title: When norepinephrine becomes a driver of breathing irregularities: how intermittent hypoxia fundamentally alters the modulatory response of the respiratory network.
abstract: Neuronal networks are endogenously modulated by aminergic and peptidergic substances. These modulatory processes are critical for maintaining normal activity and adapting networks to changes in metabolic, behavioral, and environmental conditions. However, disturbances in neuromodulation have also been associated with pathologies. Using whole animals (in vivo) and functional brainstem slices (in vitro) from mice, we demonstrate that exposure to acute intermittent hypoxia (AIH) leads to fundamental changes in the neuromodulatory response of the respiratory network located within the preBötzinger complex (preBötC), an area critical for breathing. Norepinephrine, which normally regularizes respiratory activity, renders respiratory activity irregular after AIH. Respiratory irregularities are caused both in vitro and in vivo by AIH, which increases synaptic inhibition within the preBötC when norepinephrine is endogenously or exogenously increased. These irregularities are prevented by blocking synaptic inhibition before AIH. However, regular breathing cannot be reestablished if synaptic inhibition is blocked after AIH. We conclude that subtle changes in synaptic transmission can have dramatic consequences at the network level as endogenously released neuromodulators that are normally adaptive become the drivers of irregularity. Moreover, irregularities in the preBötC result in irregularities in the motor output in vivo and in incomplete transmission of inspiratory activity to the hypoglossus motor nucleus. Our finding has basic science implications for understanding network functions in general, and it may be clinically relevant for understanding pathological disturbances associated with hypoxic episodes such as those associated with myocardial infarcts, obstructive sleep apneas, apneas of prematurity, Rett syndrome, and sudden infant death syndrome.
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98101, and Department of Neurological Surgery, University of Washington, Seattle, Washington 98104.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Zanella
authors.forename: Atsushi
authors.initials: A
authors.lastname: Doi
authors.forename: Alfredo J
authors.initials: AJ
authors.lastname: Garcia
authors.forename: Frank
authors.initials: F
authors.lastname: Elsen
authors.forename: Sarah
authors.initials: S
authors.lastname: Kirsch
authors.forename: Aguan D
authors.initials: AD
authors.lastname: Wei
authors.forename: Jan-Marino
authors.initials: JM
authors.lastname: Ramirez
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D005260:Female; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D051379:Mice; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology* / Q000502:physiology; D009924:Organ Culture Techniques; D012119:Respiration / Q000187:drug effects; D012125:Respiratory Center / Q000187:drug effects / Q000378:metabolism*; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D009638:Norepinephrine
keywords: breathing; glycine; intermittent hypoxia; neuromodulation; preBötzinger complex; rhythmogenesis