The Cellular Building Blocks of Breathing

Abstract

Respiratory brainstem neurons fulfill critical roles in controlling breathing: they generate the activity patterns for breathing and contribute to various sensory responses including changes in O2 and CO2. These complex sensorimotor tasks depend on the dynamic interplay between numerous cellular building blocks that consist of voltage-, calcium-, and ATP-dependent ionic conductances, various ionotropic and metabotropic synaptic mechanisms, as well as neuromodulators acting on G-protein coupled receptors and second messenger systems. As described in this review, the sensorimotor responses of the respiratory network emerge through the state-dependent integration of all these building blocks. There is no known respiratory function that involves only a small number of intrinsic, synaptic, or modulatory properties. Because of the complex integration of numerous intrinsic, synaptic, and modulatory mechanisms, the respiratory network is capable of continuously adapting to changes in the external and internal environment, which makes breathing one of the most integrated behaviors. Not surprisingly, inspiration is critical not only in the control of ventilation, but also in the context of “inspiring behaviors” such as arousal of the mind and even creativity. Far-reaching implications apply also to the underlying network mechanisms, as lessons learned from the respiratory network apply to network functions in general.

Peripheral chemoreceptors tune inspiratory drive via tonic expiratory neuron hubs in the medullary ventral respiratory column network

“…These circuits for breathing have remarkable adaptive and emergent properties (Devinney et al 2013;Lindsey et al 1992Lindsey et al , 2012Ramirez et al 2012) and participate in the generation of numerous other behaviors (Bartlett and Leiter 2012), including vocal communication (McLean et al 2013), coughing and swallowing, and their coordinated expression as a metabehavioral response to aspiration Shannon et al 2000). Breathing may also bind orofacial sensations (Kleinfeld et al 2014) and be involved in hippocampal processes for learning and memory (Lockmann and Belchior 2014).…”

The Dynamic Role of Breathing and Cellular Membrane Potentials in the Experience of Consciousness

“…Respiration consists of an intricate web of intrinsic, synaptic, and modulatory properties that allow the respiratory network to continuously adapt to external and internal environmental changes [38]. Breathing can modulate behavior and behavior can modulate breathing [5] [38] [39].…”

“…For example, breathing can modulate fear, arousal, and cognitive states; and vocalization, sleep, arousal, fear, exercise, hypoxia, or hypercapnia can modulate breathing [5] [38] [39] [40]. Respiration affects sympathetic and parasympathetic activity by decreasing or increasing cardiorespiratory coherence [3] [41] [42]; therefore, we propose that respiration allows for the constant, real-time communication between the brain and sensory organs.…”

Defining modulatory inputs into CNS neuronal subclasses by functional pharmacological profiling

“…One key network within the VRC is the pre-Bötzinger complex (preBötC), which contains the circuitry essential for generating the respiratory rhythm (9)(10)(11)(12). This network of inspiratory neurons is heterogeneous, encompassing neurons with unique pharmacological profiles (13)(14)(15)(16)(17). Moreover, the tissue immediately surrounding the preBötC also contains neuronal networks important to cardiovascular control, such as cardiac parasympathetic vagal neurons of the nucleus ambiguus and noradrenergic neurons of the A2/C2 region (18,19).…”