“Losing that ability to adaptively respond to neuronal activity led to persistent cognitive impairments in these mice.” “Even minor adjustments in those myelin can actually impact neuronal communication in quite diverse ways,” she says. Myelin loss in the mice treated with chemo was found to be directly linked with deficits in short-term memory and attention. Previously, work done by Anna Geraghty (another postdoctoral fellow in Monje’s lab and study coauthor) had focused on how chemotherapy affects this process. Next, the scientists decided to investigate the effects of mild Covid-19 infection on myelinating oligodendrocytes-brain cells that generate the myelin “padding” around neurons to provide insulation for better inter-neuron communication. That turned out to be in the hippocampus-indicating that CCL11 acted on very specific cell populations in a memory-related area of the brain. Then they examined tissue from their brains to discover where the microglia had been reactive, and where fewer new neurons had grown. In a second phase of the experiment, the researchers gave shots of CCL11 to a separate group of mice. “The elevated CCL11 result was very interesting, because it could potentially explain why some Covid survivors experience cognitive symptoms,” he says. Specifically, Anthony Fernandez Castaneda, a postdoctoral researcher in Monje’s laboratory and a study coauthor, found CCL11-a factor that can decrease the generation of new neurons and impair learning or memory. To figure out what exactly caused the microglia to become reactive, the researchers looked for the cytokines that had reached elevated levels. In the hippocampus (the area of the brain closely associated with memory), this overenthusiastic cleanup effort can deter the creation of new neurons, which are linked to maintaining healthy memory. Monje’s team had seen similar elevation in this activity following chemotherapy and in brain samples from human patients who were infected with Covid-19. In the case of Covid-19, the scientists found that this reactivity persisted even at seven weeks after infection. One consequence is that they can begin eating away at needed neurons or other brain cells, which further disrupts the brain’s homeostasis. In response to these stimuli, microglia can become perpetually reactive. For the mice, this infection cleared up within one week, and they did not lose weight. Then they shot a bit of virus up the mice’s noses to cause infection, controlling the amount and delivery so that the virus was limited to the respiratory system. This receptor is the point of entry for the Covid-causing virus, allowing it to bind to the cell. Using a viral vector, Iwasaki’s group introduced the human ACE2 receptor into cells in the trachea and lungs of the mice. A mouse model is engineered as a close stand-in for a human, and this experiment was meant to mimic the experience of a person with a mild Covid-19 infection.
Her group had already established a mouse model of Covid-19, thanks to their Biosafety Level 3 clearance to work with the virus. In September 2020, Monje reached out to Iwasaki, an immunologist. “The same symptoms of impaired attention, memory, speed of information processing, dis-executive function-it really clinically looks just like the ‘chemo fog’ that people experienced and that we’d been studying.” “Very quickly, as reports of cognitive impairment started to come out, it was clear that it was a very similar syndrome,” she says. Living with those symptoms was, in her words, “hell on earth.”įor the past 20 years, Monje, a neuro-oncologist, had been trying to understand the neurobiology behind chemotherapy-induced cognitive symptoms-similarly known as “chemo fog.” When Covid-19 emerged as a major immune-activating virus, she worried about the potential for similar disruption. The high-level writing required for her job was out of the question. “I spent most of 2021 making decisions like: Is this the day where I get a shower, or I go up and microwave myself a frozen dinner?” Paige recalls.
It was accompanied by a loss of mental sharpness, part of a suite of sometimes hard-to-pin-down symptoms that are often referred to as Covid-19 “brain fog,” a general term for sluggish or fuzzy thinking. Four weeks later, when Paige (who asked to be identified only by her middle name) had recovered enough to go back to work full-time, she woke up one day with an overwhelming fatigue that just never went away. While the initial infection was not fun, what followed was worse. Things were looking “really, really good,” she says-until she got Covid-19. She could get up early in the mornings to work on creative projects.
She loved her job and the people she worked with as a communications manager for a conservation nonprofit. Her health was the best it had ever been.
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