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.
Highlights
Defining cellular and circuit mechanisms generating the vital rhythm of breathing in mammals remains a fundamental unsolved problem of wide-spread interest in neurophysiology (Richter andSmith, 2014; Del Negro et al, 2018; Ramirez and Baertsch, 2018a), with potentially far-reaching implications for understanding mechanisms of oscillatory circuit activity and rhythmic motor pattern generation in neural systems (Marder and Calabrese, 1996; Buzsaki, 2006; Grillner, 2006; Kiehn, 2006)
Establishing cellular and circuit mechanisms generating the rhythm and amplitude of respiratory oscillations in the mammalian brainstem pre-BötC has remained an unsolved problem of widespread interest in neurophysiology since this structure, essential for breathing to support mammalian life, was discovered nearly three decades ago (Smith et al, 1991). Our objective in this theoretical study was to re-examine and further define contributions of two of the main currently proposed neuronal biophysical mechanisms operating in pre-BötC excitatory circuits, mechanisms involving ICAN activated by neuronal calcium fluxes (Thoby-Brisson and Ramirez, 2001; Peña et al, 2004; Del Negro et al, 2005; Mironov, 2008; Rubin et al, 2009a ) and voltage-dependent intrinsic neuronal biophysical mechanisms—a persistent sodium current (INaP) in the circuit neurons (Butera et al, 1999a; Del Negro et al, 2002; Koizumi and Smith, 2008; Koizumi and Smith, 2008)
Based on our computational model, distinct biophysical mechanisms are involved in generating the rhythm and amplitude of inspiratory oscillations in the isolated pre-BötC excitatory circuits
Summary
Defining cellular and circuit mechanisms generating the vital rhythm of breathing in mammals remains a fundamental unsolved problem of wide-spread interest in neurophysiology 2014; Del Negro et al, 2018; Ramirez and Baertsch, 2018a), with potentially far-reaching implications for understanding mechanisms of oscillatory circuit activity and rhythmic motor pattern generation in neural systems (Marder and Calabrese, 1996; Buzsaki, 2006; Grillner, 2006; Kiehn, 2006). Numerous experimental and theoretical analyses have focused on the rhythmogenic mechanisms operating in these in vitro conditions to provide insight into biophysical and circuit processes involved, with potential relevance for rhythm generation during breathing in vivo (Feldman and Del Negro, 2006; Lindsey et al, 2012; Richter and Smith, 2014; Ramirez and Baertsch, 2018b).
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