Changes in neurochemicals within the ventrolateral medullary respiratory column in awake goats after carotid body denervation

Miller, Justin; Neumueller, Suzanne; Muere, Clarissa; Olesiak, Samantha; Pan, Lawrence; Hodges, Matthew R.; Forster, H. V.

doi:10.1152/japplphysiol.00293.2013

Cited by 16 publications

(34 citation statements)

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“…2 ). As in our past studies (21, 22), we utilized the breathing frequency response to glutamate agonist (NMDA) injections as a physiologic indicator of MT proximity to the preBötC region. Consistent with past studies, we found variation in this response to NMDA injections (inset in Fig.2 ).…”

Section: Resultsmentioning

confidence: 99%

Evidence for respiratory neuromodulator interdependence after cholinergic disruption in the ventral respiratory column

Muere

Neumueller

Miller

et al. 2015

Respiratory Physiology & Neurobiology

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Reverse dialysis of the muscarinic receptor antagonist, atropine (ATR, 50 mM), into the pre-Bötzinger Complex region of the ventral respiratory column (VRC) of awake and sleeping goats increases breathing frequency and serotonin (5-HT), substance P (SP), glycine, and GABA concentrations in the effluent dialysate. Herein, we report data from goats in which we reverse dialyzed 5 mM ATR or specific antagonists of M2 or M3 muscarinic receptors into the VRC. The effects on frequency of all three antagonists were not significantly different from time control studies. 5 mM ATR and the M3 antagonist increased SP seven-fold less than 50 mM ATR. The antagonists had no effect on 5-HT, glycine, and/or GABA, suggesting that the increases in glycine and GABA with 50 mM ATR were secondary to the larger increases in 5-HT and/or SP. These data are suggestive of neuromodulator interdependence, whereby attenuation of one neuromodulator is compensated for by local changes in other neuromodulators to stabilize breathing.

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Section: Resultsmentioning

confidence: 99%

Evidence for respiratory neuromodulator interdependence after cholinergic disruption in the ventral respiratory column

Muere

Neumueller

Miller

et al. 2015

Respiratory Physiology & Neurobiology

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“…In animals, the hypoxic ventilatory response recovers partially or totally (rats) over time presumably because of an increase in the activity of the aortic bodies. Postsurgically, carotid body denervation also produces resting hypoventilation and hypercapnia, an effect that decreases days to week after surgery but may never recover completely depending on the species (45, 285, 298). Similar hypoventilation has been observed in man [(443) and references therein].…”

Section: Interplay Between Peripheral and Central Chemoreceptorsmentioning

confidence: 99%

Regulation of Breathing and Autonomic Outflows by Chemoreceptors

Guyenet

2014

Comprehensive Physiology

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Lung ventilation fluctuates widely with behavior but arterial PCO2 remains stable. Under normal conditions, the chemoreflexes contribute to PaCO2 stability by producing small corrective cardiorespiratory adjustments mediated by lower brainstem circuits. Carotid body (CB) information reaches the respiratory pattern generator (RPG) via nucleus solitarius (NTS) glutamatergic neurons which also target rostral ventrolateral medulla (RVLM) presympathetic neurons thereby raising sympathetic nerve activity (SNA). Chemoreceptors also regulate presympathetic neurons and cardiovagal preganglionic neurons indirectly via inputs from the RPG. Secondary effects of chemoreceptors on the autonomic outflows result from changes in lung stretch afferent and baroreceptor activity. Central respiratory chemosensitivity is caused by direct effects of acid on neurons and indirect effects of CO2 via astrocytes. Central respiratory chemoreceptors are not definitively identified but the retrotrapezoid nucleus (RTN) is a particularly strong candidate. The absence of RTN likely causes severe central apneas in congenital central hypoventilation syndrome. Like other stressors, intense chemosensory stimuli produce arousal and activate circuits that are wake- or attention-promoting. Such pathways (e.g., locus coeruleus, raphe, and orexin system) modulate the chemoreflexes in a state-dependent manner and their activation by strong chemosensory stimuli intensifies these reflexes. In essential hypertension, obstructive sleep apnea and congestive heart failure, chronically elevated CB afferent activity contributes to raising SNA but breathing is unchanged or becomes periodic (severe CHF). Extreme CNS hypoxia produces a stereotyped cardiorespiratory response (gasping, increased SNA). The effects of these various pathologies on brainstem cardiorespiratory networks are discussed, special consideration being given to the interactions between central and peripheral chemoreflexes.

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“…Given the apparent absence of plasticity of CO 2 -responsive central chemoreceptors (rats, this study), a slight change in CB sensory transduction could also in theory explain why CBD produces such a long-lasting hypoventilation and rise in PCO 2 set point in large species and not in rats (Forster, 2003;Miller et al, 2013;Angelova et al, 2015). A major species difference in the central circuitry underlying the chemoreflexes need not be invoked to explain these observations.…”

Section: Central Chemoreflex Plasticity After Carotid Body Denervatiomentioning

confidence: 82%

“…This discrepancy implies that some form of central plasticity of the respiratory network unrelated to oxygen sensing develops. This interpretation is supported by evidence of neurochemical changes in the brainstem and of changes in the respiratory stimulation elicited by activating raphe neurons (Hodges et al, 2005;Mouradian et al, 2012;Miller et al, 2013).…”

Section: Introductionmentioning

confidence: 79%

“…The carotid body afferents of normal quietly resting rats breathing room air may be silent and the temporary breathing changes that follow CB denervation may have other causes than the mere silencing of these sensory afferents. We acknowledge that, in goats, in which CBD produces an extremely long-lasting hypopnea, neurochemical changes which could, at least theoretically, underlie these persistent changes in breathing, have been observed in the brainstem (Pan et al, 1998;Miller et al, 2013). We did not find clear evidence of RTN plasticity in rats a week after CBD but the contribution of the carotid bodies to resting ventilation could be highly species-dependent and it is also possible that following CBD, adaptive changes in respiratory circuitry are species-specific or occur somewhere else than in RTN.…”

Section: Central Chemoreflex Plasticity After Carotid Body Denervatiomentioning

confidence: 99%

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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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Changes in neurochemicals within the ventrolateral medullary respiratory column in awake goats after carotid body denervation

Cited by 16 publications

References 50 publications

Evidence for respiratory neuromodulator interdependence after cholinergic disruption in the ventral respiratory column

Evidence for respiratory neuromodulator interdependence after cholinergic disruption in the ventral respiratory column

Regulation of Breathing and Autonomic Outflows by Chemoreceptors

Neural Control of Respiration by the Retrotrapezoid Nucleus.

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