Too much stress can keep you up at night. A pressing deadline, watching the news, anxiety—sometimes you can find yourself tossing and turning, even though you are so tired from stress. Many research studies have linked stress to sleep issues, and insomnia. And now scientists at Cold Spring Harbor Laboratory (CSHL) have pinpointed the neural circuit responsible for sleepless nights due to stress. Their findings also revealed that the same circuit induced changes in the immune system.

The mouse study, “Hypothalamic circuitry underlying stress-induced insomnia and peripheral immunosuppression,” is published in the journal Science Advances. The study’s corresponding authors are Luis de Lecea, PhD, Professor of Psychiatry and Behavioral Sciences at Stanford University, and Shi-Bin Li, PhD, a postdoctoral research fellow in de Lecea’s lab.

“The neural substrates of insomnia/hyperarousal induced by stress remain unknown. Here, we show that restraint stress leads to hyperarousal associated with strong activation of corticotropin-releasing hormone neurons in the paraventricular nucleus of hypothalamus and hypocretin neurons in the lateral hypothalamus,” noted the researchers.

“This sort of stress-induced insomnia is well known among anybody that’s tried to get to sleep with a looming deadline or something the next day,” explained Jeremy Borniger, PhD, a co-author of the study who was a former postdoc in de Lecea’s lab and is now an assistant professor at CSHL. “And in the clinical world, it’s been known for a long time that chronically stressed patients typically do worse on a variety of different treatments and across a variety of different diseases.”

The scientists discovered a connection between neurons sensitive to stress in the brain that motivated cortisol’s release and nearby neurons that promote insomnia. The researchers found that signals from the hormone-releasing brain cells have a strong effect on the insomnia-inducing neurons.

The researchers interfered with the connection, which enabled mice to sleep peacefully even after being exposed to a stressful situation. “It seems like it’s a pretty sensitive switch, in that even very weak stimulation of the circuit can drive insomnia,” Borniger added.

To their surprise, they also discovered the immune system went under extensive changes to cell distribution by the connection. The amount of immune cells in the blood, as well as signaling pathways inside, were disrupted. The researchers were able to mimic the changes simply by stimulating the same neurons that link stress to insomnia.

“Single-cell mass cytometry by time of flight (CyTOF) revealed extensive changes to immune cell distribution and functional responses in peripheral blood during hyperarousal upon optogenetic stimulation of CRHPVN neurons simulating stress-induced insomnia,” observed the authors.

Looking towards the future, Borniger is interested in discovering how distinct circuits in the brain can be manipulated that are associated with systemic inflammation such as inflammatory bowel disease or cancer. “… if we can understand and manipulate the immune system using the natural circuitry in the body rather than using a drug that hits certain targets within the system, I think that would be much more effective in the long run, because it just co-opts the natural circuits in the body,” Borniger concluded.

Their work highlights a new potential target for the treatment of insomnia and stress-induced changes in systemic physiology.

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