We humans spend a third or more of our time sleeping—but why? Nora Volkow, a psychiatry researcher and director of the National Institute on Drug Abuse (NIDA) at the National Institutes of Health, sees the question of why we sleep as a fundamental mystery of the brain. In the Kim and Judy Davis Dean’s Lecture she delivered at Radcliﬀe in March, Volkow described nearly a decade of research in her lab that has begun to unravel connections between sleep and other key brain functions.
“Biologically, we cannot forgo sleep,” Volkow said, “which highlights that it must play an extraordinarily fundamental role.” When we’re badly sleep deprived, our cognitive abilities decline; sleep impairment leads to more fatal accidents than alcohol use. Poor sleep has been associated with health problems such as obesity and a higher risk of dementia. Drugs can alter sleep behavior, yet the connection between sleep and addiction hasn’t been fully appreciated. Volkow sees the two as intrinsically linked.
Volkow is known for her work using brain imaging to tease apart the mechanisms of addiction in the brain, and particularly for demonstrating how cocaine damages the brain. She recounted how studying cocaine use led her to become interested in sleep. People who are addicted to cocaine often have signiﬁcant disruption of sleep patterns. And when animals are allowed to use drugs freely, she said, cocaine is the only drug that will actually cause them to skip sleeping entirely. “As a result of forgoing sleep, these animals will be dead within three weeks,” she said; it’s striking “how profoundly a drug can remove the basic instincts of survival, that it could lead an animal to stop sleeping in order to get the drug.”
One question has always intrigued her, she said: “Why is it that, in general, drug-taking behavior tends to occur much more towards the end of the day?” One answer, of course, is social norms: we work during the day and party at night. But this behavioral pattern is also “likely to reﬂect the biology of our circadian rhythms,” Volkow said. Could these rhythms make drugs more rewarding toward the end of the day? Are people more sensitive to drugs—or perhaps even more likely to engage in risk-taking behaviors—at night?
Questions like these spurred Volkow to begin studying how sleep affects the brain systems underlying addiction, along with other brain systems important for health.
The Dopamine–Sleep Connection
Volkow’s lab has conducted a series of studies on the connection between sleep and the dopamine system. Dopamine is a neurotransmitter that helps to mediate motivation, movement, and the anticipation of rewards, and it’s also the primary mechanism through which drugs of abuse work. Although the role of dopamine in sleep-wake cycles has been debated over the years, Volkow said, “it has become clear that the dopamine system is fundamental for arousal.” Levels of dopamine in the brain have also been found to vary depending on time of day.
Volkow has pioneered the use of positron emission tomography (PET), an imaging technique that makes it possible to track the activity of speciﬁc molecules in the brain. Her lab has used it to study dopamine-releasing cells in a part of the brain called the striatum. Volkow described studies using PET and functional MRI to compare the eﬀects of a night of sleep deprivation on healthy human subjects and those who had a good night’s sleep. One of their molecular targets of interest has been dopamine D2 receptors, proteins on the surface of brain cells that interact with dopamine and help transmit its signals to cells. They found that sleep deprivation noticeably lowers the level of dopamine D2 receptors in the brain.
In animal studies, Volkow said, a decrease of these receptors makes the animals more vulnerable to drug-seeking, impulsive, or compulsive behaviors. She speculated that by depriving the brain of dopamine D2 receptors, sleep deprivation could increase the risk that people will compensate for the loss by seeking out drugs and other stimuli that produce more dopamine. The ﬁndings have prompted her team to look back at previous studies that documented a decrease in dopamine D2 receptors in response to drugs. Some of those drug-induced eﬀects, Volkow said, “may be also driven by the profound disruption of sleep.” The ﬁndings suggest that sleep disturbance and deprivation can be seen as a fundamental part of the pathology of addiction.
A recent study from her lab found that the alertness-boosting drug caffeine may work through an opposite effect. Using PET imaging, the researchers found that caffeine causes an increase in the availability of dopamine receptors in the striatum, which could at least partly explain its eﬀects on alertness and arousal.
The Brain’s Waste Disposal System
Volkow then turned to a new thread of her research on sleep, prompted by an emerging theory about its role as a detoxiﬁcation process.
All our organs are connected to the lymphatic system, which helps clear the body of wastes—all except the brain. “The brain is the most energetically demanding organ, so how is it getting rid of those wastes?” she said. About ﬁve years ago, the Danish neuroscientist Maiken Nedergaard found evidence that wastes may be carried from cerebrospinal ﬂuid into blood vessels by way of glial cells, connecting cells in the brain. The system, which she dubbed the “glymphatic system,” seems to operate during sleep.
“I couldn’t stop thinking about it—I said, ‘Oh my God, this is fascinating,’” Volkow reported. She and her colleagues have not yet found a way to use imaging to demonstrate conclusively that the glymphatic system is working in the brain. But they took a ﬁrst step toward proving the concept by studying how sleep affects the clearance of a brain protein associated with disease.
New results in human subjects published by Volkow’s team in April show that a single night without sleep leads to about a 5 percent increase in beta amyloid, a protein that builds up in the brains of people with Alzheimer’s disease. The effect was particularly noticeable in the hippocampus, a center of memory. “A single night of sleep deprivation produces a signiﬁcant increase in beta amyloid in the human brain,” she said.
The effect on beta amyloid clearance may be temporary, but it raises the question of whether chronic sleep deprivation has long-term effects on health. Volkow said that sleep has long been overlooked as a subject of basic research, but it has also been neglected as a potential therapeutic intervention. We know that sleep deprivation is harmful; actively promoting good sleep habits could be a way to prevent disease and keep us healthy.
Courtney Humphries is a freelance science writer based in Boston.