Pontine respiratory activity involved in inspiratory/expiratory phase transition

Mörschel, Michael; Dutschmann, Mathias

doi:10.1098/rstb.2009.0074

Cited by 91 publications

(110 citation statements)

References 74 publications

(124 reference statements)

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“…Rather, these simulated patterns constitute low amplitude events that may seed burstlets and preinspiratory activity (29). Another important feature of the preBötC network is its rapid responsiveness to phasic inputs from central or peripheral (reflex) origins (30)(31)(32). Therefore, we sought to evaluate the minimal number of concurrently active neurons necessary for initiating a preBötC network response.…”

Section: Rhythmic Activity Depends On the Number And Strength Of Connmentioning

confidence: 99%

Robust network oscillations during mammalian respiratory rhythm generation driven by synaptic dynamics

Guerrier

Hayes

Fortin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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How might synaptic dynamics generate synchronous oscillations in neuronal networks? We address this question in the preBötzinger complex (preBötC), a brainstem neural network that paces robust, yet labile, inspiration in mammals. The preBötC is composed of a few hundred neurons that alternate bursting activity with silent periods, but the mechanism underlying this vital rhythm remains elusive. Using a computational approach to model a randomly connected neuronal network that relies on short-term synaptic facilitation (SF) and depression (SD), we show that synaptic fluctuations can initiate population activities through recurrent excitation. We also show that a two-step SD process allows activity in the network to synchronize (bursts) and generate a population refractory period (silence). The model was validated against an array of experimental conditions, which recapitulate several processes the preBötC may experience. Consistent with the modeling assumptions, we reveal, by electrophysiological recordings, that SF/SD can occur at preBötC synapses on timescales that influence rhythmic population activity. We conclude that nondeterministic neuronal spiking and dynamic synaptic strengths in a randomly connected network are sufficient to give rise to regular respiratory-like rhythmic network activity and lability, which may play an important role in generating the rhythm for breathing and other coordinated motor activities in mammals.central pattern generator | synaptic depression | mathematical modeling | numerical simulations | breathing C entral pattern generators (CPGs) are neuronal circuits that generate coordinated activity in the absence of sensory input (1). One such mammalian CPG, the preBötzinger complex (preBötC), gives rise to the eupneic respiratory rhythm (2, 3). Located in the medulla, the preBötC preserves a spontaneous respiratory-like rhythm when isolated in transverse slices, but the precise nature of the cellular and synaptic mechanisms underlying rhythmogenesis remains elusive (3-7). An early hypothesis was that the neuronal activity is driven by intrinsically bursting pacemaker neurons synchronized via excitatory synaptic connections (2,6,8,9). However, electrophysiological and modeling studies (7, 10-12) now suggest the rhythm emerges through stochastic activation of intrinsic currents conveyed by recurrent synaptic connections, without the need for pacemaker neurons (3,4,11,13,14). In either case, excitatory synapses are required for rhythm generation; the possibility that synaptic properties also underlie periodic burst initiation and termination is yet to be demonstrated.Synaptic transmission relies on the release of vesicles, which can be modulated at the presynaptic terminal. Synaptic depression (SD), based on vesicular release, consists of decaying release probability after sustained activity, which subsequently decreases excitability within the underlying connected network. Conversely, synaptic facilitation (SF) enhances vesicular release probability and promotes neuronal synchronizatio...

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Section: Rhythmic Activity Depends On the Number And Strength Of Connmentioning

confidence: 99%

Robust network oscillations during mammalian respiratory rhythm generation driven by synaptic dynamics

Guerrier

Hayes

Fortin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition to serving as a target for diverse sensory modalities, including somatic, visceral, and nociceptive afferent information (Jiang et al, 2004), the PB/KF is now recognized to be strongly implicated in respiratory control, and especially in the transition between inspiratory and expiratory phases (Dutschmann and Herbert, 2006;Mörschel and Dutschmann, 2009). The reciprocal synaptic connectivity of the PB/KF with the ventrolateral medulla (Herbert and Saper, 1990;Ezure, 2004;Ezure and Tanaka, 2006) where the respiratory centers are located (Smith et al, 1991;Mellen et al, 2003;Onimaru and Homma, 2003;Barnes et al, 2007), further implicates these pontine nuclei in the organization of breathing.…”

Section: Role Of Spinal and Pontine Relays In Somatic Afferent-inducementioning

confidence: 99%

Spinal and Pontine Relay Pathways Mediating Respiratory Rhythm Entrainment by Limb Proprioceptive Inputs in the Neonatal Rat

et al. 2012

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The coordination of locomotion and respiration is widespread among mammals, although the underlying neural mechanisms are still only partially understood. It was previously found in neonatal rat that cyclic electrical stimulation of spinal cervical and lumbar dorsal roots (DRs) can fully entrain (1:1 coupling) spontaneous respiratory activity expressed by the isolated brainstem/spinal cord. Here, we used a variety of preparations to determine the type of spinal sensory inputs responsible for this respiratory rhythm entrainment, and to establish the extent to which limb movement-activated feedback influences the medullary respiratory networks via direct or relayed ascending pathways. During in vivo overground locomotion, respiratory rhythm slowed and became coupled 1:1 with locomotion. In hindlimb-attached semi-isolated preparations, passive flexion-extension movements applied to a single hindlimb led to entrainment of fictive respiratory rhythmicity recorded in phrenic motoneurons, indicating that the recruitment of limb proprioceptive afferents could participate in the locomotor-respiratory coupling. Furthermore, in correspondence with the regionalization of spinal locomotor rhythmgenerating circuitry, the stimulation of DRs at different segmental levels in isolated preparations revealed that cervical and lumbosacral proprioceptive inputs are more effective in this entraining influence than thoracic afferent pathways. Finally, blocking spinal synaptic transmission and using a combination of electrophysiology, calcium imaging and specific brainstem lesioning indicated that the ascending entraining signals from the cervical or lumbar limb afferents are transmitted across first-order synapses, probably monosynaptic, in the spinal cord. They are then conveyed to the brainstem respiratory centers via a brainstem pontine relay located in the parabrachial/ Kölliker-Fuse nuclear complex.

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“…This makes the rhythm-generating pre-BötC (1) an important target for modulating adjustment of breathing movements in vivo. However, by taking a systems overview, such modulation must involve not only preinspiratory or early-inspiratory neurons in pre-BötC (28), but also glycinergic postinspiratory neurons, which are localized in the rostral VRG and also in the pons (3,4). mice).…”

Section: Figurementioning

confidence: 99%

“…1, 2) and receives important feedback control through postinspiratory neurons of the pontine respiratory group (PRG; refs. 3,4). This distributed respiratory network contains various types of respiratory neurons (5) capable of generating alternating burst discharges that are necessary for rhythmic breathing movements.…”

Section: Introductionmentioning

confidence: 99%

Serotonin receptor 1A–modulated phosphorylation of glycine receptor α3 controls breathing in mice

Manzke¹,

Niebert²,

Koch³

et al. 2010

J. Clin. Invest.

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Rhythmic breathing movements originate from a dispersed neuronal network in the medulla and pons. Here, we demonstrate that rhythmic activity of this respiratory network is affected by the phosphorylation status of the inhibitory glycine receptor α3 subtype (GlyRα3), which controls glutamatergic and glycinergic neuronal discharges, subject to serotonergic modulation. Serotonin receptor type 1A-specific (5-HTR 1A -specific) modulation directly induced dephosphorylation of GlyRα3 receptors, which augmented inhibitory glycine-activated chloride currents in HEK293 cells coexpressing 5-HTR 1A and GlyRα3. The 5-HTR 1A -GlyRα3 signaling pathway was distinct from opioid receptor signaling and efficiently counteracted opioid-induced depression of breathing and consequential apnea in mice. Paradoxically, this rescue of breathing originated from enhanced glycinergic synaptic inhibition of glutamatergic and glycinergic neurons and caused disinhibition of their target neurons. Together, these effects changed respiratory phase alternations and ensured rhythmic breathing in vivo. GlyRα3-deficient mice had an irregular respiratory rhythm under baseline conditions, and systemic 5-HTR 1A activation failed to remedy opioid-induced respiratory depression in these mice. Delineation of this 5-HTR 1A -GlyRα3 signaling pathway offers a mechanistic basis for pharmacological treatment of opioid-induced apnea and other breathing disturbances caused by disorders of inhibitory synaptic transmission, such as hyperekplexia, hypoxia/ischemia, and brainstem infarction.

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Pontine respiratory activity involved in inspiratory/expiratory phase transition

Cited by 91 publications

References 74 publications

Robust network oscillations during mammalian respiratory rhythm generation driven by synaptic dynamics

Robust network oscillations during mammalian respiratory rhythm generation driven by synaptic dynamics

Spinal and Pontine Relay Pathways Mediating Respiratory Rhythm Entrainment by Limb Proprioceptive Inputs in the Neonatal Rat

Serotonin receptor 1A–modulated phosphorylation of glycine receptor α3 controls breathing in mice

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