Corticotropin-releasing hormone (CRH) as a regulator of waking

Corticotropin-releasing hormone (CRH), expressed in widely distributed regions of the central nervous system (CNS), mediates the hypothalamic-pituitary-adrenal (HPA) axis and autonomic components of responses to stressors. Sleep, a fundamental CNS process, is altered in response to a variety of stressors. Although there is an extensive literature on the role of CRH in responses to stressors, there is relatively little information on the role of CRH in normal, spontaneous behavior. We hypothesize that CRH is involved in the regulation of waking in the absence of overt stressors. Some of the early evidence supporting this hypothesis was indirect. We summarize in this review studies from our laboratory and others that provide direct evidence that CRH is involved in the regulation of spontaneous waking. We also suggest on the basis of recent studies that some effects of CRH on waking and sleep may be mediated by actions within the CNS of the immunomodulatory cytokine interleukin (IL)-1. Collectively, these observations suggest that CRH contributes to the regulation of spontaneous waking in the absence of stressors, and also indicate a potential mechanism mediating complex alterations in sleep that occur in response to immune challenge.