Atoh1-dependent rhombic lip neurons are required for temporal delay between independent respiratory oscillators in embryonic mice

Tupal, Srinivasan; Huang, Wei-Hsiang; Picardo, Maria Cristina D.; Ling, Guoyu; Negro, Christopher A. Del; Zoghbi, Huda Y.; Gray, Paul A.

doi:10.7554/elife.02265

Cited by 23 publications

(32 citation statements)

References 103 publications

(274 reference statements)

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“…Appropriate parcellation of distinct respiratory functions to definable brainstem regions is essential for understanding neural control of breathing. Since the identification of the parafacial RTN (Smith et al, 1989;Ellenberger and Feldman, 1990;Li et al, 1999;Mulkey et al, 2004), increasing attention has been focused on understanding its role and, as more data became available (Onimaru and Homma, 2003;Janczewski and Feldman, 2006;Pagliardini et al, 2011;Tupal et al, 2014), e.g., the role of other parafacial regions. In adult rats, we found that two anatomically separate parafacial regions, the pF V and pF L , perform very distinct roles in control of breathing, with an overlapping role in central chemoreception.…”

Section: Discussionmentioning

confidence: 99%

Role of Parafacial Nuclei in Control of Breathing in Adult Rats

et al. 2015

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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 CO 2 -chemoreception and for gating active expiration. By transfecting different populations of neighboring neurons with allatostatin or HM 4 D G i/o -coupled receptors, we analyzed the effect of their hyperpolarization on respiration in spontaneously breathing vagotomized urethaneanesthetized rats. We identify two functionally separate parafacial nuclei: ventral (pF V ) and lateral (pF L ). Disinhibition of the pF L with bicuculline and strychnine led to active expiration. Hyperpolarizing pF L neurons had no effect on breathing at rest, or changes in inspiratory activity induced by hypoxia and hypercapnia; however, hyperpolarizing pF L neurons attenuated active expiration when it was induced by hypercapnia, hypoxia, or disinhibition of the pF L . In contrast, hyperpolarizing pF V 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 pF V provides a generic excitatory drive to breathe, even at rest, whereas the pF L is a conditional oscillator quiet at rest that, when activated, e.g., during exercise, drives active expiration.

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Section: Discussionmentioning

confidence: 99%

Role of Parafacial Nuclei in Control of Breathing in Adult Rats

et al. 2015

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“…The lung powerstroke and priming areas in the frog are in r5 and r4-6, respectively; rhombomeres r4-6 in mammals contains the PreI/pFRG/BötC that is hypothesized to be important in expiration (Huckstepp et al, 2015;Pagliardini et al, 2011;Smith et al, 2007;Tupal et al, 2014). Active expiration in mammals, like lung/priming burst complexes, is strongly recruited by chemosensory activation (Burke et al, 2015).…”

Section: A Primer For Expirationmentioning

confidence: 97%

“…Under conditions of high CO 2 or low tidal volume triggering active expiration, a more rostral burst generator is activated in the adult that induces rhythmic adnominal bursts even in the absence of inspiration. This may be located in the lateral para-facial nucleus (Huckstepp et al, 2015;Pagliardini et al, 2011;Tupal et al, 2014).…”

Section: Rhythm Phase and Burst-shapementioning

confidence: 98%

“…These data suggest the burst generator for the priming phase extends rostrally and caudally of the lung powerstroke area, that is nonetheless functionally and anatomically distinct from the buccal area. This interpretation assumes loss of the priming phase in nerve roots reflects silencing of corresponding burst generator, rather than a phase shift in activity, such that all burst generating neurons become synchronized (Tupal et al, 2014).…”

Section: The Priming Burst Generatormentioning

confidence: 99%

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Diving into the mammalian swamp of respiratory rhythm generation with the bullfrog

Baghdadwala

Duchcherer

Trask

et al. 2016

Respiratory Physiology & Neurobiology

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“…Components of the circuitry responsible for active expiration (expiratory rhythm generator) overlap anatomically with the caudal RTN (Pagliardini et al, 2011;Feldman et al, 2013;Tupal et al, 2014). As shown here, active expiration can be triggered by stimulating RTN neurons located rostral to this region (Pagliardini et al, 2011;Feldman et al, 2013 (Guyenet & Mulkey, 2010), can activate this oscillator but is probably not part of it.…”

Section: State-dependent Control Of Active Expiration By Rtnmentioning

confidence: 66%

Neural Control of Respiration by the Retrotrapezoid Nucleus.

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Rationale and objectives: Central respiratory chemoreceptors (CRCs) detect brain PaCO 2 and adjust lung ventilation to maintain PaCO 2 and pH constant regardless of the absolute level of lung ventilation. They perform this function in cooperation with the carotid bodies, sensory organs that respond to hypoxia in a pH-dependent manner. The existence of CRCs has been known for over a century but their cellular nature and location have remained highly controversial until recently. The retrotrapezoid nucleus (RTN), a collection of ~2000 glutamatergic neurons in rats that are activated by hypercapnia in vivo and by acidification in slices, had been identified as a CRC candidate just prior to my PhD work. My first objective was to seek additional and critical evidence that RTN neurons are CRCs by determining whether these neurons stimulate breathing in proportion to arterial PCO 2 in intact unanesthetized rats.Having verified that this was the case I tested a logical corollary of this theory namely that RTN is silenced under hypoxic conditions due to respiratory alkalosis. Then I proceeded to test whether RTN neurons sustain breathing automaticity during sleep. Finally, I tested whether RTN compensates for the lack peripheral chemoreceptor input.Methods: RTN neurons were bilaterally transduced to express the proton pump archaerhodopsin using a lentiviral vector. Using anesthetized rats, I confirmed that RTN neurons were silenced by activating archaerhodopsin with green light. I examined the effect of short periods of RTN inhibition (10s) on breathing (plethysmography), EEG and neck EMG in conscious rats in which arterial pH was changed by exposing the animals to various FiO 2 levels alone or with the addition of 3% FiCO 2 or acetazolamide (ACTZ). Rats were studied in different states of vigilance (quiet awake/non-REM/REM). Arterial blood gases (PaO 2 , PaCO 2 ), pHa and HCO 3 were measured under each condition.ii Results: RTN inhibition (bilateral) reduced breathing frequency and amplitude in direct proportion to arterial plasma pH (pHa) below a threshold of 7.53. Above this level, RTN inhibition had no effect suggesting that the nucleus was silent. In normoxia, RTN inhibition reduced breathing equally during non-REM sleep and quiet wake. By contrast RTN inhibition had very little effect on breathing during REM sleep.Conclusions: RTN drives breathing in direct proportion to arterial PCO 2 in intact unaesthetized rats, consistent with the theory that these neurons are CRCs. RTN neurons are silent above pHa 7.5 and increasingly active below this value. RTN regulates breathing automaticity about equally during non-REM sleep and quiet waking, conditions under which the respiratory pattern generator is autorhythmic. By contrast, RTN has a much reduced influence on breathing during Viar for surgery skills, science advice, life advice, wanted/unwanted music advice and so much more. Together, they made a dynamic group of personalities that provided a stimulating and encouraging atmosphere that will never be forgotten....

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Atoh1-dependent rhombic lip neurons are required for temporal delay between independent respiratory oscillators in embryonic mice

Cited by 23 publications

References 103 publications

Role of Parafacial Nuclei in Control of Breathing in Adult Rats

Role of Parafacial Nuclei in Control of Breathing in Adult Rats

Diving into the mammalian swamp of respiratory rhythm generation with the bullfrog

Neural Control of Respiration by the Retrotrapezoid Nucleus.

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