If you’ve ever suffered a restless or sleepless night due to a stressful day, you already know that stress can trigger mind-numbing insomnia. But how does psychological stress affect the brain circuitry that otherwise allows us to transition so effortlessly between wakefulness and sleep?
This question is of great professional as well as personal interest to sleep researcher Georgina Cano, a former instructor in neurology at Beth Israel Deaconess Medical Center, who has experienced stress-induced insomnia first-hand.
Cano, now an assistant professor of neuroscience at the University of Pittsburgh, recently developed a rat model of stress-induced insomnia, which has revealed a new twist in how sleep is regulated. Cano’s results, published in the Oct.1 Journal of Neuroscience, highlight the role of the brain’s limbic system in regulating sleep and suggest that this constellation of brain regions could be a useful target for therapeutic intervention.
Sleep is generally thought to be controlled by sleep centers in the brain that are antagonized by a set of wake centers. “It’s like arm wrestling,” explained Clifford Saper, the James Jackson Putnam professor of neurology at HMS and BID and senior author of the study, which describes how the sleep centers of the brain actively inhibit the wake centers during sleep and vice versa during wakefulness. “Normally one side wins,” he continued, “but in the case of insomnia, they reach a standoff.”
Cano and Saper, who is also chair of neurology at BID, witnessed a physiological correlate of this standoff when they modeled stress-induced insomnia in rats. When male rats were exposed to a psychological stressor, being housed in a territory marked by another male, they showed signs of insomnia several hours later. During this period, EEG recordings of brain activity showed high-voltage slow waves, characteristic of non-REM sleep, concurrent with low-voltage fast waves, consistent with wakefulness. To Cano, it appeared as if “the brain was asleep and awake at the same time.”
Cano reasoned that the explanation of this apparent standoff between sleep and wake centers lay in the neuronal circuitry. To determine which brain regions were active during insomnia, she stained the rat brains for the transcription factor Fos, a well-established marker of neuronal activation. She discovered that the sleep and wake centers were, indeed, simultaneously active during stress-induced insomnia.
The sleep centers should have had the upper hand, given the strong circadian drive and homeostatic pressure to sleep that accumulates with wakefulness. Why weren’t the sleep centers winning the wrestling match?
It turns out that not only were the sleep and wake centers active during stress-induced insomnia, but parts of the cerebral cortex and the limbic system were very active as well. These areas process emotions and anxiety, and their activation by recent stress appears to be the force that enables the wake system to counteract the drive to sleep.
“The limbic system and the cerebral cortex are so anxious because of the stress that happened,” explained Saper, “that they prevent the sleep circuitry from turning off the wake circuitry.”
In support of this model, Cano and Saper found that small lesions within brain regions that make up the limbic system, such as the central amygdala and the bed nucleus of the stria terminalis, restored both non-REM and REM sleep in rats with stress-induced insomnia, as did lesions within the wake system itself. These results suggest that the limbic system might be an unexplored pharmacological target for stress-induced insomnia.
“You don’t want to fool with the sleep system, which is apparently functioning just fine,” explained Saper in regard to developing drugs to treat stress-induced insomnia. “You want to target the anxiety system, which is keeping the brain awake.” Most insomnia medications non-specifically quiet the whole brain by enhancing the activity of the inhibitory neurotransmitter GABA. Targeting the activity of the limbic system (or the wake system) might provide a more specific approach to treating this common sleep disorder.
Conflicts of interest: The authors declare no conflicts of interest.
Funding Sources: The National Institute of Mental Health; the National Heart, Lung, and Blood Institute
