title: Functional Interactions between Mammalian Respiratory Rhythmogenic and Premotor Circuitry.
abstract: Breathing in mammals depends on rhythms that originate from the preBötzinger complex (preBötC) of the ventral medulla and a network of brainstem and spinal premotor neurons. The rhythm-generating core of the preBötC, as well as some premotor circuits, consist of interneurons derived from Dbx1-expressing precursors (Dbx1 neurons), but the structure and function of these networks remain incompletely understood. We previously developed a cell-specific detection and laser ablation system to interrogate respiratory network structure and function in a slice model of breathing that retains the preBötC, the respiratory-related hypoglossal (XII) motor nucleus and XII premotor circuits. In spontaneously rhythmic slices, cumulative ablation of Dbx1 preBötC neurons decreased XII motor output by ∼50% after ∼15 cell deletions, and then decelerated and terminated rhythmic function altogether as the tally increased to ∼85 neurons. In contrast, cumulatively deleting Dbx1 XII premotor neurons decreased motor output monotonically but did not affect frequency nor stop XII output regardless of the ablation tally. Here, we couple an existing preBötC model with a premotor population in several topological configurations to investigate which one may replicate the laser ablation experiments best. If the XII premotor population is a "small-world" network (rich in local connections with sparse long-range connections among constituent premotor neurons) and connected with the preBötC such that the total number of incoming synapses remains fixed, then the in silico system successfully replicates the in vitro laser ablation experiments. This study proposes a feasible configuration for circuits consisting of Dbx1-derived interneurons that generate inspiratory rhythm and motor pattern.
  
  
  
  To produce a breathing-related motor pattern, a brainstem core oscillator circuit projects to a population of premotor interneurons, but the assemblage of this network remains incompletely understood. Here we applied network modeling and numerical simulation to discover respiratory circuit configurations that successfully replicate photonic cell ablation experiments targeting either the core oscillator or premotor network, respectively. If premotor neurons are interconnected in a so-called "small-world" network with a fixed number of incoming synapses balanced between premotor and rhythmogenic neurons, then our simulations match their experimental benchmarks. These results provide a framework of experimentally testable predictions regarding the rudimentary structure and function of respiratory rhythm- and pattern-generating circuits in the brainstem of mammals.
authors.affiliation: Departments of Applied Science and.
authors.forename: Hanbing
authors.identifier: 0000-0002-2164-8813
authors.initials: H
authors.lastname: Song
authors.affiliation: Departments of Applied Science and.
authors.forename: John A
authors.identifier: 0000-0003-2849-7672
authors.initials: JA
authors.lastname: Hayes
authors.affiliation: Departments of Applied Science and.
authors.forename: Nikolas C
authors.identifier: 0000-0003-4139-0642
authors.initials: NC
authors.lastname: Vann
authors.affiliation: Departments of Applied Science and.
authors.forename: Xueying
authors.identifier: 0000-0002-2399-8083
authors.initials: X
authors.lastname: Wang
authors.affiliation: Biology, College of William and Mary, Williamsburg, Virginia 23187.
authors.forename: M Drew
authors.identifier: 0000-0002-4037-1848
authors.initials: MD
authors.lastname: LaMar
authors.affiliation: Departments of Applied Science and cadeln@wm.edu.
authors.forename: Christopher A
authors.identifier: 0000-0002-7848-8224
authors.initials: CA
authors.lastname: Del Negro
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D018398:Homeodomain Proteins / Q000378:metabolism; D007395:Interneurons / Q000502:physiology; D008959:Models, Neurological; D009046:Motor Neurons / Q000502:physiology*; D009415:Nerve Net / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010507:Periodicity; D012119:Respiration; D012125:Respiratory Center / Q000166:cytology* / Q000502:physiology; D012154:Reticular Formation / Q000166:cytology; D013116:Spinal Cord / Q000166:cytology*
chemical_list: C103403:Dbx1 protein, mouse; D018398:Homeodomain Proteins
keywords: central pattern generator; pre-Bötzinger complex; respiration