Researchers Show How Lost Sleep Leads to Lost Neurons

Most people appreciate that not getting enough sleep impairs cognitive performance. For the chronically sleep-deprived such as shift workers, students, or truckers, a common strategy is simply to catch up on missed slumber on the weekends. According to common wisdom, catch up sleep repays one’s “sleep debt,” with no lasting effects. But a new Penn Medicine study shows disturbing evidence that chronic sleep loss may be more serious than previously thought and may even lead to irreversible physical damage to and loss of brain cells. The research is published today in The Journal of Neuroscience.

Using a mouse model of chronic sleep loss, Sigrid Veasey, MD, associate professor of Medicine and a member of the Center for Sleep and Circadian Neurobiology at the Perelman School of Medicine and collaborators from Peking University, have determined that extended wakefulness is linked to injury to, and loss of, neurons that are essential for alertness and optimal cognition, the locus coeruleus (LC) neurons. 

"In general, we’ve always assumed full recovery of cognition following short- and long-term sleep loss," Veasey says. "But some of the research in humans has shown that attention span and several other aspects of cognition may not normalize even with three days of recovery sleep, raising the question of lasting injury in the brain. We wanted to figure out exactly whether chronic sleep loss injures neurons, whether the injury is reversible, and which neurons are involved."

Mice were examined following periods of normal rest, short wakefulness, or extended wakefulness, modeling a shift worker’s typical sleep pattern. The Veasey lab found that in response to short-term sleep loss, LC neurons upregulate the sirtuin type 3 (SirT3) protein, which is important for mitochondrial energy production and redox responses, and protect the neurons from metabolic injury. SirT3 is essential across short-term sleep loss to maintain metabolic homeostasis, but in extended wakefulness, the SirT3 response is missing. After several days of shift worker sleep patterns, LC neurons in the mice began to display reduced SirT3, increased cell death, and the mice lost 25 percent of these neurons.

"This is the first report that sleep loss can actually result in a loss of neurons," Veasey notes. Particularly intriguing is, that the findings suggest that mitochondria in LC neurons respond to sleep loss and can adapt to short-term sleep loss but not to extended wake. This raises the possibility that somehow increasing SirT3 levels in the mitochondria may help rescue neurons or protect them across chronic or extended sleep loss. The study also demonstrates the importance of sleep for restoring metabolic homeostasis in mitochondria in the LC neurons and possibly other important brain areas, to ensure their optimal functioning during waking hours.

Veasey stresses that more work needs to be done to establish whether a similar phenomenon occurs in humans and to determine what durations of wakefulness place individuals at risk of neural injury. “In light of the role for SirT3 in the adaptive response to sleep loss, the extent of neuronal injury may vary across individuals. Specifically, aging, diabetes, high-fat diet and sedentary lifestyle may all reduce SirT3. If cells in individuals, including neurons, have reduced SirT3 prior to sleep loss, these individuals may be set up for greater risk of injury to their nerve cells.”

The next step will be putting the SirT3 model to the test. “We can now overexpress SirT3 in LC neurons,” explains Veasey.  “If we can show that we can protect the cells and wakefulness, then we’re launched in the direction of a promising therapeutic target for millions of shift workers.” 

The team also plans to examine shift workers post-mortem for evidence of increased LC neuron loss and signs of neurodegenerative disorders such as Alzheimer’s and Parkinson’s, since some previous mouse models have shown that lesions or injury to LC neurons can accelerate the course of those diseases. While not directly causing theses diseases, “injuring LC neurons due to sleep loss could potentially facilitate or accelerate neurodegeneration in individuals who already have these disorders,” Veasey says.

While more research will be needed to settle these questions, the present study provides another confirmation of a rapidly growing scientific consensus:  sleep is more important than was previously believed. In the past, Veasey observes, “No one really thought that the brain could be irreversibly injured from sleep loss.”  It’s now clear that it can be.

Sleep to protect your brain

A new study from Uppsala University, Sweden, shows that one night of sleep deprivation increases morning blood concentrations of NSE and S-100B in healthy young men. These molecules are typically found in the brain. Thus, their rise in blood after sleep loss may indicate that a lack of snoozing might be conducive to a loss of brain tissue. The findings are published in the journal SLEEP.

Fifteen normal-weight men participated in the study. In one condition they were sleep-deprived for one night, while in the other condition they slept for approximately 8 hours.

“We observed that a night of total sleep loss was followed by increased blood concentrations of NSE and S-100B. These brain molecules typically rise in blood under conditions of brain damage. Thus, our results indicate that a lack of sleep may promote neurodegenerative processes”, says sleep researcher Christian Benedict at the Department of Neuroscience, Uppsala University, who lead the study. 

“In conclusion, the findings of our trial indicate that a good night’s sleep may be critical for maintaining brain health”, says Christian Benedict.

Unusual comparison nets new sleep loss marker

For years, Paul Shaw, PhD, a researcher at Washington University School of Medicine in St. Louis, has used what he learns in fruit flies to look for markers of sleep loss in humans.

Shaw reverses the process in a new paper, taking what he finds in humans back to the flies and gaining new insight into humans as a result: identification of a human gene that is more active after sleep deprivation.

“I’m calling the approach cross-translational research,” says Shaw, associate professor of neurobiology. “Normally we go from model to human, but there’s no reason why we can’t take our studies from human to model and back again.”

Shaw and his colleagues plan to use the information they are gaining to create a panel of tests for sleep loss. The tests may one day help assess a person’s risk of falling asleep at the wheel of a car or in other dangerous contexts.

PLOS One published the results on April 24.

Scientists have known for years that sleep disorders and disruption raise blood serum levels of interleukin 6, an inflammatory immune compound. Shaw showed that this change is also detectable in saliva samples from sleep-deprived rats and humans.

Based on this link, Shaw tested the activity of other immune proteins in humans to see if any changed after sleep loss. The scientists took saliva samples from research participants after they had a normal night’s sleep and after they stayed awake for 30 hours. They found two immune genes whose activity levels rose during sleep deprivation.

“Normally we would do additional human experiments to verify these links,” Shaw says. “But those studies can be quite expensive, so we thought we’d test the connections in flies first.”

The researchers identified genes in the fruit fly that were equivalent to the human genes, but their activity didn’t increase when flies lost sleep. When they screened other, similar fruit fly genes, though, the scientists found one that did.

“We’ve seen this kind of switch happen before as we compared families of fly genes and families of human genes,” Shaw says. “Sometimes the gene performing a particular role will change, but the task will still be handled by a gene in the same family.”

When the scientists looked for the human version of the newly identified fly marker for sleep deprivation, they found ITGA5 and realized it hadn’t been among the human immune genes they screened at the start of the study. Testing ITGA5 activity in the saliva samples revealed that its activity levels increased during sleep deprivation.

“We will need more time to figure out how useful this particular marker will be for detecting sleep deprivation in humans,” Shaw says. “In the meantime, we’re going to continue jumping between our flies and humans to maximize our insights.”

Sleep loss precedes Alzheimer’s symptoms

Sleep is disrupted in people who likely have early Alzheimer’s disease but do not yet have the memory loss or other cognitive problems characteristic of full-blown disease, researchers at Washington University School of Medicine in St. Louis report March 11 in JAMA Neurology.

The finding confirms earlier observations by some of the same researchers. Those studies showed a link in mice between sleep loss and brain plaques, a hallmark of Alzheimer’s disease. Early evidence tentatively suggests the connection may work in both directions: Alzheimer’s plaques disrupt sleep, and lack of sleep promotes Alzheimer’s plaques.

“This link may provide us with an easily detectable sign of Alzheimer’s pathology,” says senior author David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of Washington University’s Department of Neurology. “As we start to treat people who have markers of early Alzheimer’s, changes in sleep in response to treatments may serve as an indicator of whether the new treatments are succeeding.”

Sleep problems are common in people who have symptomatic Alzheimer’s disease, but scientists recently have begun to suspect that they also may be an indicator of early disease. The new paper is among the first to connect early Alzheimer’s disease and sleep disruption in humans.

(Image: iStockphoto)