The Experts below are selected from a list of 687 Experts worldwide ranked by ideXlab platform
Jack L. Feldman - One of the best experts on this subject based on the ideXlab platform.
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Monosynaptic projections to excitatory and inhibitory preBötzinger Complex neurons
bioRxiv, 2019Co-Authors: Cindy F. Yang, Edward M. Callaway, Jack L. FeldmanAbstract:The key driver of breathing rhythm is the preBotzinger Complex (preBotC) whose activity is modulated by various categorical inputs, e.g., volitional, physiological, emotional. While the preBotC is highly interconnected with other regions of the breathing central pattern generator (bCPG) in the brainstem, there is no data about the direct projections to either excitatory and inhibitory preBotC subpopulations from other elements of the bCPG or from suprapontine regions. Using modified rabies tracing, we identified neurons throughout the brain that send monosynaptic projections to identified excitatory and inhibitory preBotC neurons. Within the brainstem, neurons from sites in the bCPG, including the contralateral preBotC, Botzinger Complex (BotC), the nucleus of the solitary tract (NTS), Parafacial region (pFL/pFV or RTN/pFRG), and parabrachial nuclei, send direct projections to both excitatory and inhibitory preBotC neurons. Suprapontine inputs to the excitatory and inhibitory preBotC neurons include the superior colliculus, red nucleus, amygdala, hypothalamus, and cortex; these projections represent potential direct pathways for volitional, emotional, and physiological control of breathing.
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distinct Parafacial regions in control of breathing in adult rats
PLOS ONE, 2018Co-Authors: Robert T R Huckstepp, Kathryn P Cardoza, Lauren E Henderson, Jack L. FeldmanAbstract:Recently, based on functional differences, we subdivided neurons juxtaposed to the facial nucleus into two distinct populations, the Parafacial ventral and lateral regions, i.e., pFV and pFL. Little is known about the composition of these regions, i.e., are they homogenous or heterogeneous populations? Here, we manipulated their excitability in spontaneously breathing vagotomized urethane anesthetized adult rats to further characterize their role in breathing. In the pFL, disinhibition or excitation decreased breathing frequency (f) with a concomitant increase of tidal volume (VT), and induced active expiration; in contrast, reducing excitation had no effect. This result is congruent with pFL neurons constituting a conditional expiratory oscillator comprised of a functionally homogeneous set of excitatory neurons that are tonically suppressed at rest. In the pFV, disinhibition increased f with a presumptive reflexive decrease in VT; excitation increased f, VT and sigh rate; reducing excitation decreased VT with a presumptive reflexive increase in f. Therefore, the pFV, has multiple functional roles that require further parcellation. Interestingly, while hyperpolarization of the pFV reduces ongoing expiratory activity, no perturbation of pFV excitability induced active expiration. Thus, while the pFV can affect ongoing expiratory activity, presumably generated by the pFL, it does not appear capable of directly inducing active expiration. We conclude that the pFL contains neurons that can initiate, modulate, and sustain active expiration, whereas the pFV contains subpopulations of neurons that differentially affect various aspects of breathing pattern, including but not limited to modulation of ongoing expiratory activity.
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Interactions between respiratory oscillators in adult rats
eLife, 2016Co-Authors: Robert T R Huckstepp, Kathryn P Cardoza, Lauren E Henderson, Jack L. FeldmanAbstract:Mammals breathe air into and out of their lungs to absorb oxygen into the body and to remove carbon dioxide. The rhythm of breathing is most likely controlled by two groups of neurons in a part of the brain called the brain stem. One group called the preBotzinger Complex drives breathing in (inspiration), and normally, breathing out (expiration) occurs when the muscles responsible for inspiration relax. The other group of neurons – known as the lateral Parafacial region – controls extra muscles that allow us to increase our breathing when we need to, such as during exercise. Huckstepp et al. set out to determine how these two groups of neurons interact with one another in anesthetized rats to produce a reliable and efficient pattern of breathing. The experiments provide further evidence that inspiration is mainly driven by the preBotzinger Complex. Whilst activity from the lateral Parafacial region is needed to cause the rats to breathe out more forcefully than normal, a second low level of activity from another source is also required. This source could either be the preBotzinger Complex, or some unknown neurons that change their activity in response to the levels of oxygen and carbon dioxide in the blood or fluid of the brain. Further investigation is required to identify how these interactions go awry in diseases that affect breathing, such as sleep apneas.
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The peptidergic control circuit for sighing
Nature, 2016Co-Authors: Peng Li, Wiktor A. Janczewski, Kevin Yackle, Kaiwen Kam, Silvia Pagliardini, Mark A. Krasnow, Jack L. FeldmanAbstract:© 2016 Macmillan Publishers Limited. Sighs are long, deep breaths expressing sadness, relief or exhaustion. Sighs also occur spontaneously every few minutes to reinflate alveoli, and sighing increases under hypoxia, stress, and certain psychiatric conditions. Here we use molecular, genetic, and pharmacologic approaches to identify a peptidergic sigh control circuit in murine brain. Small neural subpopulations in a key breathing control centre, the retrotrapezoid nucleus/Parafacial respiratory group (RTN/pFRG), express bombesin-like neuropeptide genes neuromedin B (Nmb) or gastrin-releasing peptide (Grp). These project to the preBötzinger Complex (preBötC), the respiratory rhythm generator, which expresses NMB and GRP receptors in overlapping subsets of ∼200 neurons. Introducing either neuropeptide into preBötC or onto preBötC slices, induced sighing or in vitro sigh activity, whereas elimination or inhibition of either receptor reduced basal sighing, and inhibition of both abolished it. Ablating receptor-expressing neurons eliminated basal and hypoxia-induced sighing, but left breathing otherwise intact initially. We propose that these overlapping peptidergic pathways comprise the core of a sigh control circuit that integrates physiological and perhaps emotional input to transform normal breaths into sighs.
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role of Parafacial nuclei in control of breathing in adult rats
The Journal of Neuroscience, 2015Co-Authors: Robert T R Huckstepp, Kathryn P Cardoza, Lauren E Henderson, Jack L. FeldmanAbstract:Contiguous brain regions associated with a given behavior are increasingly being divided into subregions associated with distinct aspects of that behavior. Using recently developed neuronal hyperpolarizing technologies, we functionally dissect the Parafacial region in the medulla, which contains key elements of the central pattern generator for breathing that are important in central CO2-chemoreception and for gating active expiration. By transfecting different populations of neighboring neurons with allatostatin or HM4D Gi/o-coupled receptors, we analyzed the effect of their hyperpolarization on respiration in spontaneously breathing vagotomized urethane-anesthetized rats. We identify two functionally separate Parafacial nuclei: ventral (pFV) and lateral (pFL). Disinhibition of the pFL with bicuculline and strychnine led to active expiration. Hyperpolarizing pFL neurons had no effect on breathing at rest, or changes in inspiratory activity induced by hypoxia and hypercapnia; however, hyperpolarizing pFL neurons attenuated active expiration when it was induced by hypercapnia, hypoxia, or disinhibition of the pFL. In contrast, hyperpolarizing pFV neurons affected breathing at rest by decreasing inspiratory-related activity, attenuating the hypoxia- and hypercapnia-induced increase in inspiratory activity, and when present, reducing expiratory-related abdominal activity. Together with previous observations, we conclude that the pFV provides a generic excitatory drive to breathe, even at rest, whereas the pFL is a conditional oscillator quiet at rest that, when activated, e.g., during exercise, drives active expiration.
Silvia Pagliardini - One of the best experts on this subject based on the ideXlab platform.
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role of the Parafacial respiratory group in the recruitment of abdominal activity across sleep states
Revista Cubana de Investigaciones Biomédicas, 2020Co-Authors: Annette Pisanski Hernandezabad, Nils Koch, Xiu Ding, Silvia PagliardiniAbstract:Introduction : In resting conditions, breathing is typically characterized by an active inspiratory phase and a passive expiratory phase. Expiration may become active through abdominal (ABD) muscle recruitment during periods of increased inspiratory requirements. This respiratory rhythm is thought to be controlled by three coupled oscillators: preBotzinger complex (preBotC) for generating inspiration, the Parafacial respiratory group (pFRG) for generating active expiration, and the post-inspiratory complex (PiCo) which is thought to control the post-inspiratory phase. Research addressing the role of pFRG in ventilation and rhythm generation across sleep states is limited. Recent work in our laboratory reports the occurrence of ABD recruitment during REM sleep, despite the induction of muscle paralysis during this sleep state. This ABD recruitment was associated with a stabilization of breathing in healthy rats. Because pFRG generates active expiration through the engagement of ABD muscles, we hypothesize that the expiratory oscillator is also responsible for the ABD recruitment observed during REM sleep in healthy rats. Objective : To demonstrate of the Parafacial respiratory group in the recruitment of abdominal activity across sleep states. Material and Methods: To test this hypothesis, we inhibited and activated the pFRG oscillator using a chemogenetic approach (DREADDs) while simultaneously recording EEG, airflow, DIA, ABD and neck EMG of transfected rats across sleep/wake cycles. Results : Manipulation of pFRG activity does not affect the sleep architecture. However, activity of pFRG seems to have an effect in the occurrence of ABD recruitment events during REM sleep. Inhibition of pFRG (N=7) significantly reduced the number of REM events with ABD recruitment and the intensity of these events (described as the ABD to DIA ratio), whereas activation of this oscillator (N=8) resulted in an increase of the number of REM events in which ABD recruitment was observed and the intensity of those events. Interestingly, modulation of pFRG activity did not seem to affect the occurrence of ABD recruitment during NREM sleep. Conclusions : The occurrence of ABD recruitment during sleep may be state dependent. Further research investigating the mechanisms behind the recruitment of ABD activity specifically during REM and NREM sleep will be necessary.
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Chemogenetic modulation of the Parafacial respiratory group influences the recruitment of abdominal activity during REM sleep.
Sleep, 2019Co-Authors: Annette Pisanski, Xiuqing Ding, Nils A Koch, Silvia PagliardiniAbstract:Current theories on respiratory control postulate that the respiratory rhythm is generated by oscillatory networks in the medulla: preBötzinger complex (preBötC) is the master oscillator responsible for generating inspiration, while Parafacial respiratory group (pFRG) drives active expiration through recruitment of expiratory abdominal muscle (ABD) activity. Research addressing the role of pFRG in ventilation and rhythm generation across sleep states is limited. We recently reported the occurrence of ABD recruitment occurring despite the induction of muscle paralysis during REM sleep. This ABD recruitment was associated with increased tidal volume and regularization of the respiratory period in rats. As pFRG generates active expiration through the engagement of ABD muscles, we hypothesized that the expiratory oscillator is also responsible for the ABD recruitment observed during REM sleep. To test this hypothesis, we inhibited and activated pFRG using chemogenetics (i.e. designer receptors exclusively activated by designer drugs) while recording EEG and respiratory muscle EMG activities across sleep/wake cycles in male Sprague Dawley rats. Our results suggest that inhibition of pFRG reduced the number of REM events expressing ABD recruitment, in addition to the intensity and prevalence of these events. Conversely, activation of pFRG resulted in an increase in the number of REM events in which ABD recruitment was observed, as well as the intensity and prevalence of ABD recruitment. Interestingly, modulation of pFRG activity did not affect ABD recruitment during NREM sleep or wakefulness. These results suggest that the occurrence of ABD recruitment during sleep is dependent on pFRG activity and is state dependent.
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the Parafacial respiratory group and the control of active expiration
Respiratory Physiology & Neurobiology, 2019Co-Authors: Annette Pisanski, Silvia PagliardiniAbstract:Abstract Breathing at rest is typically characterized by three phases: active inspiration, post-inspiration (or stage 1 expiration), and passive expiration (or stage 2 expiration). Breathing during periods of increased respiratory demand, on the other hand, engages active expiration through recruitment of abdominal muscles in order to increase ventilation. It is currently hypothesized that different phases of the respiratory rhythm are driven by three coupled oscillators: the preBotzinger Complex, driving inspiration, the Parafacial respiratory group (pFRG), driving active expiration and the post-inspiratory Complex, driving post-inspiration. In this paper we review advances in the understanding of the pFRG and its role in the generation of active expiration across different developmental stages and vigilance states. Recent experiments suggest that the abdominal recruitment varies across development depending on the vigilance state, possibly following the maturation of the network responsible for the generation of active expiration and neuromodulatory systems that influence its activity. The activity of the pFRG is tonically inhibited by GABAergic inputs and strongly recruited by cholinergic systems. However, the sources of these modulatory inputs and the physiological conditions under which these mechanisms are used to recruit active expiration and increase ventilation need further investigation. Some evidence suggests that active expiration during hypercapnia is evoked through disinhibition, while during hypoxia it is elicited through activation of catecholaminergic C1 neurons. Finally, a discussion of experiments indicating that the pFRG is anatomically and functionally distinct from the adjacent and partially overlapping chemosensitive neurons of the retrotrapezoid nucleus is also presented.
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cholinergic modulation of the Parafacial respiratory group
The Journal of Physiology, 2017Co-Authors: Rozlyn C.t. Boutin, Zaki Alsahafi, Silvia PagliardiniAbstract:Active inspiration and expiration are opposing respiratory phases generated by two separate oscillators in the brainstem; inspiration driven by a neuronal network located in the preBotzinger Complex (preBotC) and expiration driven by a neuronal network located in the Parafacial Respiratory Group (pFRG). While continuous activity of the preBotC is necessary for maintaining ventilation, the pFRG behaves as a conditional expiratory oscillator, being silent in resting conditions and becoming rhythmically active in presence of increased respiratory drive (e.g., hypoxia, hypercapnia, exercise, or through release of inhibition). Recent evidence from our laboratory suggests that expiratory activity in the principal expiratory pump muscles, the abdominals, is modulated in a state-dependent fashion, frequently occurring during periods of REM sleep. We hypothesised that acetylcholine, a neurotransmitter released in wakefulness and REM sleep by mesopontine structures, contributes to the activation of pFRG neurons and thus acts to promote the recruitment of expiratory abdominal muscle activity. We investigated the stimulatory effect of cholinergic neurotransmission on pFRG activity and recruitment of active expiration in vivo under anaesthesia. We demonstrate that local application of the acetylcholinesterase inhibitor physostigmine into the pFRG potentiated expiratory activity. Furthermore, local application of the cholinomimetic carbachol into the pFRG activated late expiratory neurons and induced long lasting rhythmic active expiration. This effect was completely abolished by pre-application of the muscarinic antagonist scopolamine, and more selective M3 antagonists 4DAMP and J104129. We conclude that cholinergic muscarinic transmission contributes to excitation of pFRG neurons and promotes both active recruitment of abdominal muscles and active expiratory flow. This article is protected by copyright. All rights reserved
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Cholinergic modulation of the Parafacial respiratory group
Journal of Physiology, 2017Co-Authors: Rozlyn C.t. Boutin, Zaki Alsahafi, Silvia PagliardiniAbstract: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. We observed distinct physiological responses between the more medial chemosensitive region of the retrotrapezoid nucleus and the more lateral region of pFRG. These results support the hypothesis that pFRG is under cholinergic neuromodulation and the region surrounding the facial nucleus contains a group of neurons with distinct physiological roles. ABSTRACT: Active inspiration and expiration are opposing respiratory phases generated by two separate oscillators in the brainstem: inspiration driven by a neuronal network located in the preBotzinger complex (preBotC) and expiration driven by a neuronal network located in the Parafacial respiratory group (pFRG). While continuous activity of the preBotC is necessary for maintaining ventilation, the pFRG behaves as a conditional expiratory oscillator, being silent in resting conditions and becoming rhythmically active in the presence of increased respiratory drive (e.g. hypoxia, hypercapnia, exercise and through release of inhibition). Recent evidence from our laboratory suggests that expiratory activity in the principal expiratory pump muscles, the abdominals, is modulated in a state-dependent fashion, frequently occurring during periods of REM sleep. We hypothesized that acetylcholine, a neurotransmitter released in wakefulness and REM sleep by mesopontine structures, contributes to the activation of pFRG neurons and thus acts to promote the recruitment of expiratory abdominal muscle activity. We investigated the stimulatory effect of cholinergic neurotransmission on pFRG activity and recruitment of active expiration in vivo under anaesthesia. We demonstrate that local application of the acetylcholinesterase inhibitor physostigmine into the pFRG potentiated expiratory activity. Furthermore, local application of the cholinomimetic carbachol into the pFRG activated late expiratory neurons and induced long lasting rhythmic active expiration. This effect was completely abolished by pre-application of the muscarinic antagonist scopolamine, and more selective M3 antagonists 4DAMP and J104129. We conclude that cholinergic muscarinic transmission contributes to excitation of pFRG neurons and promotes both active recruitment of abdominal muscles and active expiratory flow
Patrick M Fuller - One of the best experts on this subject based on the ideXlab platform.
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activation of the gabaergic Parafacial zone maintains sleep and counteracts the wake promoting action of the psychostimulants armodafinil and caffeine
Neuropsychopharmacology, 2018Co-Authors: Christelle Anaclet, Kobi Griffith, Patrick M FullerAbstract:Activation of the GABAergic Parafacial Zone Maintains Sleep and Counteracts the Wake-Promoting Action of the Psychostimulants Armodafinil and Caffeine
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Activation of the GABAergic Parafacial Zone Maintains Sleep and Counteracts the Wake-Promoting Action of the Psychostimulants Armodafinil and Caffeine
Neuropsychopharmacology, 2018Co-Authors: Christelle Anaclet, Kobi Griffith, Patrick M FullerAbstract:We previously reported that acute and selective activation of GABA-releasing Parafacial zone (PZ^Vgat) neurons in behaving mice produces slow-wave-sleep (SWS), even in the absence of sleep deficit, suggesting that these neurons may represent, at least in part, a key cellular substrate underlying sleep drive. It remains, however, to be determined if PZ^Vgat neurons actively maintain, as oppose to simply gate, SWS. To begin to experimentally address this knowledge gap, we asked whether activation of PZ^Vgat neurons could attenuate or block the wake-promoting effects of two widely used wake-promoting psychostimulants, armodafinil or caffeine. We found that activation of PZ^Vgat neurons completely blocked the behavioral and electrocortical wake-promoting action of armodafinil. In some contrast, activation of PZ^Vgat neurons inhibited the behavioral, but not electrocortical, arousal response to caffeine. These results suggest that: (1) PZ^Vgat neurons actively maintain, as oppose to simply gate, SWS and cortical slow-wave-activity; (2) armodafinil cannot exert its wake-promoting effects when PZ^Vgat neurons are activated, intimating a possible shared circuit/molecular basis for mechanism of action; (3) caffeine can continue to exert potent cortical desynchronizing, but not behavioral, effects when PZ^Vgat neurons are activated, inferring a shared and divergent circuit/molecular basis for mechanism of action; and 4) PZ^Vgat neurons represent a key cell population for SWS induction and maintenance.
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Brainstem regulation of slow-wave-sleep.
Current Opinion in Neurobiology, 2017Co-Authors: Christelle Anaclet, Patrick M FullerAbstract:Recent work has helped reconcile puzzling results from brainstem transection studies first performed over 60 years ago, which suggested the existence of a sleep-promoting system in the medullary brainstem. It was specifically shown that GABAergic neurons located in the medullary brainstem Parafacial zone (PZGABA) are not only necessary for normal slow-wave-sleep (SWS) but that their selective activation is sufficient to induce SWS in behaving animals. In this review we discuss early experimental findings that inspired the hypothesis that the caudal brainstem contained SWS-promoting circuitry. We then describe the discovery of the SWS-promoting PZGABA and discuss future experimental priorities.
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corrigendum the gabaergic Parafacial zone is a medullary slow wave sleep promoting center
Nature Neuroscience, 2014Co-Authors: Christelle Anaclet, Loris L Ferrari, E Arrigoni, Caroline E Bass, Clifford B Saper, Jun Lu, Patrick M FullerAbstract:Nat. Neurosci. 17, 1217–1224 (2014); published online 17 August 2014; corrected after print 28 August 2014 In the version of this article initially published, the colors of the data points were reversed relative to the key in Figure 3d, left panel. The error has been corrected in the HTML and PDF versions of the article.
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Corrigendum: The GABAergic Parafacial zone is a medullary slow wave sleep–promoting center
Nature Neuroscience, 2014Co-Authors: Christelle Anaclet, Loris L Ferrari, E Arrigoni, Caroline E Bass, Clifford B Saper, Jun Lu, Patrick M FullerAbstract:Nat. Neurosci. 17, 1217–1224 (2014); published online 17 August 2014; corrected after print 28 August 2014 In the version of this article initially published, the colors of the data points were reversed relative to the key in Figure 3d, left panel. The error has been corrected in the HTML and PDF versions of the article.
Hiroshi Onimaru - One of the best experts on this subject based on the ideXlab platform.
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Optogenetic analysis of respiratory neuronal networks in the ventral medulla of neonatal rats producing channelrhodopsin in Phox2b-positive cells
Pflügers Archiv - European Journal of Physiology, 2019Co-Authors: Keiko Ikeda, Kiyoshi Kawakami, Hiroyuki Igarashi, Hiromu Yawo, Kazuto Kobayashi, Satoru Arata, Masahiko Izumizaki, Hiroshi OnimaruAbstract:Paired-like homeobox gene Phox2b is predominantly expressed in pre-inspiratory neurons in the Parafacial respiratory group (pFRG) in newborn rat rostral ventrolateral medulla. To analyse detailed local networks of the respiratory centre using optogenetics, the effects of selective activation of Phox2b-positive neurons in the ventral medulla on respiratory rhythm generation were examined in brainstem–spinal cord preparations isolated from transgenic newborn rats with Phox2b-positive cells expressing channelrhodopsin variant ChRFR(C167A). Photostimulation up to 43 s increased the respiratory rate > 200% of control, whereas short photostimulation (1.5 s) of the rostral pFRG reset the respiratory rhythm. At the cellular level, photostimulation depolarised Phox2b-positive pre-inspiratory, inspiratory and respiratory-modulated tonic neurons and Phox2b-negative pre-inspiratory neurons. In contrast, changes in membrane potential of Phox2b-negative inspiratory and expiratory neurons varied depending on characteristics of ongoing synaptic connections in local respiratory networks in the rostral medulla. In the presence of tetrodotoxin, photostimulation depolarised Phox2b-positive cells, but caused no significant changes in membrane potential of Phox2b-negative cells. We concluded that depolarisation of Phox2b-positive neurons was due to cell-autonomous photo-activation and summation of excitatory postsynaptic potentials, whereas membrane potential changes of Phox2b-negative neurons depended on the network configuration. Our findings shed further light on local networks among respiratory-related neurons in the rostral ventrolateral medulla and emphasise the important role of pre-inspiratory neurons in respiratory rhythm generation in the neonatal rat en bloc preparation.
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the expression of galanin in the Parafacial respiratory group and its effects on respiration in neonatal rats
Neuroscience, 2018Co-Authors: Tara G Bautista, Keiko Ikeda, Kiyoshi Kawakami, Angelina Y Fong, Paul M Pilowsky, Darko Spirovski, Hiroshi OnimaruAbstract:Abstract The inhibitory peptide galanin is expressed within the retrotrapezoidal nucleus (RTN) – a key central chemoreceptor site that also contains the active expiratory oscillator. It was previously reported that microinjection of galanin into pre-Botzinger complex – containing the inspiratory oscillator – exerts inhibitory effects on inspiratory motor output and respiratory rhythm. In neonatal rats, the present study aimed to investigate: (1) expression of galanin within the Parafacial respiratory group (pFRG), which overlaps anatomically and functionally with the adult RTN, and; (2) effects of galanin on respiratory rhythm using the in vitro brainstem-spinal cord preparation. We showed that 14 ± 2% of Phox2b-immunoreactive (ir) neurons in the Parafacial region were also galanin-ir. Galanin peptide expression was confirmed within 3/9 CO2-sensitive, Phox2b-ir Pre-Inspiratory neurons (Pre-I) recorded in Parafacial region. Bath application of galanin (0.1–0.2 µM): (1) decreased the duration of membrane depolarization in both Pre-I and inspiratory pFRG neurons, and; (2) decreased the number of C4 bursts that were associated with each burst in Pre-I neurons within the pFRG. In preparations showing episodic breathing at baseline, the respiratory patterning reverted to the ‘normal’ pattern of single, uniformly rhythmic C4 bursts (n = 10). In preparations with normal respiratory patterning at baseline, slowing of C4 rhythm (n = 7) resulted although rhythmic bursting in recorded Pre-I neurons remained unperturbed (n = 6). This study therefore demonstrates that galanin is expressed within the pFRG of neonatal rats, including neurons that are intrinsically chemosensitive. Overall the peptide has an inhibitory effect on inspiratory motor output, as previously shown in adults.
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confocal calcium imaging analysis of respiratory related burst activity in the Parafacial region
Brain Research Bulletin, 2018Co-Authors: Hiroshi Onimaru, Keiko Ikeda, Kiyoshi Kawakami, Shiro Nakamura, Tomio InoueAbstract:Abstract The Parafacial respiratory group (pFRG) surrounding the ventrolateral part of the facial motor nucleus is one of respiratory rhythm generators that consists of pre-inspiratory (Pre-I) neurons. Previous studies showed that most of the Pre-I neurons locating in the Phox2b cluster of the rostral ventral medulla were also Phox2b positive and intrinsically CO2 sensitive. However, it is not clear what percentage of Phox2b-expressing cells in the pFRG of the ventral medulla are Pre-I neurons. To address this issue, we analyzed the activity of Phox2b-positive cells by calcium imaging using a confocal laser microscope in transgenic rats in which Phox2b-positive cells expressed EYFP. We found that more than 60% of the EYFP/Phox2b-positive cells showed Pre-I neuron-like rhythmic burst activity in the Parafacial region of newborn rat.
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cytoarchitecture and co2 sensitivity of phox2b positive Parafacial neurons in the newborn rat medulla
Progress in Brain Research, 2014Co-Authors: Hiroshi Onimaru, Keiko Ikeda, Tani Mariho, Kiyoshi KawakamiAbstract:Abstract Preinspiratory (Pre-I) neurons in the Parafacial respiratory group (pFRG) compose one of the respiratory rhythm generators in the medulla of the newborn rat. It has been shown that a subgroup of pFRG/Pre-I neurons could also work as central chemoreceptor neurons, because the CO 2 sensitivity of these Pre-I neurons was preserved even after blockade of Na + channels and Ca 2 + channels, and the membrane depolarization induced by hypercapnic stimulation was mainly because of the closing of K + channels. These neurons, some of which were identified to be glutamatergic, express the transcription factor Phox2b. Phox2b expression was one of the most noticeable characteristics of pFRG/Pre-I neurons. We also found that Phox2b-expressing neurons in the Parafacial region of the rostral ventral medulla tended to assemble around capillary blood vessels. In contrast, another subclass of the pFRG/Pre-I neurons was Phox2b-negative and CO 2 -insensitive. Some of these neurons were identified to be glycinergic or GABAergic. Thus, Phox2b expression is a key genetic marker that can be used to more clearly establish the cell architecture of the pFRG, which consists of heterogeneous neuronal subtypes. In this chapter, we elaborate on the CO 2 sensitivity of Phox2b-positive/negative Parafacial neurons and the cytoarchitecture in the newborn rat medulla, and discuss ionic mechanisms of CO 2 responsiveness.
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relationship between the distribution of the paired like homeobox gene phox2b expressing cells and blood vessels in the Parafacial region of the ventral medulla of neonatal rats
Neuroscience, 2012Co-Authors: Hiroshi Onimaru, Keiko Ikeda, Kiyoshi KawakamiAbstract:Abstract It has been reported that central chemoreceptor cells in the medulla are distributed in close apposition to capillary blood vessels in the medulla. Phox2b-expressing neurons in the retrotrapezoid nucleus (RTN) respond to high CO 2 /H + stimulation and have been suggested to play an important role in central chemoreception. In newborn rats, the RTN overlaps at least partially with the Parafacial respiratory group (pFRG), which consists predominantly of preinspiratory neurons. In the present study, we visualized the blood vessels in the ventral medulla of newborn rats using a neurobiotin method and examined the relationship between the blood vessels and the location of Phox2b-immunoreactive (-ir) neurons. We showed that Phox2b-ir neurons in the Parafacial region of the rostral ventral medulla tended to assemble around capillary blood vessels. We also confirmed that pFRG/preinspiratory neurons that were sensitive to hypercapnic stimulation in the presence of tetrodotoxin were Phox2b-ir neurons and were tightly apposed to the blood vessels along the longitudinal axis. Our findings suggested that the location of Phox2b-ir neurons, including preinspiratory neurons of the pFRG, matched their role as sensors of blood CO 2 concentration.
Patrice G Guyenet - One of the best experts on this subject based on the ideXlab platform.
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phox2b expressing neurons of the Parafacial region regulate breathing rate inspiration and expiration in conscious rats
The Journal of Neuroscience, 2011Co-Authors: Stephen B G Abbott, Ruth L Stornetta, Melissa B Coates, Patrice G GuyenetAbstract:The retrotrapezoid nucleus contains Phox2b-expressing glutamatergic neurons (RTN-Phox2b neurons) that regulate breathing in a CO 2 -dependent manner. Here we use channelrhodopsin-based optogenetics to explore how these neurons control breathing in conscious and anesthetized adult rats. Respiratory entrainment (pacing) of breathing frequency (fR) was produced over 57% (anesthetized) and 28% (conscious) of the natural frequency range by burst activation of RTN-Phox2b neurons (3–8 × 0.5–20 ms pulses at 20 Hz). In conscious rats, pacing under normocapnic conditions increased tidal volume (V T ) and each inspiration was preceded by active expiration, denoting abdominal muscle contraction. During long-term pacing V T returned to prestimulation levels, suggesting that central chemoreceptors such as RTN-Phox2b neurons regulate V T partly independently of their effect on fR. Randomly applied light trains reset the respiratory rhythm and shortened the expiratory phase when the stimulus coincided with late-inspiration or early-expiration. Importantly, continuous (20 Hz) photostimulation of the RTN-Phox2b neurons and a saturating CO 2 concentration produced similar effects on breathing that were much larger than those elicited by phasic RTN stimulation. In sum, consistent with their anatomical projections, RTN-Phox2b neurons regulate lung ventilation by controlling breathing frequency, inspiration, and active expiration. Adult RTN-Phox2b neurons can entrain the respiratory rhythm if their discharge is artificially synchronized, but continuous activation of these neurons is much more effective at increasing lung ventilation. These results suggest that RTN-Phox2b neurons are no longer rhythmogenic in adulthood and that their average discharge rate may be far more important than their discharge pattern in driving lung ventilation.
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retrotrapezoid nucleus and Parafacial respiratory group
Respiratory Physiology & Neurobiology, 2010Co-Authors: Patrice G Guyenet, Daniel K MulkeyAbstract:The rat retrotrapezoid nucleus (RTN) contains about 2000 Phox2b-expressing glutamatergic neurons (ccRTN neurons; 800 in mice) with a well-understood developmental lineage. ccRTN neuron development fails in mice carrying a Phox2b mutation commonly present in the congenital central hypoventilation syndrome. In adulthood, ccRTN neurons regulate the breathing rate and intensity, and may regulate active expiration along with other neighboring respiratory neurons. Prenatally, ccRTN neurons form an autonomous oscillator (embryonic Parafacial group, e-pF) that activates and possibly paces inspiration. The pacemaker properties of the ccRTN neurons probably vanish after birth to be replaced by synaptic drives. The neonatal Parafacial respiratory group (pfRG) may represent a transitional phase during which ccRTN neurons lose their group pacemaker properties. ccRTN neurons are activated by acidification via an intrinsic mechanism or via ATP released by glia. In summary, throughout life, ccRTN neurons seem to be a critical hub for the regulation of CO2 via breathing.
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Retrotrapezoid nucleus, respiratory chemosensitivity and breathing automaticity.
Respiratory physiology & neurobiology, 2009Co-Authors: Patrice G Guyenet, Michal G Fortuna, Ruth L Stornetta, Douglas A Bayliss, Stephen B G Abbott, Seth D DepuyAbstract:Breathing automaticity and CO(2) regulation are inseparable neural processes. The retrotrapezoid nucleus (RTN), a group of glutamatergic neurons that express the transcription factor Phox2b, may be a crucial nodal point through which breathing automaticity is regulated to maintain CO(2) constant. This review updates the analysis presented in prior publications. Additional evidence that RTN neurons have central respiratory chemoreceptor properties is presented, but this is only one of many factors that determine their activity. The RTN is also regulated by powerful inputs from the carotid bodies and, at least in the adult, by many other synaptic inputs. We also analyze how RTN neurons may control the activity of the downstream central respiratory pattern generator. Specifically, we review the evidence which suggests that RTN neurons (a) innervate the entire ventral respiratory column and (b) control both inspiration and expiration. Finally, we argue that the RTN neurons are the adult form of the Parafacial respiratory group in neonate rats.
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botzinger expiratory augmenting neurons and the Parafacial respiratory group
The Journal of Neuroscience, 2008Co-Authors: Michal G Fortuna, Gavin H West, Ruth L Stornetta, Patrice G GuyenetAbstract:In neonatal rat brains in vitro, the rostral ventral respiratory column (rVRC) contains neurons that burst just before the phrenic nerve discharge (PND) and rebound after inspiration (pre-I neurons). These neurons, called Parafacial respiratory group (pfRG), have been interpreted as a master inspiratory oscillator, an expiratory rhythm generator or simply as neonatal precursors of retrotrapezoid (RTN) chemoreceptor neurons. pfRG neurons have not been identified in adults, and their phenotype is unknown. Here, we confirm that the rVRC normally lacks pre-I neurons in adult anesthetized rats. However, we show that, during hypercapnic hypoxia, a population of rVRC expiratory-augmenting (E-AUG) neurons consistently develops a pre-I discharge. These cells reside in the Botzinger region of the rVRC, they express glycine-transporter-2, and their axons arborize throughout the VRC. Hypoxia triggers an identical pre-I pattern in retroambigual expiratory bulbospinal neurons, but this pattern is not elicited in Botzinger expiratory-decrementing neurons, Botzinger inspiratory neurons, RTN neurons, and blood pressure-regulating neurons. In conclusion, under hypoxia in vivo, abdominal expiratory premotor neurons of adult rats develop a pre-I pattern reminiscent of that observed in neonate brainstems in vitro. In the rVRC of adult rats, pre-I cells include selected rhythmogenic neurons (glycinergic Botzinger neurons) but not RTN chemoreceptors. We suggest that the pfRG may not be an independent rhythm generator but a heterogeneous collection of E-AUG neurons (glycinergic Botzinger neurons, possibly facial motor and premotor neurons), the discharge of which becomes preinspiratory under specific experimental conditions resulting from, in part, a prolonged and intensified activity of postinspiratory neurons.
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BotzingerExpiratory-AugmentingNeuronsandthe ParafacialRespiratoryGroup
2008Co-Authors: Patrice G GuyenetAbstract:MichalG.Fortuna,GavinH.West,RuthL.Stornetta,andPatriceG.Guyenet DepartmentofPharmacology,UniversityofVirginia,Charlottesville,Virginia22908 In neonatal rat brains in vitro, the rostral ventral respiratory column (rVRC) contains neurons that burst just before the phrenic nerve discharge (PND) and rebound after inspiration (pre-I neurons). These neurons, called Parafacial respiratory group (pfRG), have been interpretedasamasterinspiratoryoscillator,anexpiratoryrhythmgeneratororsimplyasneonatalprecursorsofretrotrapezoid(RTN) chemoreceptor neurons. pfRG neurons have not been identified in adults, and their phenotype is unknown. Here, we confirm that the rVRCnormallylackspre-Ineuronsinadultanesthetizedrats.However,weshowthat,duringhypercapnichypoxia,apopulationofrVRC
