Neurobiologist Dragana Rogulja, PhD, who’s using fruit flies and mice to explore why we need to sleep and how we disconnect from the world during sleep, has identified a critical connection between the brain and the gut in her latest research, published in Cell.

In a conversation with Harvard Medicine News, Rogulja, associate professor of neurobiology at the Blavatnik Institute at Harvard Medical School, delved into the details of her sleep research.

Harvard Medicine News: You just published a new paper in Cell that explores how the brain disconnects from the environment during sleep. Tell us more.

Rogulja: Until now, we knew almost nothing about this. It wasn’t clear if there is a single place in the brain where all sensory information is attenuated during sleep or if there are multiple such places. For example, are touch and temperature processed the same way during sleep? Iris Titos, a postdoctoral researcher in my lab, built a system that can deliver mild, medium, or high levels of vibration to fruit flies. 

Typically, when you use low-intensity vibrations, very few flies wake up, and when you use high-intensity vibrations, almost all the flies react. Then, we did a large-scale screen to identify genes that control how easily flies wake up—so genes that make flies super easy to wake up and genes that allow flies to essentially sleep through an earthquake.

HMNews: What did the genetic screen show?

Rogulja: The results of the screen were very interesting. We identified a gene that codes for a molecule called CCHa1. When we depleted CCHa1 in the flies, they woke up very easily—so instead of 20% waking up at a particular level of vibration, 90% woke up.

However, while CCHa1 is present in both the nervous system and the gut, it was only when we depleted it in the gut that flies were roused more easily. The cells in the gut that produce CCHa1 are called enteroendocrine cells, and they actually share many characteristics with neurons and can even connect and communicate with neurons. These cells face the inside of the gut, and they sort of “taste” the contents of the gut.

We found that the higher concentration of protein in the diet, the more CCHa1 these gut cells produced. This molecule then travels from the gut to the brain, where it signals to a small group of dopaminergic neurons that also receive information about vibrations. These neurons produce dopamine, which usually promotes arousal but, in this case, suppresses arousal. Vibrations weaken the activity of the dopaminergic neurons, which causes the flies to wake up more easily. CCHa1 produced by the gut essentially buffers the dopaminergic neurons against vibrations, allowing the flies to ignore the environment to a greater degree and sleep more deeply.

We also found that the CCHa1 pathway, while critical for gating mechanosensory information, has no influence on how easily the flies wake up when exposed to heat, suggesting that different sensory modalities such as vibration and temperature can be gated independently. Finally, we showed that a higher protein diet also improved the quality of sleep in mice, making them more resistant to mechanical disturbances. We are now testing whether a similar signaling pathway is involved in mice.

HMNews: What do these findings tell you?

Rogulja: Well, we know from other research that when animals are starving, they suppress sleep in order to forage. By contrast, when they’re satiated, and especially when they’re satiated with proteins, they tend to sleep more. Now, we’ve shown that when there’s more protein in the diet, animals also sleep more deeply and become less responsive. 

This suggests that if animals don’t need to look for food, they can disconnect from the environment and hide somewhere to sleep, which might be safer. More broadly, our study implies that dietary choices impact sleep quality. Now we can explore this connection in humans to understand how diet could be manipulated to improve sleep. 

Photo 39254992 © Isselee | Dreamstime.com

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