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Cytokine signaling in the brain promotes cognitive flexibility.

Cytokines are small signaling proteins that play essential roles in the body’s inflammatory process. They are produced primarily by immune cells, but they are also produced at basal levels in the brain, where they participate in memory and learning. Findings from a 2014 study suggest that cytokine signaling in the brain is necessary for reversal learning.

Reversal learning is a form of cognitive flexibility. It allows an organism to determine that a reward for a particular activity has changed and then adjust its behavior accordingly. Reversal learning enables an organism to disengage from ongoing behavior, a quality that is related to impulsive or compulsive actions. Evidence suggests that reversal learning is impaired in neuropsychiatric disorders such as depression, schizophrenia, and obsessive-compulsive disorder.

The researchers conducted a three-part experiment. First, they blocked the production of interleukin-6 (IL-6), a type of cytokine, in the brains of rats. They subjected one-half of the rats to cold stress (which has been shown to impair reversal learning), and the other half was left in a non-stressful environment. Then they tested both the stressed and non-stressed animals' reversal learning capacities. Surprisingly, they found that blocking IL-6 impaired reversal learning in both groups of animals, suggesting that basal IL-6 activity in the brain (in the absence of stress or inflammation) may aid learning.

In their second experiment, the researchers determined that IL-6 is produced in the orbitofrontal cortex, a region of the brain responsible for decision-making and learning. They also determined that the mechanism by which IL-6 facilitates reversal learning was a signaling pathway called JAK/STAT, which is involved in multiple physiological processes.

Finally, they restored IL-6 levels in the orbitofrontal cortex region of the animals' brains. They subjected them to cold stress again and re-tested their reversal learning capacities. They found that restoring IL-6 to the animals' brains attenuated the stress-induced reversal learning losses.

These findings suggest that a basal level of the cytokine IL-6 is essential for reversal learning in rats. The researchers posited that although IL-6 is typically a pro-inflammatory cytokine, it may exert differential effects under different conditions. For example, it may promote learning deficits under inflammatory conditions, but facilitate learning under basal (non-stressed, non-inflammatory) conditions.

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