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

Elife. 2019 Mar 25;8:e41555. doi: 10.7554/eLife.41555.

Abstract

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.

Keywords: CAN current; brainstem; computational biology; neuroscience; none; persistent sodium current; respiratory rhythm and pattern; systems biology; transient receptor potential channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Clocks / physiology*
  • Biophysical Phenomena*
  • Brain Stem / physiology*
  • Calcium / metabolism
  • Computer Simulation
  • Humans
  • Models, Neurological*
  • Nerve Net / physiology*
  • Neurons / metabolism
  • Pulmonary Ventilation / physiology*
  • Sodium / metabolism

Substances

  • Sodium
  • Calcium