Have you ever pulled an all-nighter and wound up feeling wired, hyper, even a bit like you’re drunk? Well, scientists are looking to harness that feeling to see if it could help people suffering from depression, and a new study in mice has uncovered the changes in the sleep-deprived brain that seem to cause it.
For most of us, the thought of having to forego a night of restful sleep is not a cheerful one. But, when forced awake by a nightshift, long trip, or last-minute study session, many people find they feel surprisingly upbeat the next day. You might describe it as feeling “tired and wired”, or giddy, or even a bit delirious (but in a good way).
If just one all-nighter can have this kind of effect, scientists reasoned, this could help us better understand how the brain changes to affect our mood, and how some antidepressants, like ketamine, can kick in so quickly.
“Interestingly, changes in mood state after acute sleep loss feel so real, even in healthy subjects, as experienced by myself and many others,” said Mingzheng Wu, postdoctoral fellow at Northwestern University and first author of a new study into sleep deprivation, in a statement. “But the exact mechanisms in the brain that lead to these effects have remained poorly understood.”
To learn more, Wu and the team performed experiments in healthy adult mice. They devised a system for keeping the animals awake whilst minimizing the amount of stress they were under, using an enclosure with a raised platform above a slowly rotating beam. The mice could either chill on the platform, or go for an explore down below, but they had to keep moving to keep out of the way of the beam. The authors tested the device and found that when mice were housed in it, they got significantly less sleep.
The authors could see that dopamine signaling was increased in the animals’ brains, but they weren’t sure whether this was specific to certain regions or a whole-brain effect. They took a closer look at four regions – the prefrontal cortex, nucleus accumbens, hypothalamus, and dorsal striatum – monitoring them for dopamine release and then silencing them one by one.
“The antidepressant effect persisted except when we silenced dopamine inputs in the prefrontal cortex,” explained senior author Yevgenia Kozorovitskiy. “That means the prefrontal cortex is a clinically relevant area when searching for therapeutic targets. But it also reinforces the idea that has been building in the field recently: Dopamine neurons play very important but very different roles in the brain. They are not just this monolithic population that simply predicts rewards.”
This point about therapeutic targets is key. According to the Centers for Disease Control and Prevention (CDC), depression affects 16 million American adults each year, and antidepressant medications are widely used. Whilst some people have found traditional antidepressants to be transformative, they don’t work for everyone and can have significant side effects. Studies are exploring the potential of new approaches, such as psychedelics, for the hardest-to-treat cases, but there’s always a need for improved understanding that could lead to new therapies.
That’s not to say, however, that Kozorovitskiy would recommend pulling an all-nighter as a quick fix. Organisms may have evolved this state of heightened awareness for times when delaying sleep and being on high alert could protect them from predation and other threats, but over time the problems of chronic sleep deprivation will quickly begin to outweigh these benefits.
It is, however, an important new avenue for researchers to continue to explore.
“We found that sleep loss induces a potent antidepressant effect and rewires the brain,” Kozorovitskiy said. “This is an important reminder of how our casual activities, such as a sleepless night, can fundamentally alter the brain in as little as a few hours.”
The study is published in the journal Neuron.