Neural circuitry of stress-induced insomnia in rats.
Sleep architecture is often disturbed after a stressful event; nevertheless, little is known about the brain circuitry responsible for the sleep perturbations induced by stress. We exposed rats to a psychological stressor (cage exchange) that initially causes an acute stress response, but several hours later generates a pattern of sleep disturbances similar to that observed in stress-induced insomnia in humans: increased sleep latency, decreased non-REM (nREM) and REM sleep, increased fragmentation, and high-frequency EEG activity during nREM sleep. We examined the pattern of Fos expression to identify the brain circuitry activated, and found increased Fos in the cerebral cortex, limbic system, and parts of the arousal and autonomic systems. Surprisingly, there was simultaneous activation of the sleep-promoting areas, most likely driven by ongoing circadian and homeostatic pressure. The activity in the cerebral cortex and arousal system while sleeping generates a novel intermediate state characterized by EEG high-frequency activity, distinctive of waking, during nREM sleep. Inactivation of discrete limbic and arousal regions allowed the recovery of specific sleep components and altered the Fos pattern, suggesting a hierarchical organization of limbic areas that in turn activate the arousal system and subsequently the cerebral cortex, generating the high-frequency activity. This high-frequency activity during nREM was eliminated in the stressed rats after inactivating parts of the arousal system. These results suggest that shutting down the residual activity of the limbic-arousal system might be a better approach to treat stress-induced insomnia, rather than potentiation of the sleep system, which remains fully active.
Cano
Georgina
G
Department of Neurology, Beth Israel Deaconess Medical Center, Division of Sleep Medicine and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02215, USA.
Mochizuki
Takatoshi
T
Saper
Clifford B
CB
D000818:Animals; D005334:Fever / Q000503:physiopathology / Q000523:psychology; D008297:Male; D009415:Nerve Net / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000502:physiology*; D007319:Sleep Initiation and Maintenance Disorders / Q000503:physiopathology* / Q000523:psychology; D012894:Sleep Stages / Q000502:physiology; D013315:Stress, Psychological / Q000503:physiopathology*