To sleep, perchance to dream. Except when those dreams turn into nightmares replaying a traumatic event from the past. That’s why the study of sleep and circadian rhythm disruption is a central element of the 5-year, $13.5 million research effort at McLean Hospital that hopes to better understand the roots of post-traumatic stress disorder (PTSD).
“Sleep problems are common to virtually every psychiatric illness,” said Bill Carlezon, PhD, chief of the Jerry and Phyllis Rappaport Center of Excellence in Basic Neuroscience Research and director of the Behavioral Genetics Laboratory at McLean. “People have nightmares. People can’t sleep. One of the things that can happen when a person experiences these problems is they are tempted to self-medicate—by drinking or taking drugs—anything to make them feel relaxed.”
What will make this project different is the parallel focus on the role of two neuropeptides, corticotropin-releasing factor (CRF) and pituitary adenylate cyclase-activating polypeptide (PACAP), that regulate the stress hormone cortisol and other biological processes that can affect the sleep process.
“It is important to study sleep and to understand how these stress peptides affect it, because sleep disruption is not only a profound influence on PTSD itself, but it also plays a role in frequently co-occurring conditions like addiction, which compound the health problems and make them much more difficult to treat,” he said.
PTSD is usually triggered by violence or abuse. Symptoms generally include nightmares and flashbacks as a person relives the trauma.
These symptoms alone do not indicate PTSD; they are not uncommon. But for 5 to 10% of the population, key symptoms can persist after a month, a sign of PTSD. Other indicators are problems like being constantly on edge, having trouble focusing, and feelings of low self-esteem.
Disrupted sleep can also affect the circadian rhythm, the 24-hour internal clock that controls the body’s sleep/wake cycle running in the background of the brain, alternating between sleepiness and alertness. The biological clock is controlled in part by the hypothalamus, an area of the brain that also regulates hormones, including the stress hormone cortisol.
That interaction is a natural subject for Carlezon’s lab, which aims to better understand how the environment affects behavior and the biology of the brain.
“We’re looking not only at how CRF and PACAP affect sleep, but also at the inverse: how problems with sleep affect these same peptide systems,” he said. “We’re doing some of the things that we know stress does to sleep, like changing patterns of REM and non-REM sleep, and looking at whether this increases or decreases the function of these peptides.”
The working hypothesis is this represents a feed-forward cycle, where failure in a control system that should be providing balance instead creates an accelerating loss of control—a condition Carlezon likens to a runaway train.
“We believe sleep disruption can be thought of as a form of stress, and we’ve shown that other forms of stress can cause an increase in the sensitivity of these systems,” he explained. “In this case, the stress of not sleeping may amplify the stress of the previous trauma.”
Carlezon has long dreamed of playing a role in bringing new treatments for psychiatric illness into humans. His first post-college job was in the drug discovery labs at Hoechst-Roussel Pharmaceuticals, which provided him with exposure to industry-scale approaches to the development of new therapeutic agents. He envisions a use for drugs such as CRF or PACAP blockers, which can dampen or block the brain effects of these peptides, offering an opportunity to restore balance, starting with a better night of sleep.
“CRF blockers show promising anti-stress effects in animal models, but for reasons that are not understood, they don’t seem to work very well in humans with stress disorders,” he said. “Our basic hypothesis is that CRF and PACAP work together and can substitute for one another. And that’s a potential explanation for why these single medications have not worked—when we block only one peptide system in isolation, the other simply takes over.
“This suggests to us that we may need to be blocking CRF and PACAP systems at the same time, using two therapeutic approaches together instead of just one.”
“It is important to study sleep because sleep disruption is not only a profound influence on PTSD itself, but it also plays a role in frequently co-occurring conditions like addiction, which compound the health problems and make them much more difficult to treat.”
But research in animal models only takes researchers so far, noted Carlezon, one of the lead researchers on the Silvio O. Conte Center for Translational Mental Health Research grant that combines five separate projects—involving species ranging from mice to humans—in pursuit of answers.
“Sleep is common to species ranging from jellyfish to flies to mice to humans. While there are obviously important species differences, sleep has the same basic attributes in all of them,” said Carlezon. “We can set up our experiments in mice so we can track their sleep and biological rhythms for months at a time.”
And there are obvious inherent advantages in taking what is learned in animals and tracking those same responses in human beings.
“Sleep-related endpoints are becoming increasingly accessible to all of us on a real-time basis,” he said. “Our smartphones and wearables, if we enable them, can keep track of the way we sleep and our biological rhythms, providing increasingly detailed readouts. Using these endpoints, research teams studying mice or humans can start comparing apples to apples, and our ability to do that is going to make the research done in the Conte Center inherently more valuable.”