Phrenic motor neuron TrkB expression is necessary for acute intermittent hypoxia-induced phrenic long-term facilitation

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Cervical spinal adenosine 2A (A ) receptor activation elicits a prolonged increase in phrenic nerve activity, an effect known as phrenic motor facilitation (pMF). The specific cervical spinal cells expressing the relevant A receptors for pMF are unknown. This is an important question since the physiological outcome of A receptor activation is highly cell type specific. Thus, we tested the hypothesis that the relevant A receptors for pMF are expressed in phrenic motor neurons per se versus non-phrenic neurons of the cervical spinal cord. A receptor immunostaining significantly colocalized with NeuN-positive neurons (89 ± 2%). Intrapleural siRNA injections were used to selectively knock down A receptors in cholera toxin B-subunit-labelled phrenic motor neurons. A receptor knock-down was verified by a ∼45% decrease in A receptor immunoreactivity within phrenic motor neurons versus non-targeting siRNAs (siNT; P < 0.05). There was no evidence for knock-down in cervical non-phrenic motor neurons. In rats that were anaesthetized, subjected to neuromuscular blockade and ventilated, pMF induced by cervical (C3-4) intrathecal injections of the A receptor agonist CGS21680 was greatly attenuated in siA (21%) versus siNT treated rats (147%; P < 0.01). There were no significant effects of siA on phrenic burst frequency. Collectively, our results support the hypothesis that phrenic motor neurons express the A receptors relevant to A receptor-induced pMF.

“…; Dale et al . ). Thus, understanding A 2A receptor regulation of phrenic motor neurons is highly significant.…”

Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 97%

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Phrenic motor neuron adenosine 2A receptors elicit phrenic motor facilitation

Seven

Perim

Hobson

et al. 2018

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“…; TrkB: Dale et al . ; A2A receptors: Seven et al . ), without evidence of knock‐down in other cervical spinal cells.…”

Section: Discussionmentioning

confidence: 95%

Protein kinase Cδ constrains the S‐pathway to phrenic motor facilitation elicited by spinal 5‐HT₇ receptors or severe acute intermittent hypoxia

Perim

Fields

Mitchell

2018

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Key points Concurrent 5‐HT2A (Q pathway) and 5‐HT7 (S pathway) serotonin receptor activation cancels phrenic motor facilitation due to mutual cross‐talk inhibition. Spinal protein kinase Cδ (PKCδ) or protein kinase A inhibition restores phrenic motor facilitation with concurrent Q and S pathway activation, demonstrating a key role for these kinases in cross‐talk inhibition. Spinal PKCδ inhibition enhances adenosine‐dependent severe acute intermittent hypoxia‐induced phrenic long‐term facilitation (S pathway), consistent with relief of cross‐talk inhibition. Abstract Intermittent spinal serotonin receptor activation elicits long‐lasting phrenic motor facilitation (pMF), a form of respiratory motor plasticity. When activated alone, spinal Gq protein‐coupled serotonin 2A receptors (5‐HT2A) initiate pMF by a mechanism that requires ERK‐MAP kinase signalling and new BDNF protein synthesis (Q pathway). Spinal Gs protein‐coupled serotonin 7 (5‐HT7) and adenosine 2A (A2A) receptor activation also elicits pMF, but via distinct mechanisms (S pathway) that require Akt signalling and new TrkB protein synthesis. Although studies have shown inhibitory cross‐talk interactions between these competing pathways, the underlying cellular mechanisms are unknown. We propose the following hypotheses: (1) concurrent 5‐HT2A and 5‐HT7 activation undermines pMF; (2) protein kinase A (PKA) and (3) NADPH oxidase mediate inhibitory interactions between Q (5‐HT2A) and S (5‐HT7) pathways. Selective 5‐HT2A (DOI hydrochloride) and 5HT7 (AS‐19) agonists were administered intrathecally at C4 (three injections, 5‐min intervals) in anaesthetized, vagotomized and ventilated male rats. With either spinal 5‐HT2A or 5‐HT7 activation alone, phrenic amplitude progressively increased (pMF). In contrast, concurrent 5‐HT2A and 5‐HT7 activation failed to elicit pMF. The 5‐HT2A‐induced Q pathway was restored by inhibiting PKA activity (Rp‐8‐Br‐cAMPS). NADPH oxidase inhibition did not prevent cross‐talk inhibition. Therefore, we investigated alternative mechanisms to explain Q to S pathway inhibition. Spinal protein kinase C (PKC) inhibition with Gö6983 or PKCδ peptide inhibitor restored the 5‐HT7‐induced S pathway to pMF, revealing PKCδ as the relevant isoform. Spinal PKCδ inhibition enhanced the S pathway‐dependent form of pMF elicited by severe acute intermittent hypoxia. We suggest that powerful constraints between 5‐HT2A and 5‐HT7 or A2A receptor‐induced pMF are mediated by PKCδ and PKA, respectively.

“…), activation of the high‐affinity BDNF receptor tropomyosin‐related kinase B (TrkB) (Dale et al . ), activation of PKCθ (Devinney et al . ) and reactive oxygen species formation (MacFarlane & Mitchell, ; MacFarlane et al .…”

Section: Discussionmentioning

confidence: 99%

Competing mechanisms of plasticity impair compensatory responses to repetitive apnoea

Fields

Braegelmann

Meza

et al. 2019

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Key pointsr Intermittent reductions in respiratory neural activity, a characteristic of many ventilatory disorders, leads to inadequate ventilation and arterial hypoxia. Both intermittent reductions in respiratory neural activity and intermittent hypoxia trigger compensatory enhancements in inspiratory output when experienced separately, forms of plasticity called inactivity-induced inspiratory motor facilitation (iMF) and long-term facilitation (LTF), respectively.r Reductions in respiratory neural activity that lead to moderate, but not mild, arterial hypoxia occludes plasticity expression, indicating that concurrent induction of iMF and LTF impairs plasticity through cross-talk inhibition of their respective signalling pathways.r Moderate hypoxia undermines iMF by enhancing NR2B-containing NMDA receptor signalling, which can be rescued by exogenous retinoic acid, a molecule necessary for iMF.r These data suggest that in ventilatory disorders characterized by reduced inspiratory motor output, such as sleep apnoea, endogenous mechanisms of compensatory plasticity may be impaired, and that exogenously activating respiratory plasticity may be a novel strategy to improve breathing.Abstract Many forms of sleep apnoea are characterized by recurrent reductions in respiratory neural activity, which leads to inadequate ventilation and arterial hypoxia. Both recurrent reductions in respiratory neural activity and hypoxia activate mechanisms of compensatory plasticity that augment inspiratory output and lower the threshold for apnoea, inactivity-induced inspiratory motor facilitation (iMF) and long-term facilitation (LTF), respectively. However, despite frequent concurrence of reduced respiratory neural activity and hypoxia, mechanisms that induce and regulate iMF and LTF have only been studied separately. Here, we demonstrate that recurrent reductions in respiratory neural activity ('neural apnoea') accompanied by cessations in ventilation that result in moderate (but not mild) hypoxaemia do not elicit increased inspiratory output, suggesting that concurrent induction of iMF and LTF occludes plasticity. A key role for NMDA receptor activation in impairing plasticity following concurrent neural apnoea and hypoxia is indicated since recurrent hypoxic neural apnoeas triggered increased phrenic inspiratory Daryl Fields is currently a neurosurgery resident at the University of Pittsburgh. He completed his medical degree and research doctorate at the University of Wisconsin Madison under the mentorship of Dr Tracy Baker, PhD. Daryl's research is focused on creating readily translatable therapies for movement control disorders: (1) development of animal models to better understand deficits in movement control and (2) development of pharmacological therapies for improved motor rehabilitation. He has contributed to the development of several novel research directions that continue to progress the field of motor control/rehabilitation. 3952 D. P. Fields and others J Physiol 597.15 output in rats in which spinal NR2B-containing ...