40% of mice were found to have infectious SARS-CoV-2 and viral RNA in their brain tissue. However, 60% had no infectious virus and low levels of viral RNA present. Only 1/6 animals was SARS-CoV-2+ in its brain tissue 7 days after infection (dpi = days post infection). The virus was found throughout the cerebral cortex and seemed to avoid the olfactory bulb and cerebellum. This suggests that SARS-CoV-2 can cross the blood-brain barrier and does not travel across the cribriform plate to infect neuronal processes near the initial infection site in the nose. 

Figure: SARS-CoV-2 RNA staining (red) of one infected mouse brain. RNA is present in the cerebral cortex, and not in cerebellar or olfactory tissue.

SARS-CoV-2 Infection in K18-hACE2 Mice Brain Tissue

- K18-hACE2 mice brain tissue shows no viral infection in olfactory tissue

Smith College

1. Entry through the naval cavity: because intranasal drug delivery bypasses the blood brain barrier to delivery therapeutic agents directly to the CNS, it is thought that SARS-CoV-2 can likewise infect the brain via olfactory nerves.
  
2. Entry through the lungs: previous speculation that SARS-CoV could infect the , brainstem via chemoreceptors and mechanoreceptors in the respiratory system lend possibility for a neurotropic mechanism for SARS-CoV-2.

These hypotheses have yet to be validated.  
Figure below shows coronavirus infection mechanisms (Wu et. al).

Hypothesized Mechanisms for SARS-CoV-2 Direct Invasion of the CNS 

Reports Supporting SARS-CoV-2 Direct CNS Invasion Through the Lungs

- Increasing data suggest that ACE2 is not appreciably expressed in neurons in the brain at either the RNA or protein level. 
- scSeq analysis of human prefrontal cortex and hippocampus failed to identify any ACE2- expressing cells 
- multiple immunostaining studies have demonstrated ACE2 expression in brain vasculature but not in neurons or glia 


Support Against SARS-CoV-2 Direct Invasion of Neurons and Glial Cells

- Potential neuroinvasive pathways of SARS-CoV-2: Deciphering the spectrum of neurological deficit seen in coronavirus disease-2019 (COVID-19)
- SARS-CoV-2 entry through the blood brain barrier (BBB)

Potential neuroinvasive pathways of SARS-CoV-2

Viral RNA and protein found in olfactory mucosa and CNS. SARS-CoV-2 suggested to exploit the neural–mucosal interface as a port of entry into the CNS. 

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