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Nathan Andrew Baertsch, Hans Christopher Baertsch, Jan Marino Ramirez
The preBötzinger Complex (preBötC), a medullary network critical for breathing, relies on excitatory interneurons to generate the inspiratory rhythm. Yet, half of preBötC neurons are inhibitory, and the role of inhibition in rhythmogenesis remains controversial. Using optogenetics and electrophysiology in vitro and in vivo, we demonstrate that the intrinsic excitability of excitatory neurons is reduced following large depolarizing inspiratory bursts. This refractory period limits the preBötC to very slow breathing frequencies...
February 26, 2018: Nature Communications
Cindy F Yang, Jack L Feldman
The preBötzinger complex (preBötC), a compact medullary region essential for generating normal breathing rhythm and pattern, is the kernel of the breathing central pattern generator (CPG). Excitatory preBötC neurons in rats project to major breathing-related brainstem regions. Here, we provide a brainstem connectivity map in mice for both excitatory and inhibitory preBötC neurons. Using a genetic strategy to label preBötC neurons, we confirmed extensive projections of preBötC excitatory neurons within the brainstem breathing CPG including the contralateral preBötC, Bötzinger Complex (BötC), ventral respiratory group (VRG), nucleus of the solitary tract (NTS), parahypoglossal nucleus, parafacial region (RTN/pFRG or alternatively, pFL /pFV ), parabrachial and Kölliker-Füse nuclei, as well as major projections to the midbrain periaqueductal gray (PAG)...
February 23, 2018: Journal of Comparative Neurology
Wiktor S Phillips, Christopher A Del Negro, Jens C Rekling
The brainstem preBötzinger complex (preBötC) generates the inspiratory rhythm for breathing. The onset of neural activity that precipitates the inspiratory phase of the respiratory cycle may depend on the activity of type-1 preBötC neurons, which exhibit a transient outward K+ current, IA Inspiratory rhythm generation can be studied ex vivo since the preBötC remains rhythmically active in vitro , both in acute brainstem slices and organotypic cultures. Advantageous optical conditions in organotypic slice cultures from newborn mice of either sex allowed us to investigate how IA impacts Ca2+ transients occurring in the dendrites of rhythmically active type-1 preBötC neurons...
February 19, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Shahriar Sheikhbahaei, Egor A Turovsky, Patrick S Hosford, Anna Hadjihambi, Shefeeq M Theparambil, Beihui Liu, Nephtali Marina, Anja G Teschemacher, Sergey Kasparov, Jeffrey C Smith, Alexander V Gourine
Astrocytes are implicated in modulation of neuronal excitability and synaptic function, but it remains unknown if these glial cells can directly control activities of motor circuits to influence complex behaviors in vivo. This study focused on the vital respiratory rhythm-generating circuits of the preBötzinger complex (preBötC) and determined how compromised function of local astrocytes affects breathing in conscious experimental animals (rats). Vesicular release mechanisms in astrocytes were disrupted by virally driven expression of either the dominant-negative SNARE protein or light chain of tetanus toxin...
January 25, 2018: Nature Communications
Gaspard Montandon, Haiying Wu, Hattie Liu, Michael T Vu, Beverley A Orser, Richard L Horner
Persistent and stable respiratory activity across behavioral states is key to homeostasis. Extrasynaptic δ-subunit containing GABAAreceptors (δGABAARs) mediate tonic inhibition and regulate network activity. However, the influence of δGABAARs on respiratory rhythm and motor outputs is unknown. We manipulated extra-synaptic GABAAreceptor function in the preBötzinger Complex (preBötC), a site central to the generation of inspiratory motor activity in mammals. Activation of preBötC δGABAARs in anesthetized rats and wild-type mice decreased breathing rate...
December 22, 2017: Scientific Reports
Consuelo Morgado-Valle, Luis Beltran-Parrazal
Breathing is a continuous behavior essential for life in mammals and one of the few behaviors that can be studied in vivo in intact animals awake, anesthetized or decerebrated and in highly reduced in vitro and in situ preparations. The preBötzinger complex (preBötC) is a small nucleus in the brainstem that plays an essential role in normal breathing and is widely accepted as the site necessary and sufficient for generation of the inspiratory phase of the respiratory rhythm. Substantial advances in understanding the anatomical and cellular basis of respiratory rhythmogenesis have arisen from in vitro and in vivo studies in the past 25 years; however, the underlying cellular mechanisms remain unknown...
2017: Advances in Experimental Medicine and Biology
Kendall F Morris, Sarah C Nuding, Lauren S Segers, Kimberly Erin Iceman, Russell O'Connor, Jay B Dean, Mackenzie M Ott, Pierina A Alencar, Dale Shuman, Kofi-Kermit Horton, Thomas E Taylor-Clark, Donald C Bolser, Bruce G Lindsey
We tested the hypothesis that carotid chemoreceptors tune breathing through parallel circuit paths that target distinct elements of an inspiratory neuron chain in the ventral respiratory column (VRC). Microelectrode arrays were used to monitor neuronal spike trains simultaneously in the VRC, peri-nucleus tractus solitarius-medial medulla (p-NTS-MM), the dorsal parafacial region of the lateral tegmental field (FTL-pF), and medullary raphé nuclei together with phrenic nerve activity during selective stimulation of carotid chemoreceptors or transient hypoxia in 19 decerebrate, neuromuscularly-blocked, and artificially ventilated cats...
October 18, 2017: Journal of Neurophysiology
David Forsberg, Thomas Ringstedt, Eric Herlenius
Previously (Forsberg et al., 2016), we revealed that prostaglandin E2 (PGE2), released during hypercapnic challenge, increases calcium oscillations in the chemosensitive parafacial respiratory group (pFRG/RTN). Here, we demonstrate that pFRG/RTN astrocytes are the PGE2 source. Two distinct astrocyte subtypes were found using transgenic mice expressing GFP and MrgA1 receptors in astrocytes. Although most astrocytes appeared dormant during time-lapse calcium imaging, a subgroup displayed persistent, rhythmic oscillating calcium activity...
October 6, 2017: ELife
Alfredo J Garcia, Tatiana Dashevskiy, Maggie A Khuu, Jan-Marino Ramirez
The preBötzinger complex (preBötC) is a medullary brainstem network crucially involved in the generation of different inspiratory rhythms. In the isolated brainstem slice, the preBötC reconfigures to produce different rhythms that we refer to as "fictive eupnea" under baseline conditions (i.e., carbogen), and "fictive gasping" in hypoxia. We recently demonstrated that fictive eupnea is irregular following exposure to chronic intermittent hypoxia (CIH). However, it is unknown how CIH impacts fictive gasping...
2017: Frontiers in Physiology
Jinjin Wu, Paolo Capelli, Julien Bouvier, Martyn Goulding, Silvia Arber, Gilles Fortin
Breathing in mammals relies on permanent rhythmic and bilaterally synchronized contractions of inspiratory pump muscles. These motor drives emerge from interactions between critical sets of brainstem neurons whose origins and synaptic ordered organization remain obscure. Here, we show, using a virus-based transsynaptic tracing strategy from the diaphragm muscle in the mouse, that the principal inspiratory premotor neurons share V0 identity with, and are connected by, neurons of the preBötzinger complex that paces inspiration...
September 15, 2017: Nature Communications
Lauren E McElvain, Beth Friedman, Harvey J Karten, Karel Svoboda, Fan Wang, Martin Deschênes, David Kleinfeld
The world view of rodents is largely determined by sensation on two length scales. One is within the animal's peri-personal space. Sensorimotor control on this scale involves active movements of the nose, tongue, head, and vibrissa, along with sniffing to determine olfactory clues. The second scale involves the detection of more distant space through vision and audition; these detection processes also impact repositioning of the head, eyes, and ears. Here we focus on orofacial motor actions, primarily vibrissa-based touch but including nose twitching, head bobbing, and licking, that control sensation at short, peri-personal distances...
August 23, 2017: Neuroscience
Itopa E Ajayi, Paul C Mills
Augmented breaths, also known as sighs, constitute the normal repertoire of breathing in freely behaving humans and animals. The breaths are believed to be generated by neurones in the preBötzinger complex but under modulatory influence from higher brain centres, particularly in the limbic system due to the strong correlations between the expression of emotional behaviours such as anxiety and the occurrence of augmented breaths. The current study examines the role of the hippocampus in the motor expression of augmented breaths, and also examines the characteristics of eupneic breaths surrounding a sigh before and after stimulating the hippocampus in urethane anaesthetised Sprague-Dawley rats...
2017: PloS One
John A Hayes, Andrew Kottick, Maria Cristina D Picardo, Andrew D Halleran, Ronald D Smith, Gregory D Smith, Margaret S Saha, Christopher A Del Negro
We sequenced the transcriptome of brainstem interneurons in the specialized respiratory rhythmogenic site dubbed preBötzinger Complex (preBötC) from newborn mice. To distinguish molecular characteristics of the core oscillator we compared preBötC neurons derived from Dbx1-expressing progenitors that are respiratory rhythmogenic to neighbouring non-Dbx1-derived neurons, which support other respiratory and non-respiratory functions. Results in three categories are particularly salient. First, Dbx1 preBötC neurons express κ-opioid receptors in addition to μ-opioid receptors that heretofore have been associated with opiate respiratory depression, which may have clinical applications...
August 17, 2017: Scientific Reports
Victoria T Akins, Krishanthi Weragalaarachchi, Maria Cristina D Picardo, Ann L Revill, Christopher A Del Negro
The relationship between neuron morphology and function is a perennial issue in neuroscience. Information about synaptic integration, network connectivity, and the specific roles of neuronal subpopulations can be obtained through morphological analysis of key neurons within a microcircuit. Here we present morphologies of two classes of brainstem respiratory neurons. First, interneurons derived from Dbx1-expressing precursors (Dbx1 neurons) in the preBötzinger complex (preBötC) of the ventral medulla that generate the rhythm for inspiratory breathing movements...
August 1, 2017: Scientific Data
Glauber S F da Silva, João P J Sabino, Vishaal Rajani, Tucaauê S Alvares, Silvia Pagliardini, Luiz G S Branco, Gregory D Funk
Hydrogen Sulfide (H2S) is one of three gasotransmitters that modulate excitability in the CNS. Global application of H2S donors or inhibitors of H2S synthesis to the respiratory network has suggested that inspiratory rhythm is modulated by exogenous and endogenous H2S. However, effects have been variable, which may reflect that the RTN/pFRG (retrotrapezoid nucleus, parafacial respiratory group) and the preBötzinger Complex (preBötC, critical for inspiratory rhythm generation) are differentially modulated by exogenous H2S...
2017: Frontiers in Physiology
Vishaal Rajani, Yong Zhang, Venkatesh Jalubula, Vladimir Rancic, Shahriar SheikhBahaei, Jennifer D Zwicker, Silvia Pagliardini, Clayton T Dickson, Klaus Ballanyi, Sergey Kasparov, Alexander V Gourine, Gregory D Funk
KEY POINTS: The ventilatory response to reduced oxygen (hypoxia) is biphasic, comprising an initial increase in ventilation followed by a secondary depression. Our findings indicate that, during hypoxia, astrocytes in the pre-Bötzinger complex (preBötC), a critical site of inspiratory rhythm generation, release a gliotransmitter that acts via P2Y1 receptors to stimulate ventilation and reduce the secondary depression. In vitro analyses reveal that ATP excitation of the preBötC involves P2Y1 receptor-mediated release of Ca(2+) from intracellular stores...
July 5, 2017: Journal of Physiology
Andrew Kottick, Caroline A Martin, Christopher A Del Negro
The brainstem preBötzinger complex (preBötC) generates the inspiratory breathing rhythm, and its core rhythmogenic interneurons are derived from Dbx1-expressing progenitors. To study the neural bases of breathing, tamoxifen-inducible Cre-driver mice and Cre-dependent reporters are used to identify, record, and perturb Dbx1 preBötC neurons. However, the relationship between tamoxifen administration and reporter protein expression in preBötC neurons and glia has not been quantified. To address this problem, we crossed mice that express tamoxifen-inducible Cre recombinase under the control of the Dbx1 gene (Dbx1(Cre)(ERT)(2)) with Cre-dependent fluorescent reporter mice (Rosa26(tdTomato)), administered tamoxifen at different times during development, and analyzed tdTomato expression in the preBötC of their offspring...
June 2017: Physiological Reports
Marc Chevalier, Laura Cardoit, Maïté Moreau, Nathalie Sans, Mireille Montcouquiol, John Simmers, Muriel Thoby-Brisson
The central command for breathing arises mainly from two interconnected rhythmogenic hindbrain networks, the parafacial respiratory group (pFRG or epF at embryonic stages) and the preBötzinger complex (preBötC), which are comprised of a limited number of neurons located in confined regions of the ventral medulla. In rodents, both networks become active toward the end of gestation but little is known about the signaling pathways involved in their anatomical and functional establishment during embryogenesis...
June 3, 2017: Neuroscience
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
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