Simulated apnoeas induce serotonin‐dependent respiratory long‐term facilitation in rats

Mahamed, Safraaz; Mitchell, Gordon S.

doi:10.1113/jphysiol.2007.149047

Cited by 48 publications

(50 citation statements)

References 38 publications

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“…We therefore put forward the working hypothesis that PhrX creates preconditions that enhance the subsequent induction of phrenic LTF. To be clear, we are not suggesting that PhrX is a necessary precondition for LTF but, rather, that PhrX primes the phrenic motor system, possibly by increasing phrenic motoneuron excitability, and enables more robust increases in phrenic burst amplitude following IH or other stimuli (e.g., intermittent apnea) (44,68).…”

Section: Implications For the Study Of Respiratory Ltfmentioning

confidence: 82%

Phrenicotomy alters phrenic long-term facilitation following intermittent hypoxia in anesthetized rats

Sandhu

Lee

Fregosi

et al. 2010

Journal of Applied Physiology

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Sandhu MS, Lee KZ, Fregosi RF, Fuller DD. Phrenicotomy alters phrenic long-term facilitation following intermittent hypoxia in anesthetized rats. J Appl Physiol 109: 279 -287, 2010. First published April 15, 2010 doi:10.1152/japplphysiol.01422.2009 can induce a persistent increase in neural drive to the respiratory muscles known as long-term facilitation (LTF). LTF of phrenic inspiratory activity is often studied in anesthetized animals after phrenicotomy (PhrX), with subsequent recordings being made from the proximal stump of the phrenic nerve. However, severing afferent and efferent axons in the phrenic nerve has the potential to alter the excitability of phrenic motoneurons, which has been hypothesized to be an important determinant of phrenic LTF. Here we test the hypothesis that acute PhrX influences immediate and long-term phrenic motor responses to hypoxia. Phrenic neurograms were recorded in anesthetized, ventilated, and vagotomized adult male rats with intact phrenic nerves or bilateral PhrX. Data were obtained before (i.e., baseline), during, and after three 5-min bouts of isocapnic hypoxia. Inspiratory burst amplitude during hypoxia (%baseline) was greater in PhrX than in phrenic nerve-intact rats (P Ͻ 0.001). Similarly, burst amplitude 55 min after IH was greater in PhrX than in phrenic nerve-intact rats (175 Ϯ 9 vs. 126 Ϯ 8% baseline, P Ͻ 0.001).In separate experiments, phrenic bursting was recorded before and after PhrX in the same animal. Afferent bursting that was clearly observable in phase with lung deflation was immediately abolished by PhrX. The PhrX procedure also induced a form of facilitation as inspiratory burst amplitude was increased at 30 min post-PhrX (P ϭ 0.01 vs. pre-PhrX). We conclude that, after PhrX, axotomy of phrenic motoneurons and, possibly, removal of phrenic afferents result in increased phrenic motoneuron excitability and enhanced LTF following IH. axotomy; phrenic motoneurons; plasticity EXPOSURE TO INTERMITTENT HYPOXIA (IH) over short periods (e.g., minutes to hours) can evoke a persistent increase in respiratory motor output, termed long-term facilitation (LTF) (35,48,50). LTF has been observed in awake (26, 35) and sleeping humans (53) and in a wide range of animal species (22,46,48). The mechanisms underlying LTF have been studied extensively over the last 10 -15 years, primarily in anesthetized animals (reviewed in Refs. 42,49,50). In anesthetized animals, LTF is typically manifest as an increase in the inspiratory burst amplitude of phrenic (19) and/or hypoglossal (XII) extracellular nerve recordings (20). Recordings of in vivo (19) and in vitro (10) respiratory motor LTF are typically made from cut respiratory muscle nerves. More specifically, the phrenic and/or XII nerves are cut, and subsequent extracellular recordings are made from the central end of the nerve. This procedure can provide stability to the neurophysiological recording procedures, particularly when a dorsal surgical approach is used, but also has the potential to alter respiratory motor output and...

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Section: Implications For the Study Of Respiratory Ltfmentioning

confidence: 82%

Phrenicotomy alters phrenic long-term facilitation following intermittent hypoxia in anesthetized rats

Sandhu

Lee

Fregosi

et al. 2010

Journal of Applied Physiology

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“…The CO 2 apneic threshold was determined by decreasing CO 2 levels and/or increasing the ventilator rate until phrenic activity ceased, then slowly decreasing ventilator rate or increasing inspired CO 2 levels until phrenic activity resumed (the "recruitment threshold") as described previously (Mahamed and Mitchell, 2006).…”

Section: Methodsmentioning

confidence: 99%

Okadaic Acid-Sensitive Protein Phosphatases Constrain Phrenic Long-Term Facilitation after Sustained Hypoxia

Wilkerson¹,

Satriotomo²,

Baker-Herman³

et al. 2008

J. Neurosci.

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Phrenic long-term facilitation (pLTF) is a serotonin-dependent form of pattern-sensitive respiratory plasticity induced by intermittent hypoxia (IH), but not sustained hypoxia (SH). The mechanism(s) underlying pLTF pattern sensitivity are unknown. SH and IH may differentially regulate serine/threonine protein phosphatase activity, thereby inhibiting relevant protein phosphatases uniquely during IH and conferring pattern sensitivity to pLTF. We hypothesized that spinal protein phosphatase inhibition would relieve this braking action of protein phosphatases, thereby revealing pLTF after SH. Anesthetized rats received intrathecal (C4) okadaic acid (25 nM) before SH (25 min, 11% O 2 ). Unlike (vehicle) control rats, SH induced a significant pLTF in okadaic acid-treated rats that was indistinguishable from rats exposed to IH (three 5 min episodes, 11% O 2 ). IH and SH with okadaic acid may elicit pLTF by similar, serotonin-dependent mechanisms, because intravenous methysergide blocks pLTF in rats receiving IH or okadaic acid plus SH. Okadaic acid did not alter IH-induced pLTF. In summary, pattern sensitivity in pLTF may reflect differential regulation of okadaic acid-sensitive serine/threonine phosphatases; presumably, these phosphatases are less active during/after IH versus SH. The specific okadaic acid-sensitive phosphatase(s) constraining pLTF and their spatiotemporal dynamics during and/or after IH and SH remain to be determined.

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“…Unlike modulation, plasticity implies a persistent change in a response, which continues in the absence of the stimulus. There are mixed reports in the literature suggesting that intermittent episodes of hypoxia may elicit plasticity of the AT (Ling et al, 2001; Katayama et al, 2007; Mahamed and Mitchell, 2008a; 2008b; but see Chowdhuri et al, 2010a; Xie et al, 2001), which has been speculated to result in improved breathing stability. In this study, we directly examined the effect of central neural apnea (without hypoxia) on the AT and found that only specific patterns of neural apnea result in a long-lasting decrease in the AT, an effect that is predicted to promote breathing stability by increasing the amount PaCO 2 must change to induce a subsequent apnea.…”

Section: Discussionmentioning

confidence: 99%

Reduced respiratory neural activity elicits a long-lasting decrease in the CO2 threshold for apnea in anesthetized rats

Baertsch

Baker

2017

Experimental Neurology

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Two critical parameters that influence breathing stability are the levels of arterial pCO2 at which breathing ceases and subsequently resumes – termed the apneic and recruitment thresholds (AT and RT, respectively). Reduced respiratory neural activity elicits a chemoreflex-independent, long-lasting increase in phrenic burst amplitude, a form of plasticity known as inactivity-induced phrenic motor facilitation (iPMF). The physiological significance of iPMF is unknown. To determine if iPMF and neural apnea have long-lasting physiological effects on breathing, we tested the hypothesis that patterns of neural apnea that induce iPMF also elicit changes in the AT and RT. Phrenic nerve activity and end-tidal CO2 were recorded in urethane-anesthetized, ventilated rats to quantify phrenic nerve burst amplitude and the AT and RT before and after three patterns of neural apnea that differed in their duration and ability to elicit iPMF: brief intermittent neural apneas, a single brief “massed” neural apnea, or a prolonged neural apnea. Consistent with our hypothesis, we found that patterns of neural apnea that elicited iPMF also resulted in changes in the AT and RT. Specifically, intermittent neural apneas progressively decreased the AT with each subsequent neural apnea, which persisted for at least 60 min. Similarly, a prolonged neural apnea elicited a long-lasting decrease in the AT. In both cases, the magnitude of the AT decrease was proportional to iPMF. In contrast, the RT was transiently decreased following prolonged neural apnea, and was not proportional to iPMF. No changes in the AT or RT were observed following a single brief neural apnea. Our results indicate that the AT and RT are differentially altered by neural apnea and suggest that specific patterns of neural apnea that elicit plasticity may stabilize breathing via a decrease in the AT.

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Simulated apnoeas induce serotonin‐dependent respiratory long‐term facilitation in rats

Cited by 48 publications

References 38 publications

Phrenicotomy alters phrenic long-term facilitation following intermittent hypoxia in anesthetized rats

Phrenicotomy alters phrenic long-term facilitation following intermittent hypoxia in anesthetized rats

Okadaic Acid-Sensitive Protein Phosphatases Constrain Phrenic Long-Term Facilitation after Sustained Hypoxia

Reduced respiratory neural activity elicits a long-lasting decrease in the CO2 threshold for apnea in anesthetized rats

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