Abstract
Central chemoreceptors are highly sensitive neurons that respond to changes in pH and CO2 levels. An increase in CO2/H+ typically reflects a rise in the firing rate of these neurons, which stimulates an increase in ventilation. Here, we present an ionic current model that reproduces the basic electrophysiological activity of individual CO2/H+-sensitive neurons from the locus coeruleus (LC). We used this model to explore chemoreceptor discharge patterns in response to electrical and chemical stimuli. The modeled neurons showed both stimulus-evoked activity and spontaneous activity under physiological parameters. Neuronal responses to electrical and chemical stimulation showed specific firing patterns of spike frequency adaptation, postinhibitory rebound, and post-stimulation recovery. Conversely, the response to chemical stimulation alone (based on physiological CO2/H+ changes), in the absence of external depolarizing stimulation, showed no signs of postinhibitory rebound or post-stimulation recovery, and no depolarizing sag. A sensitivity analysis for the firing-rate response to the different stimuli revealed that the contribution of an applied stimulus current exceeded that of the chemical signals. The firing-rate response increased indefinitely with injected depolarizing current, but reached saturation with chemical stimuli. Our computational model reproduced the regular pacemaker-like spiking pattern, action potential shape, and most of the membrane properties that characterize CO2/H+-sensitive neurons from the locus coeruleus. This validates the model and highlights its potential as a tool for studying the cellular mechanisms underlying the altered central chemosensitivity present in a variety of disorders such as sudden infant death syndrome, depression, and anxiety. In addition, the model results suggest that small external electrical signals play a greater role in determining the chemosensitive response to changes in CO2/H+ than previously thought. This highlights the importance of considering electrical synaptic transmission in studies of intrinsic chemosensitivity.
Highlights
Central chemoreception is a neuronal sensory mechanism by which changes in CO2 and H+ levels in the brain are detected [1,2,3]
The sensory mechanism by which changes in CO2 and H+ levels are detected in the brain is known as central chemoreception
CO2/H+-sensitive neurons are present in some regions of the brain that have been identified as drug targets for the treatment of anxiety and panic disorders
Summary
Central chemoreception is a neuronal sensory mechanism by which changes in CO2 and H+ levels in the brain are detected [1,2,3] It occurs in specialized CO2/H+-sensitive centers in the brainstem that are involved in the neuronal network that regulates autonomic ventilation [4,5,6,7,8,9,10]. Brainstem neurons are considered the main sensory elements in the homeostatic regulation of respiratory gases [15,16], and when these neurons are exposed to elevated CO2/H+ (hypercapnia and/or acidosis), there is a noticeable increase in their firing rate This change in firing rate can be triggered by several signaling pathways alone or in combination, such as a decrease in intracellular or external pH [17,18], an increase in intracellular HCO3− [19] and/or a direct increase in CO2 [20].
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