title: Kölliker-Fuse nuclei regulate respiratory rhythm variability via a gain-control mechanism.
abstract: Respiration varies from breath to breath. On the millisecond timescale of spiking, neuronal circuits exhibit variability due to the stochastic properties of ion channels and synapses. Does this fast, microscopic source of variability contribute to the slower, macroscopic variability of the respiratory period? To address this question, we modeled a stochastic oscillator with forcing; then, we tested its predictions experimentally for the respiratory rhythm generated by the in situ perfused preparation during vagal nerve stimulation (VNS). Our simulations identified a relationship among the gain of the input, entrainment strength, and rhythm variability. Specifically, at high gain, the periodic input entrained the oscillator and reduced variability, whereas at low gain, the noise interacted with the input, causing events known as "phase slips", which increased variability on a slow timescale. Experimentally, the in situ preparation behaved like the low-gain model: VNS entrained respiration but exhibited phase slips that increased rhythm variability. Next, we used bilateral muscimol microinjections in discrete respiratory compartments to identify areas involved in VNS gain control. Suppression of activity in the nucleus tractus solitarii occluded both entrainment and amplification of rhythm variability by VNS, confirming that these effects were due to the activation of the Hering-Breuer reflex. Suppressing activity of the Kölliker-Fuse nuclei (KFn) enhanced entrainment and reduced rhythm variability during VNS, consistent with the predictions of the high-gain model. Together, the model and experiments suggest that the KFn regulates respiratory rhythm variability via a gain control mechanism.
authors.affiliation: Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio.|Division of Pulmonary, Critical Care & Sleep, Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Rishi R
authors.initials: RR
authors.lastname: Dhingra
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia; and.
authors.forename: Mathias
authors.initials: M
authors.lastname: Dutschmann
authors.affiliation: Department of Electrical Engineering and Computer Science, School of Engineering, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Galán
authors.affiliation: Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio; ted3@case.edu.|Division of Pulmonary, Critical Care & Sleep, Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Thomas E
authors.identifier: 0000-0003-3287-8566
authors.initials: TE
authors.lastname: Dick
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D063226:Central Pattern Generators; D003198:Computer Simulation; D025461:Feedback, Physiological / Q000502:physiology*; D006801:Humans; D065836:Kolliker-Fuse Nucleus / Q000502:physiology*; D008954:Models, Biological; D012018:Reflex / Q000502:physiology; D015203:Reproducibility of Results; D015656:Respiratory Mechanics / Q000502:physiology; D056152:Respiratory Rate / Q000502:physiology*; D012680:Sensitivity and Specificity; D013269:Stochastic Processes
keywords: Hering-Breuer reflex; in situ preparation; respiratory rhythmogenesis; stochastic nonlinear oscillator; vagal nerve stimulation