When scientists at Karolinska Institutet in Sweden infected brain organoids (pinhead-sized pieces of brain tissue grown in a lab) with the virus that causes COVID, they found that accelerated the destruction of connections between neurons called synapses.
The discovery adds to the growing understanding of how SARS-CoV-2 enters the central nervous system and causes disease. In the last two years the scientific community has documented itself long-standing neural and behavioral problems in patients with COVID-19. One such problem, known as brain fog, causes disorientation, memory loss, chronic headaches and numbness, and affects nearly 40% of patients with long-term COVID.
(Related: Long COVID remains a mystery: We follow a patient’s struggle to seek treatment)
Carl Sellgren, a psychiatrist and cell biologist, and his team at Karolinska Institutet set out to use organoids to try to find out what SARS-CoV-2 does in the brain and whether it might help explain neurological symptoms.
Their research led them to conclude that destroying too many connections between neurons, or excessive pruning, is what may be causing brain fog in long-term COVID patients. “This could be one of (probably) many reasons why we are seeing a range of neurological symptoms, even after the infection has long since cleared up,” says Samudyata, a postdoctoral researcher at Karolinska Institutet who led the study. . his works have only a name.
Ana Osório Oliveira, co-author and neuroscientist in Sellgren’s lab, says that “it was quite surprising that very small amounts of viruses could spread quite rapidly in organoids and knock out too many synapses.” The research was published in the journal Molecular psychiatry.
“This study fits perfectly with ours and others,” says Madeline Lancaster, a neurobiologist at the MRC Laboratory of Molecular Biology in Cambridge, UK. Using brain organoids, Lancaster’s research He revealed that SARS-CoV-2 damages the protective barrier of the brain. When this barrier is broken, pathogens, aberrant immune cells, and inflammatory compounds can enter the cerebrospinal fluid and brain.
(Related: From inflammation to depression: electricity is revolutionizing medicine)
Pruning the connections between neurons is essential for learning
The brain is made up of a dense and dynamic network of nerve cells that communicate through synapses that change as humans learn. “Synapses are essentially how cells talk to each other and how information is transmitted from one part of the brain to another,” says Lancaster.
Synapses are responsible for all brain functions, from memory to movement control and emotion perception, and are constantly being remodeled. “That’s how we learn,” she says.
Junctions between neurons that communicate with each other often have multiple knob-shaped ends that produce neurotransmitters (chemicals that transmit signals to other neurons) which then travel through the spaces between neurons known as the synaptic cleft. Conversely, neurons that communicate less, or not at all, have fewer synapses because they are killed, or lopped off, by immune cells called microglia. The microglia they make up up to 17% of the cell population in some parts of the human brain and perform housekeeping tasks migrating through the brain eating dead cells and removing weak synapses.
(Related: To what extent can COVID-19 affect our personality?)
Though synaptic pruning is more active in developing brains, such as those of fetuses and newborns, it continues in healthy brains throughout life and is needed to encode new memories and eliminate those that the brain no longer needs. Synaptic pruning is also essential for the brain to recover from an injury; it strengthens synapses as lost skills are relearned and removes those that no longer work.
Using brain organoids to study neuronal damage
Studying a direct relationship between COVID-19 and cognitive dysfunction, such as brain fog, is difficult in living brains. For this reason, studies are usually limited to cadavers of patients with COVID-19. But brain organoids, called minibrains, allow scientists to see in real time how SARS-CoV-2 affects living tissue.
Using brain organoids, Oliveira and his colleagues found that the virus itself didn’t prune synaptic connections directly, but instead activated microglia.
(Related: Even mild COVID-19 can shrink your brain)
“We found that after SARS-CoV-2 infection, somehow microglia become immunoreactive and eat more synapses than normal,” says Samudyata.
The study is important because it clearly shows quantitative differences in microglial activity after COVID-19 and its effect on synapses, says Ayush Batra, a neurologist at Northwestern University Feinberg School of Medicine.
But excessive pruning of synapses can be harmful and has been linked to neurodevelopmental disordersas the schizophreniaand with neurodegenerative conditionssuch as Alzheimer’s disease and Parkinson’s disease.
If the excessive removal of synapses that occurs in brain organoids after SARS-CoV-2 infection also occurs in people, it could destroy vital connections and explain why some COVID-19 patients suffer long-lasting neurological symptoms term.
“Excessive deletion of synapses is expected to affect a person’s ability to form new memories or recall existing ones, and could help explain the slow brain function seen in brain fog,” says Lancaster.
(Related: Is Alzheimer’s caused by viruses? COVID-19 gives clues about it)
This is consistent with studies conducted at the US National Institutes of Health that found this antibodies produced in response to SARS-CoV-2 can attack cells that line blood vessels in the brain, causing damage and inflammation (which activates microglia) even if the virus does not enter the brain directly. This may explain why, as Batra’s team has shown, some long-term COVID patients who are not sick enough to be hospitalized keep experimenting neurological symptoms over a year after the initial infection.
Does loss of synapses cause brain shrinkage?
And she studies also from the UK they demonstrated that even mild COVID-19 can shrink the brain through loss of gray matter (the outermost layer of the brain made up of cell bodies and is vital for movement, memory and emotion control), causing physical changes equivalent to a decade of aging . “It is not yet clear to us what might contribute, in general, to the loss of gray matter volume or thickness observed on MRIs,” says Gwenaëlle Douaud, a neuroscientist at the University of Oxford in the UK who led the study.
(Related: COVID-19 causes depression, but not in the way you imagine)
Although synapse deletion, as Samudyata’s study shows, could explain a small percentage of the change in gray matter, Douaud says, more studies combining imaging with tissue sections are needed to determine the other factors leading to the shrinkage. of the brain.
Overactive microglia can cause problems in other ways. The current study also shows that the pattern of genes turned on and off by microglia in brain organoids following SARS-CoV-2 infection mimics the gene activity seen in neurodegenerative disorders. This might explain because there is a three times greater risk of developing neurological conditions or psychiatric disorders in the six months following COVID-19 infection compared to those uninfected. In adults over the age of 65, the risk of developing dementia after a COVID-19 infection it is nearly double that of other respiratory infections.
However, scientists caution that much more research is needed to understand the effect of SARS-CoV-2 infection on the brain. Because organoids resemble immature cells (such as those found in the fetal or postnatal state), this limits extrapolation of results to mature adult brain cells.
“Although these data are intriguing and indicate that proinflammatory microglia play a role in the pathological mechanisms underlying long-term COVID, more studies are needed to validate and build on these findings,” says Oliver Harschnitz, group leader at the Center for Research in Neurogenomics at the Technopole Institute of Milan (Italy).
It’s also not known whether long-term COVID has irreversible effects on the brain. So as the pace of vacations and indoor winter activities picks up, Samudyata advises taking preventative measures and staying up to date on vaccinations to minimize the chance of contracting COVID again and again. While it’s not clear how the virus exerts deleterious effects on the brain, it is clear that it causes damage.
