When norepinephrine becomes a driver of breathing irregularities: how intermittent hypoxia fundamentally alters the modulatory response of the respiratory network

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 be...

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Bibliographic Details
Published in:The Journal of neuroscience 2014-01, Vol.34 (1), p.36-50
Main Authors: Zanella, Sébastien, Doi, Atsushi, Garcia, 3rd, Alfredo J, Elsen, Frank, Kirsch, Sarah, Wei, Aguan D, Ramirez, Jan-Marino
Format: Article
Language:English
Subjects:
Animals
Brain Stem - drug effects
Brain Stem - metabolism
Female
Hypoxia - metabolism
Male
Mice
Nerve Net - drug effects
Nerve Net - metabolism
Norepinephrine - pharmacology
Norepinephrine - physiology
Organ Culture Techniques
Respiration - drug effects
Respiratory Center - drug effects
Respiratory Center - metabolism
Respiratory Mechanics - drug effects
Respiratory Mechanics - physiology
Synaptic Transmission - drug effects
Synaptic Transmission - physiology
Time Factors
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Summary: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.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.3644-12.2014