Biophysical mechanisms in the mammalian respiratory oscillator re-examined with a new data-driven computational model

• Published in: eLife Vol. 8
• Main Authors: Phillips, Ryan S, John, Tibin T, Koizumi, Hidehiko, Molkov, Yaroslav I, Smith, Jeffrey C
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 25-03-2019; eLife Sciences Publications, Ltd
• Subjects: Animals; Biological Clocks - physiology; Biophysical Phenomena; Brain stem; Brain Stem - physiology; brainstem; Calcium; Calcium - metabolism; CAN current; Computational and Systems Biology; Computational neuroscience; Computer applications; Computer Simulation; Humans; Models, Neurological; Nerve Net - physiology; Neurons - metabolism; Neuroscience; persistent sodium current; Pulmonary Ventilation - physiology; Respiration; respiratory rhythm and pattern; Sodium; Sodium - metabolism; transient receptor potential channel; computational biology; systems biology; CAN current; respiratory rhythm and pattern; neuroscience; brainstem; none; persistent sodium current; transient receptor potential channel
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.41555

An autorhythmic population of excitatory neurons in the brainstem pre-Bötzinger complex is a critical component of the mammalian respiratory oscillator. Two intrinsic neuronal biophysical mechanisms-a persistent sodium current ([Formula: see text]) and a calcium-activated non-selective cationic current ([Formula: see text])-were proposed to individually or in combination generate cellular- and circuit-level oscillations, but their roles are debated without resolution. We re-examined these roles in a model of a synaptically connected population of excitatory neurons with [Formula: see text] and [Formula: see text]. This model robustly reproduces experimental data showing that rhythm generation can be independent of [Formula: see text] activation, which determines population activity amplitude. This occurs when [Formula: see text] is primarily activated by neuronal calcium fluxes driven by synaptic mechanisms. Rhythm depends critically on [Formula: see text] in a subpopulation forming the rhythmogenic kernel. The model explains how the rhythm and amplitude of respiratory oscillations involve distinct biophysical mechanisms.