When scientists at the Karolinska Institute in Sweden infected brain organoids – pinhead-sized pieces of brain tissue grown in the lab – with the virus that causes COVID, they found it accelerated the destruction of connections between neurons called synapses.
The finding adds to the growing understanding of how SARS-CoV-2 enters the central nervous system and causes disease. Over the past two years, scientists have documented long-lasting neural and behavioral problems in patients with COVID-19. One such condition, known as brain fog, causes disorientation, memory loss, chronic headaches and numbness, and it affects almost 40% of long-term COVID patients.
Carl Sellgren, a psychiatrist and cell biologist, and his team at the Karolinska Institute decided to use the organoids to try to find out what SARS-CoV-2 does to the brain and if it could help explain neurological symptoms.
Their research led them to conclude that destroying too many connections between neurons, or excessive pruning, can cause brain fog in long COVID patients. “This could be one of the many reasons – probably – why we observe a range of neurological symptoms, even after the infection has long been cleared,” says Samudyata, a postdoctoral researcher at the Karolinska Institute who led the study. study and bears a name.
Ana Osório Oliveira, co-author and neuroscientist in Sellgren’s lab, says, “It was quite striking that very small amounts of virus could spread quite rapidly through organoids and knock out an excessive number of synapses. The research was published in the journal Molecular psychiatry.
“This study fits perfectly with ours and several others,” says Madeline Lancaster, a neurobiologist at the MRC’s Molecular Biology Laboratory, Cambridge, UK Using brain organoids, Lancaster’s research found that SARS- CoV-2 damages the protective barrier of the brain. When this barrier is breached, pathogens, aberrant immune cells, and inflammatory compounds can enter the cerebrospinal fluid and the brain.
Pruning 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 basically how cells talk to each other and how information is passed from one part of the brain to another,” Lancaster explains.
Synapses are responsible for all brain functions, from memory to movement control to feeling emotions, and they are constantly being remodeled. “That’s how you learn,” she says.
Junctions between neurons that talk to each other often have more button-like ends that produce neurotransmitters – chemicals that transmit signals to other neurons – which then cross the gaps between neurons known as the cleft. synaptic. Conversely, neurons that communicate less or not at all have fewer synapses because they are eliminated or pruned by immune cells called microglia. Microglia make up up to 17% of the cell population in some parts of the human brain and perform household chores by migrating through the brain eating dead cells and scavenging weak synapses.
Although synaptic pruning is most active in developing brains, such as in fetuses and infants, it continues in healthy brains throughout life and is necessary to encode new memories and erase those whose brain no longer needs. Synaptic pruning is also essential for the brain to recover from injury. strengthen synapses as lost skills are relearned and remove those that no longer work.
Using brain organoids to study neuronal damage
Studying a direct link between COVID-19 and cognitive dysfunctions, such as brain fog, is difficult in living brains. This is why studies are often limited to cadavers of COVID-19 patients. But brain organoids, called mini-brains, 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 did not directly prune synaptic connections, but activated microglia.
“We found that following SARS-CoV-2 infection, microglia somehow become immunoreactive and eat more synapses than normal,” says Samudyata.
The study is important because it clearly shows the 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 too much synapse pruning can be detrimental and has been linked to neurodevelopmental disorders such as schizophrenia, as well as neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
If the excessive synapse removal that occurs in brain organoids after SARS-CoV-2 infection also occurs in humans, it may destroy vital connections and explain why some people with COVID-19 suffer from long-term neurological symptoms.
“Too much synapse removal would be expected to affect a person’s ability to form new memories or recall existing ones, and could help explain the slow brain functions seen in brain fog” , says Lancaster.
This is consistent with studies done at the US National Institutes of Health which found that antibodies produced in response to SARS-CoV-2 can attack cells lining blood vessels in the brain, causing damage and inflammation – which activate microglia – even if the virus does not enter the brain directly. This may explain why, as Batra’s team showed, some long-time COVID patients who aren’t sick enough to be hospitalized continue to show neurological symptoms beyond a year after the initial infection.
Does Loss of Synapses Cause Brain Shrinkage?
A British study has also shown that even mild COVID-19 can shrink the brain through the loss of gray matter – the outermost layer of the brain which is made up of cell bodies and is vital for controlling movement, memory and emotions. – causing physical changes equivalent to a decade of aging. “We still don’t know what may contribute, in general, to a loss of gray matter volume or thickness observed using MRI,” says Gwenaëlle Douaud, a neuroscientist at the University of Oxford who led the study.
While removal of synapses, as shown in Samudyata’s study, might account for a small percentage of the change in gray matter, Douaud says, further studies combining imaging with tissue sections are needed to determine the other factors that lead to brain shrinkage.
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 after SARS-CoV-2 infection mimicked gene activity seen in neurodegenerative disorders. This may explain why there is a three times higher risk of developing neurological or psychiatric disorders within six months of COVID-19 compared to those who have not been infected. In adults over 65, the risk of developing dementia after COVID-19 infection is almost double that of other respiratory infections.
However, scientists warn that much more research is needed to understand the effect of SARS-CoV-2 infection on the brain. As organoids resemble immature cells, such as those in the fetal or postnatal state, this limits the extrapolation of results to mature adult brain cells.
“While these data are exciting and indicate a role for pro-inflammatory microglia in the disease mechanisms underlying long COVID, further studies are needed to validate and build on these findings,” says Oliver. Harschnitz, group leader at the Neurogenomics Research Center of the Human Technopole Institute. in Milan, Italy.
It’s also unclear if the long 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 keeping up to date with vaccinations to minimize the chances of contracting COVID again and again. Although it is not clear how the virus exerts adverse effects on the brain, it is clear that it causes damage.
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