Selected Contribution: Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia

Fuller, David D.; Zabka, A. G.; Baker, Tracy L.; Mitchell, Gordon S.

doi:10.1152/jappl.2001.90.5.2001

Cited by 183 publications

(196 citation statements)

References 28 publications

(51 reference statements)

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“…Thus, apnea-induced vagal modulation only triggers noradrenergic-dependent LTF of hypoglossal motor outflow; it does not directly affect phrenic motoneuron activity and hence plasticity. This is in sharp contrast to hypoxia-induced plasticity, which evokes LTF of both phrenic and hypoglossal motor outflow via serotonergic-dependent mechanisms (Bach and Mitchell, 1996;Fuller et al, 2001).…”

Section: Discussionmentioning

confidence: 82%

Identification of a Novel Form of Noradrenergic-Dependent Respiratory Motor Plasticity Triggered by Vagal Feedback

Tadjalli¹,

Duffin²,

Peever³

2010

J. Neurosci.

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The respiratory control system is not just reflexive, it is smart, it learns, and, in fact, it has a memory. The respiratory system listens to and carefully remembers how previous stimuli affect breathing. Respiratory memory is laid down by adjusting synaptic strength between respiratory neurons. For example, repeated hypoxic bouts trigger a form of respiratory memory that functions to strengthen the ability of respiratory motoneurons to trigger contraction of breathing muscles. This type of respiratory plasticity is known as long-term facilitation (LTF). Although chemical feedback, such as hypoxia, initiates LTF, it is unknown whether natural modulation of mechanical feedback (from vagal inputs) also causes motor plasticity. Here, we used reverse microdialysis, electrophysiology, neuropharmacology, and histology to determine whether episodic modulation of vagally mediated mechanical feedback is able to induce respiratory LTF in anesthetized adult rats. We show that repeated obstructive apneas disrupt vagal feedback and trigger LTF of hypoglossal motoneuron activity and genioglossus muscle tone. This same stimulus does not cause LTF of diaphragm activity. Hypoxic episodes do not cause apnea-induced LTF; instead, LTF is triggered by modulation of vagal feedback. Unlike hypoxia-induced respiratory plasticity, vagusinduced LTF does not require 5-HT 2 receptors but instead relies on activation of ␣1-adrenergic receptors on hypoglossal motoneurons. In summary, we identify a novel form of hypoxia-and 5-HT-independent respiratory motor plasticity that is triggered by physiological modulation of vagal feedback and is mediated by ␣1-adrenergic receptor activation on (or near) hypoglossal motoneurons.

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Section: Discussionmentioning

confidence: 82%

Identification of a Novel Form of Noradrenergic-Dependent Respiratory Motor Plasticity Triggered by Vagal Feedback

Tadjalli¹,

Duffin²,

Peever³

2010

J. Neurosci.

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“…For example, during hypoxic depression, serotonin levels increase, and 5-HT 1A receptor activation may contribute to the cessation of eupneic activity (Richter et al, 1999). 5-HT 2A modulation has also been proposed to play a critical role in long-term facilitation of phrenic activity after intermittent hypoxia (Millhorn et al, 1980;Kinkead and Mitchell, 1999;Fuller et al, 2001;Mitchell et al, 2001;Baker-Herman and Mitchell, 2002;Blitz and Ramirez, 2002;Baker-Herman et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Naive slice preparations were used to avoid potential hysteresis from repetitive exposure to hypoxic/anoxic conditions (Millhorn et al, 1980;Kinkead and Mitchell, 1999;Fuller et al, 2001;Mitchell et al, 2001;Blitz and Ramirez, 2002;Bocchiaro and Feldman, 2004). In six naive preparations, we applied nonoxygenated ACSF for 10 min to evoke fictive gasping in all examined preparations.…”

Section: Fictive Gasping During Anoxic Conditionsmentioning

confidence: 99%

Gasping ActivityIn Vitro: A Rhythm Dependent on 5-HT_2AReceptors

2006

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Many rhythmic behaviors are continuously modulated by endogenous peptides and amines, but whether neuromodulation is critical to the expression of a rhythmic behavior often remains unknown, particularly in mammals. Here, we address this issue in the respiratory network that was isolated in spontaneously rhythmic medullary slice preparations from mice. Under control conditions, the respiratory network generates fictive eupneic activity. We hypothesized previously that this activity depends on two types of pacemaker neurons. The bursting properties of one pacemaker rely on the persistent sodium current (I Na(p) ) and are insensitive to blockade of calcium channels with cadmium (CI-pacemakers), whereas bursting mechanisms of a second pacemaker are sensitive to cadmium (CS-pacemakers) and the calcium-dependent nonspecific cation current blocker flufenamic acid. During hypoxia, fictive eupneic activity is supplanted by the neural correlate of gasping, which is proposed to depend only on CI-pacemakers. Because CI-pacemakers require endogenous activation of 5-HT 2A receptors, we tested the hypothesis that 5-HT 2A receptor activation is critical for gasping. Here, we demonstrate that fictive gasping and CI-pacemaker bursting were selectively eliminated by the 5-HT 2A receptor antagonist piperidine or ketanserin. Neither 5-HT 2A antagonist eliminated bursting by CS-pacemakers and ventral respiratory group (VRG) population activity. However, this VRG activity was very different from eupneic activity. In the presence of 5-HT 2A antagonists, VRG activity was eliminated by flufenamic acid and could not be reliably restored by adding substance P. These data support the hypothesis that two types of pacemaker bursting mechanisms underlie fictive eupnea, whereas only one burst mechanism is critical for gasping.

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“…An important body of literature shows that LTF depends on activation of brain stem raphe neurons, leading to spinal serotonin release and serotonin receptor activation (15), which leads to de novo brain-derived neurotrophic factor synthesis, strengthening synaptic efficiency on spinal respiratory motoneurons (2,34). Other mechanisms involve spinal adenosine, and adenosine A 2A receptors, which enhances phrenic activity in the absence of hypoxia (16) but reduces the magnitude of LTF induced by IH (22).…”

Section: Respiratory Responses To Repeated Hypoxic Cycles In Control mentioning

confidence: 99%

Carotid sinus nerve stimulation, but not intermittent hypoxia, induces respiratory LTF in adult rats exposed to neonatal intermittent hypoxia

Julien

Niane

Kinkead

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Julien CA, Niane L, Kinkead R, Bairam A, Joseph V. Carotid sinus nerve stimulation, but not intermittent hypoxia, induces respiratory LTF in adult rats exposed to neonatal intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol 299: R192-R205, 2010. First published April 21, 2010 doi:10.1152/ajpregu.00707.2009.-We tested the hypothesis that exposure to neonatal intermittent hypoxia (n-IH) in rat pups alters central integrative processes following acute and intermittent peripheral chemoreceptor activation in adults. Newborn male rats were exposed to n-IH or normoxia for 10 consecutive days after birth. We then used both awake and anesthetized 3-to 4-mo-old rats to record ventilation, blood pressure, and phrenic and splanchnic nerve activities to assess responses to peripheral chemoreflex activation (acute hypoxic response) and long-term facilitation (LTF, long-term response after intermittent hypoxia). In anesthetized rats, phrenic and splanchnic nerve activities and hypoxic responses were also recorded with or without intact carotid body afferent signal (bilateral chemodenervation) or in response to electrical stimulations of the carotid sinus nerve. In awake rats, n-IH alters the respiratory pattern (higher frequency and lower tidal volume) and increased arterial blood pressure in normoxia, but the ventilatory response to repeated hypoxic cycles was not altered. In anesthetized rats, phrenic nerve responses to repeated hypoxic cycles or carotid sinus nerve stimulation were not altered by n-IH; however, the splanchnic nerve response was suppressed by n-IH compared with control. In control rats, respiratory LTF was apparent in anesthetized but not in awake animals. In n-IH rats, respiratory LTF was not apparent in awake and anesthetized animals. Following intermittent electrical stimulation, however, phrenic LTF was clearly present in n-IH rats, being similar in magnitude to controls. We conclude that, in adult n-IH rats: 1) arterial blood pressure is elevated, 2) peripheral chemoreceptor responses to hypoxia and its central integration are not altered, but splanchnic nerve response is suppressed, 3) LTF is suppressed, and 4) the mechanisms involved in the generation of LTF are still present but are masked most probably as the result of an augmented inhibitory response to hypoxia in the central nervous system. neonatal intermittent hypoxia; long-term facilitation DEVELOPMENT OF THE RESPIRATORY control system is tightly regulated by complex interactions between genetic and environmental factors that contribute to shape the mature phenotypic expression of this neural network (4). Over the past years, several studies have documented that alterations in environmental oxygen levels during development lead to important changes of the respiratory control system (4). A particular importance has been given to intermittent hypoxic exposure (38, 47, 50) because it may be used in laboratory animals to reproduce some of the effects encountered in human newborn suffering from apneas, which remains one of the major cause...

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Selected Contribution: Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia

Cited by 183 publications

References 28 publications

Identification of a Novel Form of Noradrenergic-Dependent Respiratory Motor Plasticity Triggered by Vagal Feedback

Identification of a Novel Form of Noradrenergic-Dependent Respiratory Motor Plasticity Triggered by Vagal Feedback

Gasping ActivityIn Vitro: A Rhythm Dependent on 5-HT_2AReceptors

Carotid sinus nerve stimulation, but not intermittent hypoxia, induces respiratory LTF in adult rats exposed to neonatal intermittent hypoxia

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Selected Contribution: Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia

Cited by 183 publications

References 28 publications

Identification of a Novel Form of Noradrenergic-Dependent Respiratory Motor Plasticity Triggered by Vagal Feedback

Identification of a Novel Form of Noradrenergic-Dependent Respiratory Motor Plasticity Triggered by Vagal Feedback

Gasping ActivityIn Vitro: A Rhythm Dependent on 5-HT2AReceptors

Carotid sinus nerve stimulation, but not intermittent hypoxia, induces respiratory LTF in adult rats exposed to neonatal intermittent hypoxia

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Gasping ActivityIn Vitro: A Rhythm Dependent on 5-HT_2AReceptors