title: Stimulation of the Pontine Parabrachial Nucleus Promotes Wakefulness via Extra-thalamic Forebrain Circuit Nodes.
abstract: 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.
authors.affiliation: Department of Neurobiology, School of Basic Medical Science, Fudan University, Shanghai 200032, China; Department of Pharmacology, School of Basic Medical Science, Fudan University, Shanghai 200032, China; Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. Electronic address: mhqiu@shmu.edu.cn.
authors.forename: Mei Hong
authors.initials: MH
authors.lastname: Qiu
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Chen
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Fuller
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. Electronic address: jlu@bidmc.harvard.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
mesh_terms: D000818:Animals; D001143:Arousal; D066187:Basal Forebrain / Q000502:physiology*; D004569:Electroencephalography; D005786:Gene Expression Regulation; D007026:Hypothalamic Area, Lateral / Q000502:physiology*; D008297:Male; D065823:Parabrachial Nucleus / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016760:Proto-Oncogene Proteins c-fos
keywords: DREADD; EEG; basal forebrain; chemogenetic; hypothalamus; sleep; thalamus