with acute and postacute cognitive and neuropsychiatric symptoms including impaired memory, concentration, attention, sleep and affect. Mechanisms underlying these brain symptoms remain understudied. Here we report that SARS-CoV-2-infected hamsters exhibit a lack of viral neuroinvasion despite aberrant blood–brain barrier permeability. Hamsters and patients deceased from coronavirus disease 2019 (COVID-19) also exhibit microglial activation and expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the medulla oblongata, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uraemia or trauma. In the hippocampal dentate gyrus of both COVID-19 hamsters and humans, we observed fewer neuroblasts and immature neurons. Protracted inflammation, blood–brain barrier disruption and microglia activation may result in altered neurotransmission, neurogenesis and neuronal damage, explaining neuropsychiatric presentations of COVID-19. The involvement of the hippocampus may explain learning, memory and executive dysfunctions in COVID-19 patients.

Anosmia in COVID-19 could be associated with long-term deficits in the consolidation of procedural and verbal declarative memories

“…Studies have described how the virus can infect microglia and astrocytes, causing activation of these glial cells, and this effect may affect communication between neurons and neurogenesis (Vargas et al, 2020). In fact, neurogenesis is altered in the hippocampus of patients and rodents infected by the virus (Soung et al, 2022). Neuroimaging studies have detected that the hippocampus, 10.3389/fnins.2022.1082811 parahippocampal cortex, and amygdala, which are brain areas connected to the olfactory bulb, show degeneration and volume reduction in subjects suffering from mild COVID-19 infection (Douaud et al, 2022).…”

Neurological post‐acute sequelae of SARS‐CoV‐2 infection

“…Recent studies have demonstrated SARS‐CoV‐2 infection in golden hamsters develop inflammatory reaction in the olfactory bulb and epithelium without viral particles 164 . Similarly, hamsters and patients who died from COVID‐19 showed microglial activation and expression of interleukin 1β and 6, especially within the hippocampus and the medulla oblongata 165 . A large number and well organized human brain study showed that COVID‐19 brain changes are more likely caused by blood‐borne immune mediators and trans‐synaptic gene expression changes arising from the olfactory bulb deafferentation 166 .…”

“…164 Similarly, hamsters and patients who died from COVID-19 showed microglial activation and expression of interleukin 1β and 6, especially within the hippocampus and the medulla oblongata. 165 A large number and well organized human brain study showed that COVID-19 brain changes are more likely caused by blood-borne immune mediators and trans-synaptic gene expression changes arising from the olfactory bulb deafferentation. 166 Further research may clarify the mechanism of PASC and aid in the development of effective treatment strategies.…”

Reviewing the Potential Links between Viral Infections and TDP-43 Proteinopathies

“…Most interestingly, in addition to respiratory disease, several abnormalities in the central nervous system such as cognitive decline, neuronal autoimmune disease, and delirium have been observed in patients suffering from SARS-CoV-2 pathology [ 63 ]. As a result, it has been suggested that coronaviruses contribute to trigger these neuropathologies through different mechanisms, including direct neurotoxic effects on synaptic transport [ 64 ], as well as neuronal inflammation [ 65 ].…”