Asymmetric control of inspiratory and expiratory phases by excitability in the respiratory network of neonatal mice in vitro

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 (similar to 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 (\u3c 0.02 Hz) spontaneous rhythms, evoked motor output could follow a spontaneous burst at short ( 60 s. We observed during inspiration a large magnitude (similar to 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

Interactions between respiratory oscillators in adult rats

Breathing in mammals is hypothesized to result from the interaction of two distinct oscillators: the preBötzinger Complex (preBötC) driving inspiration and the lateral parafacial region (pFL) driving active expiration. To understand the interactions between these oscillators, we independently altered their excitability in spontaneously breathing vagotomized urethane-anesthetized adult rats. Hyperpolarizing preBötC neurons decreased inspiratory activity and initiated active expiration, ultimately progressing to apnea, i.e., cessation of both inspiration and active expiration. Depolarizing pFL neurons produced active expiration at rest, but not when inspiratory activity was suppressed by hyperpolarizing preBötC neurons. We conclude that in anesthetized adult rats active expiration is driven by the pFL but requires an additional form of network excitation, i.e., ongoing rhythmic preBötC activity sufficient to drive inspiratory motor output or increased chemosensory drive. The organization of this coupled oscillator system, which is essential for life, may have implications for other neural networks that contain multiple rhythm/pattern generators

Rhythmogenic neuronal networks, pacemakers, and k-cores

Neuronal networks are controlled by a combination of the dynamics of individual neurons and the connectivity of the network that links them together. We study a minimal model of the preBotzinger complex, a small neuronal network that controls the breathing rhythm of mammals through periodic firing bursts. We show that the properties of a such a randomly connected network of identical excitatory neurons are fundamentally different from those of uniformly connected neuronal networks as described by mean-field theory. We show that (i) the connectivity properties of the networks determines the location of emergent pacemakers that trigger the firing bursts and (ii) that the collective desensitization that terminates the firing bursts is determined again by the network connectivity, through k-core clusters of neurons.Comment: 4+ pages, 4 figures, submitted to Phys. Rev. Let

α4* Nicotinic Receptors in preBotzinger Complex Mediate Cholinergic/Nicotinic Modulation of Respiratory Rhythm

Acetylcholine and nicotine can modulate respiratory patterns by acting on nicotinic acetylcholine receptors (nAChRs) in the preBötzinger complex (preBötC). To further explore the molecular composition of these nAChRs, we studied a knock-in mouse strain with a leucine-to-alanine mutation in the M2 pore-lining region (L9′A) of the nAChR α4 subunit; this mutation renders α4-containing receptors hypersensitive to agonists. We recorded respiratory-related rhythmic motor activity from hypoglossal nerve (XIIn) and patch-clamped preBötC inspiratory neurons in an in vitro medullary slice preparation from neonatal mice. Nicotine affected respiratory rhythm at concentrations ∼100-fold lower in the homozygous L9′A knock-in mice compared with wild-type mice. Bath application of 5 nm nicotine increased the excitability of preBötC inspiratory neurons, increased respiratory frequency, and induced tonic/seizure-like activities in XIIn in L9′A mice, effects similar to those induced by 1 μm nicotine in wild-type mice. In L9′A mice, microinjection of low nanomolar concentrations of nicotine into the preBötC increased respiratory frequency, whereas injection into the ipsilateral hypoglossal (XII) nucleus induced tonic/seizure-like activity. The α4*-selective nAChR antagonist dihydro-β-erythroidine produced opposite effects and blocked the nicotinic responses. These data, showing that nAChRs in the preBötC and XII nucleus in L9'A mice are hypersensitive to nicotine and endogenous ACh, suggest that functional α4* nAChRs are present in the preBötC. They mediate cholinergic/nicotinic modulation of the excitability of preBötC inspiratory neurons and of respiratory rhythm. Furthermore, functional α4* nAChRs are present in XII nucleus and mediate cholinergic/nicotinic modulation of tonic activity in XIIn

Synaptically activated burst-generating conductances may underlie a group-pacemaker mechanism for respiratory rhythm generation in mammals

Breathing, chewing, and walking are critical life-sustaining behaviors in mammals that consist essentially of simple rhythmic movements. Breathing movements in particular involve the diaphragm, thorax, and airways but emanate from a network in the lower brain stem. This network can be studied in reduced preparations in vitro and using simplified mathematical models that make testable predictions. An iterative approach that employs both in vitro and in silico models argues against canonical mechanisms for respiratory rhythm in neonatal rodents that involve reciprocal inhibition and pacemaker properties. We present an alternative model in which emergent network properties play a rhythmogenic role. Specifically, we show evidence that synaptically activated burst-generating conductances-which are only available in the context of network activity-engender robust periodic bursts in respiratory neurons. Because the cellular burst-generating mechanism is linked to network synaptic drive we dub this type of system a group pacemaker. © 2010 Elsevier B.V

The routinisation of management controls in software.

Author's post-print version. Final version published by Springer; available online at http://link.springer.com/Our paper aims to explore management control as complex and intertwining process over time, rather than the (mainstream) fixation on rational, optimising tools for ensuring business success. We set out to contribute towards our understanding of why and how particular management controls evolve over time as they do. We discuss how the management control routines of one organisation emerged and reproduced (through software), and moved towards a situation of becoming accepted and generally unquestioned across much of the industry. The creativity and championing of one particular person was found to be especially important in this unfolding change process. Our case study illuminates how management control (software) routines can be an important carrier of organisational knowledge, both as an engine for continuity but also potentially as a catalyst for change. We capture this process by means of exploring the ‘life-story’ of a piece of software that is adopted in the corrugated container industry

Realistic Standard Model Fermion Mass Relations in Generalized Minimal Supergravity (GmSUGRA)

Grand Unified Theories (GUTs) usually predict wrong Standard Model (SM) fermion mass relation m_e/m_{\mu} = m_d/m_s toward low energies. To solve this problem, we consider the Generalized Minimal Supergravity (GmSUGRA) models, which are GUTs with gravity mediated supersymmetry breaking and higher dimensional operators. Introducing non-renormalizable terms in the super- and K\"ahler potentials, we can obtain the correct SM fermion mass relations in the SU(5) model with GUT Higgs fields in the {\bf 24} and {\bf 75} representations, and in the SO(10) model. In the latter case the gauge symmetry is broken down to SU(3)_C X SU(2)_L X SU(2)_R X U(1)_{B-L}, to flipped SU(5)X U(1)_X, or to SU(3)_C X SU(2)_L X U(1)_1 X U(1)_2. Especially, for the first time we generate the realistic SM fermion mass relation in GUTs by considering the high-dimensional operators in the K\"ahler potential.Comment: JHEP style, 29 pages, no figure,references adde