Although immune system activation by viruses has long been linked to cognitive problems, the underlying mechanisms have been poorly understood. In the new report, researchers found that virus-associated immune activation causes a loss of connections between nerve cells within brain circuits in the cortex, the brain region responsible for learning. Such mice then do worse on established tests of learning ability.
The observed changes in nerve connections were triggered, not in the brain, but out in the body (the periphery) where viral infection first makes contact with CX3CR1highLY6Clow monocytes in the bloodstream, say the authors.
"This study in animals resonates with what we see in the clinic, where patients with acute or chronic infectious diseases often have weaker performance on motor skills and experience memory decline," says Guang Yang, PhD, assistant professor in the Department of Anesthesiology, Perioperative Care, and Pain Medicine at NYU Langone. "Our results suggest that existing anti-inflammatory treatments that target TNFα may protect against brain dysfunction during peripheral infection." ...
In the current study, experiments found that, once exposed to a mimic (mimetic) of viral infection called poly(I:C), mice eliminated more than twice the percentage of dendritic spines as did mice whose immune systems were not activated, suggesting the disruption of synaptic networks.
Furthermore, in mice being trained to run on a rotating rod, which requires muscle coordination (motor) learning, those exposed to poly(I:C) formed significantly fewer dendritic spines.
Researchers also measured the levels of pro-inflammatory signaling proteins (cytokines) in mice at several time points after the injection of poly(I:C), and found a larger, longer-lasting increase in levels of TNFα than in other cytokines. Given their findings, the team guessed that the impact of systemic immune response on brain cell connections was executed through TNFα signaling. Indeed, mice engineered to lack TNFα signals in white blood cells saw neither a drop in dendritic spine formation nor in motor learning ability when exposed to the viral mimetic.
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