The Kölliker‐Fuse nucleus gates the postinspiratory phase of the respiratory cycle to control inspiratory off‐switch and upper airway resistance in rat

Dutschmann, Mathias; Herbert, Horst

doi:10.1111/j.1460-9568.2006.04981.x

Cited by 257 publications

(296 citation statements)

References 64 publications

(73 reference statements)

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“…This implicitly supports the conclusion that both these rhythms are generated by network mechanisms without significant contribution of an I NaP -dependent intrinsic mechanism. Another conclusion drawn from these studies is that the input from the pons is necessary for the expression of the postinspiratory activity in the network and the three-phase rhythm (at least in the absence of pulmonary stretch receptor inputs as in the in situ preparation), which supports previous findings (Rybak et al, 2004a;Dutschmann and Herbert, 2006). Based on our experimental studies we also conclude that removal of neural circuits rostral to pre-BötC decreases the role of inhibitory network interactions (provided by the expiratory populations of BötC) and increases the role of the endogenous I NaP -dependent rhythmicity in the pre-BötC network.…”

Section: Discussionsupporting

confidence: 78%

“…5A, B. Based on indirect evidence about a strong excitatory influence of the pons on the post-I neurons (Rybak et al, 2004a;Dutschmann and Herbert, 2006), we have suggested that with the removal of the pons and adjacent medullary regions, all post-I populations of BötC lose a significant portion of the excitatory drive (see Fig. 3B), whereas the drive to aug-E(2) is less dependent on these regions.…”

Section: Computational Modeling Of the Brainstem Respiratory Networkmentioning

confidence: 99%

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Spatial organization and state-dependent mechanisms for respiratory rhythm and pattern generation

Rybak

Abdala

Markin

et al. 2007

Progress in Brain Research

135

199

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The brainstem respiratory network can operate in multiple functional states engaging different statedependent neural mechanisms. These mechanisms were studied in the in situ perfused rat brainstemspinal cord preparation using sequential brainstem transections and administration of riluzole, a pharmacological blocker of persistent sodium current (I NaP ). Dramatic transformations in the rhythmogenic mechanisms and respiratory motor pattern were observed after removal of the pons and subsequent medullary transactions down to the rostral end of pre-Bötzinger complex (pre-BötC). A computational model of the brainstem respiratory network was developed to reproduce and explain these experimental findings. The model incorporates several interacting neuronal compartments, including the ventral respiratory group (VRG), pre-BötC, Bötzinger complex (BötC), and pons. Simulations mimicking the removal of circuit components following transections closely reproduce the respiratory motor output patterns recorded from the intact and sequentially reduced brainstem preparations. The model suggests that both the operating rhythmogenic mechanism (i.e., networkbased or pacemaker-driven) and the respiratory pattern generated (e.g., three-phase, two-phase, or one-phase) depend on the state of the pre-BötC (expression of I NaP -dependent intrinsic rhythmogenic mechanisms) and the BötC (providing expiratory inhibition in the network). At the same time, tonic drives from pons and multiple medullary chemoreceptive sites appear to control the state of these compartments and hence the operating rhythmogenic mechanism and motor pattern. Our results suggest that the brainstem respiratory network has a spatial (rostral-to-caudal) organization extending from the rostral pons to the VRG, in which each functional compartment is controlled by more rostral compartments. The model predicts a continuum of respiratory network states relying on different contributions of intrinsic cellular properties versus synaptic interactions for the generation and control of the respiratory rhythm and pattern.

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Section: Discussionsupporting

confidence: 78%

Section: Computational Modeling Of the Brainstem Respiratory Networkmentioning

confidence: 99%

Spatial organization and state-dependent mechanisms for respiratory rhythm and pattern generation

Rybak

Abdala

Markin

et al. 2007

Progress in Brain Research

135

199

View full text Add to dashboard Cite

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“…Recent evidence supports a role for the pons: microtransection studies in rat that eliminated the pons abolished post-I recorded from cVN (25,26). Moreover, glutamate stimulation of Kölliker-Fuse (KF) neurons caused a prolongation of post-I recorded from the recurrent laryngeal nerve of juvenile rats in situ, whereas GABA receptor activation at the identical injection sites completely suppressed post-I activity (27). In addition, there is evidence that medullary sites also play a role.…”

Section: Insufficient Gaba a Inhibition Underlies Tonic Activity In Ementioning

confidence: 95%

Correction of respiratory disorders in a mouse model of Rett syndrome

Abdala

Dutschmann

Bissonnette

et al. 2010

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

Self Cite

153

159

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Rett syndrome (RTT) is an autism spectrum disorder caused by mutations in the X-linked gene that encodes the transcription factor methyl-CpG-binding protein 2 (MeCP2). A major debilitating phenotype in affected females is frequent apneas, and heterozygous Mecp2-deficient female mice mimic the human respiratory disorder. GABA defects have been demonstrated in the brainstem of Mecp2-deficient mice. Here, using an intact respiratory network, we show that apnea in RTT mice is characterized by excessive excitatory activity in expiratory cranial and spinal nerves. Augmenting GABA markedly improves the respiratory phenotype. In addition, a serotonin 1a receptor agonist that depresses expiratory neuron activity also reduces apnea, corrects the irregular breathing pattern, and prolongs survival in MeCP2 null males. Combining a GABA reuptake blocker with a serotonin 1a agonist in heterozygous females completely corrects their respiratory defects. The results indicate that GABA and serotonin 1a receptor activity are candidates for treatment of the respiratory disorders in Rett syndrome.R ett syndrome (RTT) is an autism spectrum disorder that is caused by mutations in the X-linked gene that encodes methyl-CpG-binding protein 2 (MeCP2) (1). The role of this transcription factor is incompletely understood. Until recently, on the basis of animal studies primarily in embryonic or early neonatal brain, Mecp2 was considered a translational repressor (2, 3). Recently, however, Skene et al. (4) found in neuronal nuclei of mature (6-8 wk) WT littermates of Mecp2 null males that Mecp2 expression is ≈fivefold greater than that at birth. The amount of Mecp2 bound to DNA was proportional to the methylation density of CpG sequences. Importantly, in adult mice, it has been shown that restoring Mecp2 reverses the abnormalities in mobility, gait, hind limb clasping, tremor, breathing, and general condition that they developed during the period that the transcription factor was deficient (5). Thus, Mecp2 deficiency does not cause neuronal degeneration, nor is it necessary for the correct development of neuronal networks. Strategies aimed at pharmacological corrections of symptoms are therefore essential in treating RTT.Respiratory disorders are prominent and one of the most disturbing features of RTT (6, 7). These abnormalities are faithfully mimicked in mouse models of RTT (8). In Mecp2 null male animals studied in situ phrenic (PN) apneas were characterized by prolonged postinspiratory (post-I) activity in the central vagus nerve (9). Post-I activity is linked to the control of laryngeal adductors that control expiratory airflow and protect the lower airways from aspiration during swallowing. Active breath-hold with laryngeal closure is a common feature of RTT (6,7,10).This raises the possibility that the apneas are due to overactive brainstem expiratory neurons in Mecp2 heterozygote mice, perhaps consequent to a lack of synaptic inhibitory control. In this regard, examination of GABA synaptic inhibition in the ventrolateral medulla of Mec...

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“…8, B, B1, and B2. Based on experimental evidence that stimulation of the dorsolateral pons (PB/KF region) provides strong activation of post-I neurons (Dutschmann and Herbert 2006;Rybak et al 2004a), we suggested that a major portion of excitatory tonic drive to post-I neurons of BötC comes from the pons. In contrast, the aug-E population in the model is less dependent on pontine drive but receives a major excitatory drive from the RTN and other medullary sources.…”

Section: Modeling Reorganization Of Rhythm Generating Mechanisms Aftementioning

confidence: 99%

Spatial and Functional Architecture of the Mammalian Brain Stem Respiratory Network: A Hierarchy of Three Oscillatory Mechanisms

Smith¹,

Abdala²,

Koizumi³

et al. 2007

Journal of Neurophysiology

410

704

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Smith JC, Abdala AP, Koizumi H, Rybak IA, Paton JF. Spatial and functional architecture of the mammalian brain stem respiratory network: a hierarchy of three oscillatory mechanisms. J Neurophysiol 98: 3370 -3387, 2007. First published October 3, 2007; doi:10.1152/jn.00985.2007. Mammalian central pattern generators (CPGs) producing rhythmic movements exhibit extremely robust and flexible behavior. Network architectures that enable these features are not well understood. Here we studied organization of the brain stem respiratory CPG. By sequential rostral to caudal transections through the pontine-medullary respiratory network within an in situ perfused rat brain stem-spinal cord preparation, we showed that network dynamics reorganized and new rhythmogenic mechanisms emerged. The normal three-phase respiratory rhythm transformed to a two-phase and then to a one-phase rhythm as the network was reduced. Expression of the three-phase rhythm required the presence of the pons, generation of the two-phase rhythm depended on the integrity of Bötzinger and pre-Bötzinger complexes and interactions between them, and the one-phase rhythm was generated within the pre-Bötzinger complex. Transformation from the three-phase to a two-phase pattern also occurred in intact preparations when chloridemediated synaptic inhibition was reduced. In contrast to the threephase and two-phase rhythms, the one-phase rhythm was abolished by blockade of persistent sodium current (I NaP ). A model of the respiratory network was developed to reproduce and explain these observations. The model incorporated interacting populations of respiratory neurons within spatially organized brain stem compartments. Our simulations reproduced the respiratory patterns recorded from intact and sequentially reduced preparations. Our results suggest that the three-phase and two-phase rhythms involve inhibitory network interactions, whereas the one-phase rhythm depends on I NaP . We conclude that the respiratory network has rhythmogenic capabilities at multiple levels of network organization, allowing expression of motor patterns specific for various physiological and pathophysiological respiratory behaviors. I N T R O D U C T I O NThe structural and functional organizations of various central pattern generators (CPGs) producing rhythmic movements have been studied for decades in an attempt to understand the neural basis of motor behavior. In contrast to CPGs in several invertebrates and lower vertebrates (Grillner 2006;Marder and Calabrese 1996;Selverston and Ayers 2006), the spatial and functional architectures of CPG circuits in the mammalian CNS, such as those generating breathing movements, have not been well defined. Breathing in mammals is a dynamically mutable motor behavior that not only performs a vital homeostatic function but is also integrated with many other physiological functions including suckling, swallowing, sniffing, chewing, and vocalization. With such functional diversity, respiratory CPG circuits must have a robust, yet highly flexible organ...

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The Kölliker‐Fuse nucleus gates the postinspiratory phase of the respiratory cycle to control inspiratory off‐switch and upper airway resistance in rat

Cited by 257 publications

References 64 publications

Spatial organization and state-dependent mechanisms for respiratory rhythm and pattern generation

Spatial organization and state-dependent mechanisms for respiratory rhythm and pattern generation

Correction of respiratory disorders in a mouse model of Rett syndrome

Spatial and Functional Architecture of the Mammalian Brain Stem Respiratory Network: A Hierarchy of Three Oscillatory Mechanisms

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