COVID-19 induces neuroinflammation and loss of hippocampal neurogenesis

Abstract

Infection with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is associated with onset of neurological and psychiatric symptoms during and after the acute phase of illness1-4. Acute SARS-CoV-2 disease (COVID-19) presents with deficits of memory, attention, movement coordination, and mood. The mechanisms of these central nervous system symptoms remain largely unknown.In an established hamster model of intranasal infection with SARS-CoV-25, and patients deceased from COVID-19, we report a lack of viral neuroinvasion despite aberrant BBB permeability, microglial activation, and brain expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the inferior olivary nucleus of the medulla, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uremia or trauma. In the hippocampus dentate gyrus of both COVID-19 hamsters and humans, fewer cells expressed doublecortin, a marker of neuroblasts and immature neurons.Despite absence of viral neurotropism, we find SARS-CoV-2-induced inflammation, and hypoxia in humans, affect brain regions essential for fine motor function, learning, memory, and emotional responses, and result in loss of adult hippocampal neurogenesis. Neuroinflammation could affect cognition and behaviour via disruption of brain vasculature integrity, neurotransmission, and neurogenesis, acute effects that may persist in COVID-19 survivors with long-COVID symptoms.

Morphological, cellular and molecular basis of brain infection in COVID-19 patients

“…While that study analyzed hospitalized patients, we evaluated individuals that did not require hospitalization (i.e., had mild respiratory symptoms); nonetheless, we observed notable alterations in cortical thickness. Importantly, some of these alterations correlated with the severity of symptoms of anxiety and impaired cognition, which is consistent with previous literature 51,74,75 .…”

“…Our study demonstrates structural and functional alterations in the brain tissue of COVID-19 patients which correlate with neuropsychiatric and neurological dysfunctions. This study and other reports showing alterations in brain structure and the manifestation of neurological symptoms in COVID-19 patients 49–51 raise a debate on whether these clinical features are a consequence of peripheral changes or the potential ability of the virus to invade the CNS. Our findings support the latter, at least in part, as we detect SARS-CoV-2 in brain tissue collected from patients who died of COVID-19.…”

Is Central Sensitisation the Missing Link of Persisting Symptoms after COVID-19 Infection?

“…Central cytokines and chemokines play a role in inducing hyperalgesia and allodynia, while a sustained increase leads to chronic widespread pain at several body locations, suggesting that neuroinflammation drives widespread chronic pain through central sensitisation [ 47 ]. Therefore, neuroinflammation is expected to play a role in persisting symptoms after COVID-19 infection as well [ 48 , 49 ].…”

Neuroinflammation and COVID-19

“…Histopathological analyses of SARS-CoV-2 infected primates identified evidence of neuronal death [ 67 ]. Two publications demonstrated that rodent models of acute COVID-19 exhibit decreased neurogenesis in the dentate gyrus region of the hippocampus and a loss of myelination in subcortical white matter tracts, with the former study confirming loss of neurogenesis in humans [ 22 , 68 ]. Multiple post-mortem studies of human and primate tissue noted increased GFAP staining, but more data is needed to understand alterations in astrocyte function and the sources of astrocyte activation [ 41 , 42 ].…”