Mathias Dutschmann

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

Lesion or pharmacological manipulation of the dorsolateral pons can transform the breathing pattern to apneusis (pathological prolonged inspiration). Apneusis reflects a disturbed inspiratory off‐switch mechanism (IOS) leading to a delayed phase transition from inspiration to expiration. Under intact conditions the IOS is irreversibly mediated via activation of postinspiratory (PI) neurons within the respiratory network. In parallel, populations of laryngeal premotoneurons manifest the IOS by a brief glottal constriction during the PI phase. We investigated effects of pontine excitation (glutamate injection) or temporary lesion after injection of a GABA‐receptor agonist (isoguvacine) on the strength of PI‐pool activity determined from respiratory motor outputs or kinesiological measurements of laryngeal resistance in a perfused brainstem preparation. Glutamate microinjections into distinct parts of the pontine Kölliker‐Fuse nucleus (KF) evoked a tonic excitation of PI‐motor activity or sustained laryngeal constriction accompanied by prolongation of the expiratory phase. Subsequent isoguvacine microinjections at the same loci abolished PI‐motor or laryngeal constrictor activity, triggered apneusis and established a variable and decreased breathing frequency. In summary, we revealed that excitation or inhibition of defined areas within the KF activated and blocked PI activity and, consequently, IOS. Therefore, we conclude, first, that descending KF inputs are essential to gate PI activity required for a proper pattern formation and phase control within the respiratory network, at least during absence of pulmonary stretch receptor activity and, secondly, that the KF contains large numbers of laryngeal PI premotor neurons that might have a key role in the regulation of upper airway resistance during reflex control and vocalization.

Modeling the ponto-medullary respiratory network.

The generation and shaping of the respiratory motor pattern are performed in the lower brainstem and involve neuronal interactions within the medulla and between the medulla and pons. A computational model of the ponto-medullary respiratory network has been developed by incorporating existing experimental data on the medullary neural circuits and possible interactions between the medulla and pons. The model reproduces a number of experimental findings concerning alterations of the respiratory pattern following various perturbations/stimulations applied to the pons and pulmonary afferents. The results of modeling support the concept that eupneic respiratory rhythm generation requires contribution of the pons whereas a gasping-like rhythm (and the rhythm observed in vitro) may be generated within the medulla and involve pacemaker-driven mechanisms localized within the medullary pre-Botzinger Complex. The model and experimental data described support the concept that during eupnea the respiration-related pontine structures control the medullary network mechanisms for respiratory phase transitions, suppress the intrinsic pacemaker-driven oscillations in the pre-BotC and provide inspiration-inhibitory and expiration-facilitatory reflexes which are independent of the pulmonary Hering-Breuer reflex but operate through the same medullary phase switching circuits.

Breathing dysfunctions associated with impaired control of postinspiratory activity in Mecp2−/y knockout mice

Rett syndrome (RTT) is an inborn neurodevelopmental disorder caused by mutations in the X‐linked methyl‐CpG binding protein 2 gene (MECP2). Besides mental retardation, most patients suffer from potentially life‐threatening breathing arrhythmia. To study its pathophysiology, we performed comparative analyses of the breathing phenotype of Mecp2−/y knockout (KO) and C57BL/6J wild‐type mice using the perfused working heart–brainstem preparation (WHBP). We simultaneously recorded phrenic and efferent vagal nerve activities to analyse the motor pattern of respiration, discriminating between inspiration, postinspiration and late expiration. Our results revealed respiratory disturbances in KO preparations that were similar to those reported from in vivo measurements in KO mice and also to those seen in RTT patients. The main finding was a highly variable postinspiratory activity in KO mice that correlated closely with breathing arrhythmias leading to repetitive apnoeas even under undisturbed control conditions. Analysis of the pontine and peripheral sensory regulation of postinspiratory activity in KO preparations revealed: (i) prolonged apnoeas associated with enhanced postinspiratory activity after glutamate‐induced activation of the pontine Kölliker‐Fuse nucleus; and (ii) prolonged apnoeas and lack of reflex desensitization in response to repetitive vagal stimulations. We conclude that impaired network and sensory mediated synaptic control of postinspiration induces severe breathing dysfunctions in Mecp2−/y KO preparations. As postinspiration is particularly important for the control of laryngeal adductors, the finding might explain the upper airway‐related clinical problems of patients with RTT such as apnoeas, loss of speech and weak coordination of breathing and swallowing.

Breathing disorders in Rett syndrome: progressive neurochemical dysfunction in the respiratory network after birth.

Disorders of respiratory control are a prominent feature of Rett syndrome (RTT), a severely debilitating condition caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2). RTT patients present with a complex respiratory phenotype that can include periods of hyperventilation, apnea, breath holds terminated by Valsalva maneuvers, forced and deep breathing and apneustic breathing, as well as abnormalities of heart rate control and cardiorespiratory integration. Recent studies of mouse models of RTT have begun to shed light on neurologic deficits that likely contribute to respiratory dysfunction including, in particular, defects in neurochemical signaling resulting from abnormal patterns of neurotransmitter and neuromodulator expression. The authors hypothesize that breathing dysregulation in RTT results from disturbances in mechanisms that modulate the respiratory rhythm, acting either alone or in combination with more subtle disturbances in rhythm and pattern generation. This article reviews the evidence underlying this hypothesis as well as recent efforts to translate our emerging understanding of neurochemical defects in mouse models of RTT into preclinical trials of potential treatments for respiratory dysfunction in this disease.

Correction of respiratory disorders in a mouse model of Rett syndrome

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.

Activation of XII motoneurons and premotor neurons during various oropharyngeal behaviors

Neural control of tongue muscles plays a crucial role in a broad range of oropharyngeal behaviors. Tongue movements must be rapidly and accurately adjusted in response to the demands of multiple complex motor tasks including licking/mastication, swallowing, vocalization, breathing and protective reflexes such as coughing. Yet, central mechanisms responsible for motor and premotor control of hypoglossal (XII) activity during these behaviors are still largely unknown. The aim of this article is to review the functional organization of the XII motor nucleus with particular emphasis on breathing, coughing and swallowing. Anatomical localization of XII premotor neurons is also considered. We discuss results concerned with multifunctional activity of medullary and pontine populations of XII premotor neurons, representing a single network that can be reconfigured to produce different oromotor response patterns. In this context, we introduce new data on swallowing-related activity of XII (and trigeminal) motoneurons, and finally suggest a prominent role for the pontine Kölliker-Fuse nucleus in the control of inspiratory-related activity of XII motoneurons supplying tongue protrusor and retrusor muscles.

The role of serotonin in respiratory function and dysfunction

Serotonin (5-HT) is a neuromodulator-transmitter influencing global brain function. Past and present findings illustrate a prominent role for 5-HT in the modulation of ponto-medullary autonomic circuits. 5-HT is also involved in the control of neurotrophic processes during pre- and postnatal development of neural circuits. The functional implications of 5-HT are particularly illustrated in the alterations to the serotonergic system, as seen in a wide range of neurological disorders. This article reviews the role of 5-HT in the development and control of respiratory networks in the ponto-medullary brainstem. The review further examines the role of 5-HT in breathing disorders occurring at different stages of life, in particular, the neonatal neurodevelopmental diseases such as Rett, sudden infant death and Prader-Willi syndromes, adult diseases such as sleep apnoea and mental illness linked to neurodegeneration.

Oral treatment with desipramine improves breathing and life span in Rett syndrome mouse model

Rett syndrome is a neurodevelopmental disease due to Mecp2 gene mutations that is associated to complex neurological symptoms, with bioaminergic deficits and life-threatening apneas related to sudden and unexpected death. In male mice, Mecp2-deficiency similarly induces medullary bioaminergic deficits, severe apneas and short life span. Here, we show that long-term oral treatment of Mecp2-deficient male mice with desipramine, an old drug of clinical use known to block norepinephrine uptake and to strengthen its synaptic effects, significantly alleviates their breathing symptoms and prolongs their life span. Although these mouse results identify desipramine as the first oral pharmacological treatment potentially able to alleviate breathing symptoms of Rett syndrome, we recommend further studies of desipramine effects in Mecp2-deficient mice before attempting any clinical trials in Rett patients.

The Kolliker-Fuse nucleus mediates the trigeminally induced apnoea in the rat

The present study examined whether the Kölliker-Fuse nucleus (KF) plays a role in mediating the trigeminally induced apnoea which occurs after noxious perturbation of the nasal mucosa. We stimulated the ethmoidal nerve (EN5) electrically and recorded respiratory responses before and after injections of the calcium channel blocker CoCl2 into the KF. Unilateral EN5 stimulations resulted in an apnoea or in a reduction of respiratory frequency and tidal volume. EN5 stimulations immediately after ipsilateral CoCl2 injections into the caudal KF caused only minor respiratory suppression, indicating a blockade of synaptic transmission. Recovery of the respiratory responses was observed 15-120 min after the CoCl2 injection. Our data strongly suggest that the caudal KF is an obligatory relay site for trigeminally induced apnoea.

NMDA and GABAA receptors in the rat Kölliker-Fuse area control cardiorespiratory responses evoked by trigeminal ethmoidal nerve stimulation

1 Electrical stimulation (10 s) of the ethmoidal nerve (EN5) evokes the nasotrigeminal reflex responses, including apnoea, bradycardia and rise in arterial blood pressure. In the present study, we examined the involvement of N‐methyl‐D‐aspartate (NMDA), AMPA/kainate, (γ‐aminobutyric acidA (GABAA) and glycine receptors in the Kölliker‐Fuse (KF) nucleus in the mediation of the nasotrigeminal reflex responses. 2 Unilateral injections (n= 6) of 50‐100 nl of the NMDA receptor antagonist AP5 into the KF area led to a significant blockade of the EN5‐evoked respiratory depression and bradycardia. Injections placed into the midlevel of the KF area were most effective (80‐90 % blockade). The rise in arterial blood pressure remained unaffected. 3 Unilateral injections (n= 6) of the AMPA/kainate receptor antagonist CNQX into the KF area failed to block EN5‐evoked autonomic responses significantly. 4 Unilateral injections (n= 5) of the GABAA receptor antagonist bicuculline enhanced the EN5‐evoked respiratory depression and bradycardia. The effect persisted for up to 30 s after stimulation. Bicuculline injections into the midlevel of the KF area were most effective. The increase in arterial blood pressure remained unaffected. 5 Unilateral injections (n= 5) of the glycine receptor antagonist strychnine into the KF area did not produce any significant effects on EN5‐evoked autonomic responses. 6 Our results suggest that the KF area represents a mandatory relay for the nasotrigeminally induced apnoea and bradycardia which are predominantly mediated by NMDA receptors in the KF. Furthermore, it appears that KF neurons are under a potent GABAergic inhibitory control. The EN5‐evoked rise in arterial blood pressure was not altered by any of the drugs and, therefore, appears not to be mediated via the KF.