title: Effects of ion channel noise on neural circuits: an application to the respiratory pattern generator to investigate breathing variability.
abstract: Neural activity generally displays irregular firing patterns even in circuits with apparently regular outputs, such as motor pattern generators, in which the output frequency fluctuates randomly around a mean value. This "circuit noise" is inherited from the random firing of single neurons, which emerges from stochastic ion channel gating (channel noise), spontaneous neurotransmitter release, and its diffusion and binding to synaptic receptors. Here we demonstrate how to expand conductance-based network models that are originally deterministic to include realistic, physiological noise, focusing on stochastic ion channel gating. We illustrate this procedure with a well-established conductance-based model of the respiratory pattern generator, which allows us to investigate how channel noise affects neural dynamics at the circuit level and, in particular, to understand the relationship between the respiratory pattern and its breath-to-breath variability. We show that as the channel number increases, the duration of inspiration and expiration varies, and so does the coefficient of variation of the breath-to-breath interval, which attains a minimum when the mean duration of expiration slightly exceeds that of inspiration. For small channel numbers, the variability of the expiratory phase dominates over that of the inspiratory phase, and vice versa for large channel numbers. Among the four different cell types in the respiratory pattern generator, pacemaker cells exhibit the highest sensitivity to channel noise. The model shows that suppressing input from the pons leads to longer inspiratory phases, a reduction in breathing frequency, and larger breath-to-breath variability, whereas enhanced input from the raphe nucleus increases breathing frequency without changing its pattern.
  
  
  
  A major source of noise in neuronal circuits is the "flickering" of ion currents passing through the neurons' membranes (channel noise), which cannot be suppressed experimentally. Computational simulations are therefore the best way to investigate the effects of this physiological noise by manipulating its level at will. We investigate the role of noise in the respiratory pattern generator and show that endogenous, breath-to-breath variability is tightly linked to the respiratory pattern.
authors.affiliation: School of Electrical Engineering and Automation, Tianjin University, Tianjin, People's Republic of China.|Department of Electrical Engineering and Computer Science, School of Engineering, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Haitao
authors.initials: H
authors.lastname: Yu
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio; and.
authors.forename: Rishi R
authors.initials: RR
authors.lastname: Dhingra
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio; and.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Dick
authors.affiliation: Department of Electrical Engineering and Computer Science, School of Engineering, Case Western Reserve University, Cleveland, Ohio rfgalan@case.edu.
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Galán
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D063226:Central Pattern Generators / Q000166:cytology*; D006801:Humans; D007473:Ion Channels / Q000502:physiology*; D008959:Models, Neurological; D009474:Neurons / Q000502:physiology*; D012119:Respiration; D012143:Respiratory Physiological Phenomena
chemical_list: D007473:Ion Channels
keywords: apneas; conductance-based model; ion channel gating; neural control of respiration; pons; pre-Bötzinger complex; stochastic neural dynamics