Brain orexins and wake regulation in rats exposed to maternal deprivation

Maternal deprivation (MD) is a neonatal stressor that leads to behavioral and molecular manifestations of chronic stress in adulthood. Recent evidence has suggested that stress may impact wake regulation through corticotropin-releasing hormone (CRH) and the orexinergic system. We studied the wake/sleep features and brain levels of orexin and orexin receptors in adult rats neonatally subjected to either ten days of MD or a control procedure from postnatal day 4. At 3 months of age, one set of rats from both groups underwent 48 h of polysomnographic recording. All rats (including those that did not undergo surgery) were subsequently sacrificed for ELISA, radioimmunoassay and western blot measurement of orexins, orexin receptors and CRH in multiple brain regions. Neonatal MD induced an increase of total wake time (decreased total sleep) during the light period, which corresponds to human night time. This increase was specifically composed of quiet wake, while a small but significant decrease of active wake was observed during the dark period. At the molecular level, MD led to increased hypothalamic CRH and orexin A, and frontal cortical orexin 1 receptors (OX1R). However, hippocampal orexin B was reduced in the MD group. Our study discovered for the first time that the adult MD rat has sleep and neurobiological features of hyperarousal, which is typical in human insomnia. We concluded that neonatal MD produces adult hyperarousal in sleep physiology and neurobiology, and that the adult MD rat could be a model of insomnia with an orexinergic mechanism.