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Szu-Ying Yeh, Wei-Hsiang Huang, Wei Wang, Christopher S Ward, Eugene S Chao, Zhenyu Wu, Bin Tang, Jianrong Tang, Jenny J Sun, Meike Esther van der Heijden, Paul A Gray, Mingshan Xue, Russell S Ray, Dejian Ren, Huda Y Zoghbi
Respiration is a rhythmic activity as well as one that requires responsiveness to internal and external circumstances; both the rhythm and neuromodulatory responses of breathing are controlled by brainstem neurons in the preBötzinger complex (preBötC) and the retrotrapezoid nucleus (RTN), but the specific ion channels essential to these activities remain to be identified. Because deficiency of sodium leak channel, non-selective (Nalcn) causes lethal apnea in humans and mice, we investigated Nalcn function in these neuronal groups...
April 19, 2017: Neuron
Kevin Yackle, Lindsay A Schwarz, Kaiwen Kam, Jordan M Sorokin, John R Huguenard, Jack L Feldman, Liqun Luo, Mark A Krasnow
Slow, controlled breathing has been used for centuries to promote mental calming, and it is used clinically to suppress excessive arousal such as panic attacks. However, the physiological and neural basis of the relationship between breathing and higher-order brain activity is unknown. We found a neuronal subpopulation in the mouse preBötzinger complex (preBötC), the primary breathing rhythm generator, which regulates the balance between calm and arousal behaviors. Conditional, bilateral genetic ablation of the ~175 Cdh9/Dbx1 double-positive preBötC neurons in adult mice left breathing intact but increased calm behaviors and decreased time in aroused states...
March 31, 2017: Science
Tatiana M Anderson, Jan-Marino Ramirez
Breathing is vital for survival but also interesting from the perspective of rhythm generation. This rhythmic behavior is generated within the brainstem and is thought to emerge through the interaction between independent oscillatory neuronal networks. In mammals, breathing is composed of three phases - inspiration, post-inspiration, and active expiration - and this article discusses the concept that each phase is generated by anatomically distinct rhythm-generating networks: the preBötzinger complex (preBötC), the post-inspiratory complex (PiCo), and the lateral parafacial nucleus (pF L), respectively...
2017: F1000Research
Rozlyn C T Boutin, Zaki Alsahafi, Silvia Pagliardini
KEY POINTS: This study investigates the effects of cholinergic transmission on the expiratory oscillator, the parafacial respiratory group (pFRG) in urethane anaesthetized adult rats. Local inhibition of the acetyl cholinesterase enzyme induced activation of expiratory abdominal muscles and active expiration. Local application of the cholinomimetic carbachol elicited recruitment of late expiratory neurons, expiratory abdominal muscle activity and active expiration. This effect was antagonized by local application of the muscarinic antagonists scopolamine, J104129 and 4DAMP...
February 15, 2017: Journal of Physiology
Nikolas C Vann, Francis D Pham, John A Hayes, Andrew Kottick, Christopher A Del Negro
Interneurons derived from Dbx1-expressing precursors located in the brainstem preBötzinger complex (preBötC) putatively form the core oscillator for inspiratory breathing movements. We tested this Dbx1 core hypothesis by expressing archaerhodopsin in Dbx1-derived interneurons and then transiently hyperpolarizing these neurons while measuring respiratory rhythm in vitro or breathing in vagus-intact adult mice. Transient illumination of the preBötC interrupted inspiratory rhythm in both slice preparations and sedated mice...
2016: PloS One
Gaspard Montandon, Hattie Liu, Richard L Horner
Breathing is generated by a respiratory network in the brainstem. At its core, a population of neurons expressing neurokinin-1 receptors (NK1R) and the peptide somatostatin (SST) form the preBötzinger Complex (preBötC), a site essential for the generation of breathing. PreBötC interneurons generate rhythm and follower neurons shape motor outputs by activating upper airway respiratory muscles. Since NK1R-expressing preBötC neurons are preferentially inhibited by μ-opioid receptors via activation of GIRK channels, NK1R stimulation may also involve GIRK channels...
2016: Scientific Reports
Yan Cui, Kaiwen Kam, David Sherman, Wiktor A Janczewski, Yu Zheng, Jack L Feldman
Normal breathing in rodents requires activity of glutamatergic Dbx1-derived (Dbx1(+)) preBötzinger Complex (preBötC) neurons expressing somatostatin (SST). We combined in vivo optogenetic and pharmacological perturbations to elucidate the functional roles of these neurons in breathing. In transgenic adult mice expressing channelrhodopsin (ChR2) in Dbx1(+) neurons, photoresponsive preBötC neurons had preinspiratory or inspiratory firing patterns associated with excitatory effects on burst timing and pattern...
August 3, 2016: Neuron
K Tree, J C Viemari, F Cayetanot, J Peyronnet
Impaired transplacental supply of oxygen leads to intrauterine growth restriction, one of the most important causes of perinatal mortality and respiratory morbidity. Breathing rhythm depends on the central respiratory network modulated by catecholamines. We investigated the impact of growth restriction, using prenatal hypoxia, on respiratory frequency, on central respiratory-like rhythm, and on its catecholaminergic modulation after birth. At birth, respiratory frequency was increased and confirmed in en bloc medullary preparations, where the frequency of the fourth cervical (C4) ventral root discharge was increased, and in slice preparations containing the pre-Bötzinger complex with an increased inspiratory rhythm...
October 1, 2016: Journal of Neurophysiology
Tatiana M Anderson, Alfredo J Garcia, Nathan A Baertsch, Julia Pollak, Jacob C Bloom, Aguan D Wei, Karan G Rai, Jan-Marino Ramirez
Breathing must be tightly coordinated with other behaviours such as vocalization, swallowing, and coughing. These behaviours occur after inspiration, during a respiratory phase termed postinspiration. Failure to coordinate postinspiration with inspiration can result in aspiration pneumonia, the leading cause of death in Alzheimer's disease, Parkinson's disease, dementia, and other neurodegenerative diseases. Here we describe an excitatory network that generates the neuronal correlate of postinspiratory activity in mice...
August 4, 2016: Nature
J Muñoz-Ortiz, E Muñoz-Ortiz, M L López-Meraz, L Beltran-Parrazal, C Morgado-Valle
INTRODUCTION: In mammals, the preBötzinger complex (preBötC) is a bilateral and symmetrical neural network located in the brainstem which is essential for the generation and modulation of respiratory rhythm. There are few human studies about the preBötC and, its relationship with neurological diseases has not been described. However, the importance of the preBötC in neural control of breathing and its potential participation in neurological diseases in humans, has been suggested based on pharmacological manipulation and lesion of the preBötC in animal models, both in vivo and in vitro...
July 18, 2016: Neurología: Publicación Oficial de la Sociedad Española de Neurología
Marc Chevalier, Natalia Toporikova, John Simmers, Muriel Thoby-Brisson
Breathing is a vital rhythmic behavior generated by hindbrain neuronal circuitry, including the preBötzinger complex network (preBötC) that controls inspiration. The emergence of preBötC network activity during prenatal development has been described, but little is known regarding inspiratory neurons expressing pacemaker properties at embryonic stages. Here, we combined calcium imaging and electrophysiological recordings in mouse embryo brainstem slices together with computational modeling to reveal the existence of heterogeneous pacemaker oscillatory properties relying on distinct combinations of burst-generating INaP and ICAN conductances...
2016: ELife
Hanbing Song, John A Hayes, Nikolas C Vann, Xueying Wang, M Drew LaMar, Christopher A Del Negro
UNLABELLED: Breathing in mammals depends on rhythms that originate from the preBötzinger complex (preBötC) of the ventral medulla and a network of brainstem and spinal premotor neurons. The rhythm-generating core of the preBötC, as well as some premotor circuits, consist of interneurons derived from Dbx1-expressing precursors (Dbx1 neurons), but the structure and function of these networks remain incompletely understood. We previously developed a cell-specific detection and laser ablation system to interrogate respiratory network structure and function in a slice model of breathing that retains the preBötC, the respiratory-related hypoglossal (XII) motor nucleus and XII premotor circuits...
July 6, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
David Forsberg, Zachi Horn, Evangelia Tserga, Erik Smedler, Gilad Silberberg, Yuri Shvarev, Kai Kaila, Per Uhlén, Eric Herlenius
Inflammation-induced release of prostaglandin E2 (PGE2) changes breathing patterns and the response to CO2 levels. This may have fatal consequences in newborn babies and result in sudden infant death. To elucidate the underlying mechanisms, we present a novel breathing brainstem organotypic culture that generates rhythmic neural network and motor activity for 3 weeks. We show that increased CO2 elicits a gap junction-dependent release of PGE2. This alters neural network activity in the preBötzinger rhythm-generating complex and in the chemosensitive brainstem respiratory regions, thereby increasing sigh frequency and the depth of inspiration...
2016: ELife
Robert Tr Huckstepp, Lauren E Henderson, Kathryn P Cardoza, Jack L Feldman
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...
2016: ELife
Marc Chevalier, Rafaël De Sa, Laura Cardoit, Muriel Thoby-Brisson
Breathing is a rhythmic behavior that requires organized contractions of respiratory effector muscles. This behavior must adapt to constantly changing conditions in order to ensure homeostasis, proper body oxygenation, and CO2/pH regulation. Respiratory rhythmogenesis is controlled by neural networks located in the brainstem. One area considered to be essential for generating the inspiratory phase of the respiratory rhythm is the preBötzinger complex (preBötC). Rhythmogenesis emerges from this network through the interplay between the activation of intrinsic cellular properties (pacemaker properties) and intercellular synaptic connections...
2016: Neural Plasticity
Ann L Revill, Nikolas C Vann, Victoria T Akins, Andrew Kottick, Paul A Gray, Christopher A Del Negro, Gregory D Funk
All behaviors require coordinated activation of motoneurons from central command and premotor networks. The genetic identities of premotoneurons providing behaviorally relevant excitation to any pool of respiratory motoneurons remain unknown. Recently, we established in vitro that Dbx1-derived pre-Bötzinger complex neurons are critical for rhythm generation and that a subpopulation serves a premotor function (Wang et al., 2014). Here, we further show that a subpopulation of Dbx1-derived intermediate reticular (IRt) neurons are rhythmically active during inspiration and project to the hypoglossal (XII) nucleus that contains motoneurons important for maintaining airway patency...
December 19, 2015: ELife
Jonathan-Julio Lorea-Hernández, Teresa Morales, Ana-Julia Rivera-Angulo, David Alcantara-Gonzalez, Fernando Peña-Ortega
Inflammation has been linked to the induction of apneas and Sudden Infant Death Syndrome, whereas proinflammatory mediators inhibit breathing when applied peripherally or directly into the CNS. Considering that peripheral inflammation can activate microglia in the CNS and that this cell type can directly release all proinflammatory mediators that modulate breathing, it is likely that microglia can modulate breathing generation. It might do so also in hypoxia, since microglia are sensitive to hypoxia, and peripheral proinflammatory conditions affect gasping generation and autoresuscitation...
April 2016: Glia
Wiktor S Phillips, Mikkel Herly, Christopher A Del Negro, Jens C Rekling
Study of acute brain stem slice preparations in vitro has advanced our understanding of the cellular and synaptic mechanisms of respiratory rhythm generation, but their inherent limitations preclude long-term manipulation and recording experiments. In the current study, we have developed an organotypic slice culture preparation containing the preBötzinger complex (preBötC), the core inspiratory rhythm generator of the ventrolateral brain stem. We measured bilateral synchronous network oscillations, using calcium-sensitive fluorescent dyes, in both ventrolateral (presumably the preBötC) and dorsomedial regions of slice cultures at 7-43 days in vitro...
February 1, 2016: Journal of Neurophysiology
Sheng Le, Anita J Turner, Lindsay M Parker, Peter G Burke, Natasha N Kumar, Ann K Goodchild, Simon McMullan
Microinjection of somatostatin (SST) causes site-specific effects on respiratory phase transition, frequency, and amplitude when microinjected into the ventrolateral medulla (VLM) of the anesthetized rat, suggesting selective expression of SST receptors on different functional classes of respiratory neurons. Of the six subtypes of SST receptor, somatostatin 2a (sst2a ) is the most prevalent in the VLM, and other investigators have suggested that glutamatergic neurons in the preBötzinger Complex (preBötC) that coexpress neurokinin-1 receptor (NK1R), SST, and sst2a are critical for the generation of respiratory rhythm...
May 1, 2016: Journal of Comparative Neurology
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