A Genetically Defined Circuit for Arousal from Sleep during Hypercapnia

• Published in: Neuron (Cambridge, Mass.) Mass.), 2017-12, Vol.96 (5), p.1153-1167.e5
• Main Authors: Kaur, Satvinder, Wang, Joshua L., Ferrari, Loris, Thankachan, Stephen, Kroeger, Daniel, Venner, Anne, Lazarus, Michael, Wellman, Andrew, Arrigoni, Elda, Fuller, Patrick M., Saper, Clifford B.
• Format: Article
• Language: English
• Subjects: Acoustic Stimulation; Animals; apne; Arousal; Arousal - genetics; calcitonin gene related peptide; Calcitonin Gene-Related Peptide - metabolism; Carbon Dioxide - metabolism; Carbon Dioxide - pharmacology; chemogenetics; Cocaine; Electroencephalography; Electromyography; Genetic engineering; Hypercapnia; Hypercapnia - genetics; Hypercapnia - physiopathology; Hypoxia; Mice; Mice, Inbred C57BL; Nerve Net - physiopathology; Neurons; Optogenetics; parabrachial neurons; Patch-Clamp Techniques; Peptides; Prosencephalon - physiopathology; Respiration; Rodents; Sleep; Sleep - genetics; Sleep Apnea Syndromes - physiopathology
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2017.10.009

The precise neural circuitry that mediates arousal during sleep apnea is not known. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) play a critical role in arousal to elevated CO2 or hypoxia. Because many of the PBel neurons that respond to CO2 express calcitonin gene-related peptide (CGRP), we hypothesized that CGRP may provide a molecular identifier of the CO2 arousal circuit. Here, we report that selective chemogenetic and optogenetic activation of PBelCGRP neurons caused wakefulness, whereas optogenetic inhibition of PBelCGRP neurons prevented arousal to CO2, but not to an acoustic tone or shaking. Optogenetic inhibition of PBelCGRP terminals identified a network of forebrain sites under the control of a PBelCGRP switch that is necessary to arouse animals from hypercapnia. Our findings define a novel cellular target for interventions that may prevent sleep fragmentation and the attendant cardiovascular and cognitive consequences seen in obstructive sleep apnea. [Display omitted] •Activation of external lateral parabrachial CGRP neurons causes wakefulness•Selective inhibition of these neurons prevents waking up in response to CO2•Inhibition of their terminals in the forebrain also diminishes arousal to CO2•This network is a novel target for preventing sleep disruption in obstructive sleep apnea Kaur et al. identify calcitonin gene-related peptide neurons in the parabrachial nucleus as a key switch for waking up the brain in response to elevated CO2. This switch provides a target for preventing sleep disruptions in obstructive sleep apnea.