title: Asymmetric control of inspiratory and expiratory phases by excitability in the respiratory network of neonatal mice in vitro.
abstract: Rhythmic motor behaviours consist of alternating movements, e.g. swing-stance in stepping, jaw opening and closing during chewing, and inspiration-expiration in breathing, which must be labile in frequency, and in some cases, in the duration of individual phases, to adjust to physiological demands. These movements are the expression of underlying neural circuits whose organization governs the properties of the motor behaviour. To determine if the ability to operate over a broad range of frequencies in respiration is expressed in the rhythm generator, we isolated the kernel of essential respiratory circuits using rhythmically active in vitro slices from neonatal mice. We show respiratory motor output in these slices at very low frequencies (0.008 Hz), well below the typical frequency in vitro (approximately 0.2 Hz) and in most intact normothermic mammals. Across this broad range of frequencies, inspiratory motor output bursts remained remarkably constant in pattern, i.e. duration, peak amplitude and area. The change in frequency was instead attributable to increased interburst interval, and was largely unaffected by removal of fast inhibitory transmission. Modulation of the frequency was primarily achieved by manipulating extracellular potassium, which significantly affects neuronal excitability. When excitability was lowered to slow down, or in some cases stop, spontaneous rhythm, brief stimulation of the respiratory network with a glutamatergic agonist could evoke (rhythmic) motor output. In slices with slow (<0.02 Hz) spontaneous rhythms, evoked motor output could follow a spontaneous burst at short (<or=1 s) or long (approximately 60 s) intervals. The intensity or timing of stimulation determined the latency to the first evoked burst, with no evidence for a refractory period greater than approximately 1 s, even with interburst intervals >60 s. We observed during inspiration a large magnitude (approximately 0.6 nA) outward current generated by Na(+)/K(+) ATPase that deactivated in 25-100 ms and thus could contribute to burst termination and the latency of evoked bursts but is unlikely to control the interburst interval. We propose that the respiratory network functions over a broad range of frequencies by engaging distinct mechanisms from those controlling inspiratory duration and pattern that specifically govern the interburst interval.
authors.affiliation: Systems Neurobiology Laboratory, Department of Neurobiology, David Geffen School of Medicine at the University of California Los Angeles, Box 951763, Los Angeles, CA 90095-1763, USA. cadeln@wm.edu
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Del Negro
authors.forename: Kaiwen
authors.initials: K
authors.lastname: Kam
authors.forename: John A
authors.initials: JA
authors.lastname: Hayes
authors.forename: Jack L
authors.initials: JL
authors.lastname: Feldman
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000502:physiology; D045853:Exhalation / Q000502:physiology*; D066298:In Vitro Techniques; D001239:Inhalation / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D012125:Respiratory Center / Q000187:drug effects / Q000502:physiology*; D013327:Strophanthidin / Q000494:pharmacology; D013331:Strychnine / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D010852:Picrotoxin; D011188:Potassium; D013327:Strophanthidin; D013331:Strychnine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid