Structural and functional architecture of respiratory networks in the mammalian brainstem

Smith, Jeffrey C.; Abdala, Ana Paula; Rybak, Ilya A.; Paton, Julian F. R.

doi:10.1098/rstb.2009.0081

Cited by 231 publications

(261 citation statements)

References 73 publications

Supporting

Mentioning

244

Contrasting

Unclassified

Order By: Relevance

“…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).…”

Section: Insufficient Gaba a Inhibition Underlies Tonic Activity In Ementioning

confidence: 99%

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

148

159

View full text Add to dashboard Cite

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...

show abstract

Section: Insufficient Gaba a Inhibition Underlies Tonic Activity In Ementioning

confidence: 99%

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

148

159

View full text Add to dashboard Cite

show abstract

“…The central pattern generator for respiration is located in http://dx.doi.org/10.1016/j.mehy.2014.11.010 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved. the brainstem and respiratory neurons in the central pattern generator produce synaptic drive for neurons that control respiratory muscles [9]. It has also been established that respiratory drive derives from detection of high carbon dioxide levels by peripheral chemoreceptors and receptors in the medulla [10].…”

Section: Respiratory Drivementioning

confidence: 99%

Widespread depolarization during expiration: A source of respiratory drive?

Jerath¹,

Crawford²,

Barnes

et al. 2015

Medical Hypotheses

View full text Add to dashboard Cite

a b s t r a c tRespiration influences various pacemakers and rhythms of the body during inspiration and expiration but the underlying mechanisms are relatively unknown. Understanding this phenomenon is important, as breathing disorders, breath holding, and hyperventilation can lead to significant medical conditions. We discuss the physiological modulation of heart rhythm, blood pressure, sympathetic nerve activity, EEG, and other changes observed during inspiration and expiration. We also correlate the intracellular mitochondrial respiratory metabolic processes with real-time breathing and correlate membrane potential changes with inspiration and expiration. We propose that widespread minor hyperpolarization occurs during inspiration and widespread minor depolarization occurs during expiration. This depolarization is likely a source of respiratory drive. Further knowledge of intracellular and extracellular ionic changes associated with respiration will enhance our understanding of respiration and its role as a modulator of cellular membrane potential. This could expand treatment options for a wide range of health conditions, such as breathing disorders, stress-related disorders, and further our understanding of the Hering-Breuer reflex and respiratory sinus arrhythmia.Ó 2014 Elsevier Ltd. All rights reserved. IntroductionIn addition to gas exchange and oxygenation of the blood, respiration in the lungs can regulate multiple physiological processes throughout the body. Studies of the cardiovascular system, the peripheral nervous system, and the central nervous system provide evidence that respiratory patterns can exert a significant and immediate influence on a wide range of bodily functions, including changes in blood pressure and sympathovagal balance. Patterned respiration can regulate blood pressure and heart rate [1], as well as regulate rhythmic centers of the brain that control cardiovascular output [2,3]. While the majority of these findings have demonstrated the impact of respiration on cardiac output and other processes in isolated preparations, little work has focused on respiration's direct influence on membrane potential.This article reviews the current understanding of respiration as a regulator of cardiovascular physiology and nervous system function. More specifically, we discuss the role of respiratory rhythm and rate on both systemic and local control of these systems. We describe the role of pulmonary stretch receptors (with a focus on slowly adapting receptors) in converting breathing patterns into a functional, multi-faceted, mechanism that allows respiration to communicate with, and direct various aspects of cardiovascular and nervous system physiology. We propose a hypothesis in which inspiration and expiration are associated with transient increases and decreases in membrane potential that may underlie these widespread changes and how these membrane potential changes may underlie the chaotic dynamics of rhythmic breathing.Many studies focus on the brainstem as the primary modulator of resp...

show abstract

“…Most often these different networks are studied separately from one another, perhaps because the behaviors are distinct, and the regional differentiation of hindbrain suggests that its several networks might have little in common. Thus, we have strong data for the hindbrain control of eye movements, respiration, and locomotion (3)(4)(5)(6)(7)(8)(9)(10), but fewer unifying principles of structural and functional organization that apply across the different networks.…”

mentioning

confidence: 99%

A structural and functional ground plan for neurons in the hindbrain of zebrafish

Kinkhabwala

Riley

Koyama

et al. 2011

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

191

197

View full text Add to dashboard Cite

The vertebrate hindbrain contains various sensory-motor networks controlling movements of the eyes, jaw, head, and body. Here we show that stripes of neurons with shared neurotransmitter phenotype that extend throughout the hindbrain of young zebrafish reflect a broad underlying structural and functional patterning. The neurotransmitter stripes contain cell types with shared gross morphologies and transcription factor markers. Neurons within a stripe are stacked systematically by extent and location of axonal projections, input resistance, and age, and are recruited along the axis of the stripe during behavior. The implication of this pattern is that the many networks in hindbrain are constructed from a series of neuronal components organized into stripes that are ordered from top to bottom according to a neuron's age, structural and functional properties, and behavioral roles. This simple organization probably forms a foundation for the construction of the networks underlying the many behaviors produced by the hindbrain.interneuron | locomotion | recruitment | topography T he hindbrain contains a diverse set of sensory-motor networks that control movements required for vision, respiration, mastication, and locomotion in all vertebrates (1, 2). Most often these different networks are studied separately from one another, perhaps because the behaviors are distinct, and the regional differentiation of hindbrain suggests that its several networks might have little in common. Thus, we have strong data for the hindbrain control of eye movements, respiration, and locomotion (3-10), but fewer unifying principles of structural and functional organization that apply across the different networks.Structurally, the hindbrain is divided into segments, called rhombomeres, which differ in the expression of homeotic genes, in the morphological differentiation of neurons, and in their sensory inputs and motor outputs (2, 11). Though there are clear distinctions among rhombomeres, there are indications from previous developmental work using in situ staining for transcription factors and backfilling of hindbrain neurons that there may be structural patterns that cross rhombomere boundaries (12-16). Prior work has also revealed parallels in the development of hindbrain and spinal cord, with the hindbrain sharing features of the now-classic transcription factor code that directs development in spinal cord (17)(18)(19)(20)(21)(22). Though these studies did not explore function because they were performed during early development, they raised the possibility of a broader structuralfunctional patterning that spans rhomobomeres and may underlie the organization of circuits for different behaviors.Here we show that there is indeed a broad structural and functional patterning of neurons in the hindbrain of young zebrafish. The work was initially prompted by a striking patterning observed in earlier work in which we used in situ staining for markers of neurotransmitter phenotype to reveal putative glycinergic, GABAergic, and glutamatergic ...

show abstract

Structural and functional architecture of respiratory networks in the mammalian brainstem

Cited by 231 publications

References 73 publications

Correction of respiratory disorders in a mouse model of Rett syndrome

Correction of respiratory disorders in a mouse model of Rett syndrome

Widespread depolarization during expiration: A source of respiratory drive?

A structural and functional ground plan for neurons in the hindbrain of zebrafish

Contact Info

Product

Resources

About