Lost sleep could mean lost neurons

Most of us wish we got more sleep. Every night, something — whether it’s children, work or the Internet — seems to keep us up late. Sometimes it keeps us up all night. Often we comfort ourselves with the thought that if all else fails, we can make it up with a few solid nights of sleep on the weekend.

But new research shows that the brain may not be as forgiving as we hoped. While a few extra hours on the Internet may be absolved, all-nighters like those associated with shift work (not to mention parenting) may end up killing off neurons.

There is no question that sleep is important. It cleans our brain cells and helps consolidate our memories. Lack of sleep blunts our ability to focus, makes us dangerous drivers and can make us eat too much. Jing Zhang and her colleagues at the University of Pennsylvania Perelman School of Medicine in Philadelphia were interested in the effects of sleep loss on the brain. “Many of us have pulled long nights and/or all-nighters, and we think we’re OK,” says Sigrid Veasey, a neurobiologist at Penn and coauthor on the study. “But what is the effect? Is there a compensatory mechanism? Or does the brain pay a price for repeated sleep loss?”

The researchers were particularly interested in the locus ceruleus, an area of neurons deep in the brain stem. The locus ceruleus plays an important role in attention, “fight or flight” and our sleep-wake cycles. But the locus ceruleus is also very sensitive to stress. And late nights can make those cells very frazzled indeed.

To examine how the brain might respond to decreased sleep, Zhang and colleagues put mice in new, interesting environments with other mice to play with and plenty of things to explore. With this mouse playground, the researchers could keep the animals up far past their bedtimes. The scientists looked at mice with normal sleep schedules, mice that stayed up three hours later than normal and mice with a night-shift schedule kept awake during the day for three days straight. In all cases, the mice could get as much sleep as they wanted during the night, their normal active period.

In a paper published March 19 in the Journal of Neuroscience, Zhang and her group showed that three hours of lost sleep in the mouse playground produced an increase in Sirtuin3, or SIRT3, a protein in a cell’s mitochondria. SIRT3 has a lot of functions, and one of them is reducing chemicals called reactive oxygen species. These molecules are capable of binding to and disrupting all sorts of cellular processes. ROS are a natural by-product of a cell’s daily life, but too many accumulating in the cell can get dangerous as the molecules bind to normal proteins, causing damage and eventually cell death.

By increasing SIRT3 protein when mice stay up late, the brain cells in the locus ceruleus are ready to deal with the ROS. But when the mice partied all night long, the situation reversed. SIRT3RNA levels went down, while ROS levels continued to increase. With three days of eight-hour sleep deprivation, the neurons in the locus ceruleus actually began to die. Napping didn’t make up for the sleep lost.

SIRT3 appears to be a key protein for protecting neurons from damage from ROS molecules during late nights. In mice lacking the gene for the SIRT3 protein, even three hours of sleep deprivation resulted in neuron injury from ROS.

“We didn’t think the brain got injured from sleep loss,” Veasey says. “Now we know it does.” She explains that the next step will be to see if there is similar damage in humans who have done large amounts of shift work, perhaps by examining post-mortem brains. Veasey also plans to see if increasing SIRT3 can protect against the effects of all-nighters.

While it is interesting to see a new role for SIRT3 in sleep, Matthew Hirschey, a cell biologist at Duke University, says that it’s not necessarily surprising. “SIRT3 is a mitochondrial protein, he says, “and mitochondrial function touches so much of biology.” In addition, because every cell in the body has SIRT3 in its mitochondria, increasing SIRT3 might have more effects than protecting your neurons from a late night.  “Generally,” Hirschey says, “it appears to be a good thing, but some cancer cells have high SIRT3 as well.”

It will also be important to see if the locus ceruleus can recover from neuron loss, and if it even matters. Zhang’s group did not run behavioral studies to see if the sleep-deprived mice had deficits in attention or memory, or if these reversed with recovery sleep. They also don’t know if neuron loss continues over long-term shift work, or if the brain can adjust. But Veasey says the current findings are scary enough: “All of us in the lab take sleep a lot more seriously than we used to!”