Journal article
Computational modelling of 5-HT receptor-mediated reorganization of the brainstem respiratory network
The European journal of neuroscience, v 34(8), pp 1276-1291
Oct 2011
PMID: 21899601
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Brainstem respiratory neurons express the glycine α
3
receptor (Glyα
3
R), which is a target of modulation by several serotonin (5-HT) receptor agonists. Application of the 5-HT
1A
receptor (5-HT
1A
R) agonist 8-OH-DPAT was shown (1) to depress cellular cAMP, leading to dephosphorylation of Glyα
3
R and augmentation of postsynaptic inhibition of neurons expressing Glyα
3
R (Manzke
et al. Journal of Clinical Investigation
, 120: 4118–4128, 2010), and (2) to hyperpolarize respiratory neurons through serotonin-activated potassium channels. These processes counteract opioid-induced depression and recover breathing from apnoeas often accompanying pharmacotherapy of pain. The effect is postulated to rely on the enhanced Glyα
3
R-mediated inhibition of inhibitory neurons causing disinhibition of their target neurons. To evaluate this proposal and investigate neural mechanisms involved, an established computational model of the brainstem respiratory network (Smith
et al. Journal of Neurophysiology
, 98: 3370–3387, 2007) was extended by (1) incorporating distinct subpopulations of inhibitory neurons (glycinergic and GABAergic) and their synaptic interconnections within the Bötzinger and pre-Bötzinger complexes, and (2) assigning the 5-HT
1A
R-Glyα
3
R complex to some of these inhibitory neuron types in the network. The modified model was used to simulate the effects of 8-OH-DPAT on the respiratory pattern and was able to realistically reproduce a number of experimentally observed responses, including the shift in the onset of post-inspiratory activity to inspiration and conversion of the eupnoeic three-phase rhythmic pattern into a two-phase pattern lacking the post-inspiratory phase. The model shows how 5-HT
1A
R activation can produce a disinhibition of inspiratory neurons leading to the recovery of respiratory rhythm from opioid-induced apnoeas.
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Details
- Title
- Computational modelling of 5-HT receptor-mediated reorganization of the brainstem respiratory network
- Creators
- Natalia A Shevtsova - Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USATill Manzke - Department of Neuro- and Sensory Physiology, University of Göttingen, Göttingen, GermanyYaroslav I Molkov - Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USAAnne Bischoff - Department of Neuro- and Sensory Physiology, University of Göttingen, Göttingen, GermanyJeffrey C Smith - Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USAIlya A Rybak - Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USADiethelm W Richter - Department of Neuro- and Sensory Physiology, University of Göttingen, Göttingen, Germany
- Publication Details
- The European journal of neuroscience, v 34(8), pp 1276-1291
- Publisher
- Wiley
- Grant note
- R01 NS069220-02 || NS / National Institute of Neurological Disorders and Stroke : NINDS R33 HL087379-03 || HL / National Heart, Lung, and Blood Institute : NHLBI R01 NS069220-01A1 || NS / National Institute of Neurological Disorders and Stroke : NINDS R01 NS057815-05 || NS / National Institute of Neurological Disorders and Stroke : NINDS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000297014000011
- Scopus ID
- 2-s2.0-80054683531
- Other Identifier
- 991014878297604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Neurosciences