Stimulation of the Pontine Parabrachial Nucleus Promotes Wakefulness via Extra-thalamic Forebrain Circuit Nodes

Curr Biol. 2016 Sep 12;26(17):2301-12. doi: 10.1016/j.cub.2016.07.054. Epub 2016 Aug 18.


Human and animal studies have identified an especially critical role for the brainstem parabrachial (PB) complex in regulating electrocortical (electroencephalogram [EEG]) and behavioral arousal: lesions of the PB complex produce a monotonous high-voltage, slow-wave EEG and eliminate spontaneous behaviors. We report here that targeted chemogenetic activation of the PB complex produces sustained EEG and behavioral arousal in the rat. We further establish, using viral-mediated retrograde activation, that PB projections to the preoptic-basal forebrain and lateral hypothalamus, but not to the thalamus, mediate PB-driven wakefulness. We exploited this novel and noninvasive model of induced wakefulness to explore the EEG and metabolic consequences of extended wakefulness. Repeated (daily) chemogenetic activation of the PB was highly effective in extending wakefulness over 4 days, although subsequent PB activation produced progressively lesser wake amounts. Curiously, no EEG or behavioral sleep rebound was observed, even after 4 days of induced wakefulness. Following the last of the four daily induced wake bouts, we examined the brains and observed a chimeric pattern of c-Fos expression, with c-Fos expressed in subsets of both arousal- and sleep-promoting nuclei. From a metabolic standpoint, induced extended wakefulness significantly reduced body weight and leptin but was without significant effect on cholesterol, triglyceride, or insulin levels, suggesting that high sleep pressure or sleep debt per se does not, as previously implicated, result in a deleterious metabolic phenotype.

Keywords: DREADD; EEG; basal forebrain; chemogenetic; hypothalamus; sleep; thalamus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arousal*
  • Basal Forebrain / physiology*
  • Electroencephalography
  • Gene Expression Regulation*
  • Hypothalamic Area, Lateral / physiology*
  • Male
  • Parabrachial Nucleus / physiology*
  • Proto-Oncogene Proteins c-fos / genetics*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Sprague-Dawley


  • Proto-Oncogene Proteins c-fos