Spinal AMP kinase activity differentially regulates phrenic motor plasticity

Perim, Raphael R.; Fields, Daryl P.; Mitchell, Gordon S.

doi:10.1152/japplphysiol.00546.2019

Cited by 10 publications

(5 citation statements)

References 47 publications

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“…Indeed, each plasticity mechanism is driven by molecules associated with distinct neural behaviors such as synaptogenesis 65 versus axonal growth, 66 respectively. For example, the S pathway requires Akt and mTORC1 signaling, 26,54 , 67 a pathway commonly associated with axonal growth/elongation. 66 Conversely, the Q pathway requires ERK MAPK and BDNF/TrkB signaling, 37,68–70 a pathway commonly associated with axon sprouting and synaptogenesis.…”

Section: Discussionmentioning

confidence: 99%

Magnitude and Mechanism of Phrenic Long-term Facilitation Shift Between Daily Rest Versus Active Phase

et al. 2023

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Plasticity is a fundamental property of the neural system controlling breathing. One key example of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a persistent increase in phrenic nerve activity elicited by acute intermittent hypoxia (AIH). pLTF can arise from distinct cell signaling cascades initiated by serotonin versus adenosine receptor activation, respectively; these signaling cascades interact via powerful cross-talk inhibition. Here, we demonstrate that the daily rest versus active phase and the duration of hypoxic episodes within an AIH protocol have profound impact on the magnitude and even mechanism of pLTF due to shifts in the serotonin/adenosine balance. Using the historical “standard” AIH protocol (3, 5 min moderate hypoxic episodes), we demonstrate that pLTF magnitude is unaffected by exposure in the mid-active versus mid-rest phase, yet the mechanism driving pLTF shifts from serotonin-dominant during mid-rest to adenosine-dominant in the mid-active phase. This mechanistic “flip” results from combined influences of hypoxia-evoked adenosine release and normal cycles in basal spinal adenosine between the rest versus active phase. Since AIH consisting of shorter hypoxic episodes but the same cumulative duration of hypoxia (15, 1 min episodes) elicits less adenosine release during hypoxic episodes, mid-rest pLTF is amplified due to a diminished adenosine constraint to serotonin-driven plasticity; on the other hand, this same 15 × 1 AIH protocol delivered in the mid-active phase suppresses serotonin-dominant pLTF due to elevated background adenosine levels but low hypoxia-evoked adenosine release. These findings demonstrate the importance of the serotonin/adenosine balance in regulating the amplitude and even mechanism of AIH-induced pLTF. Since AIH is emerging as a promising therapeutic modality to restore respiratory and non-respiratory movements in people with spinal cord injury or ALS, knowledge of how time-of-day and hypoxic episode duration impact the serotonin/adenosine balance and the magnitude and mechanism of pLTF has profound biological, experimental and translational implications.

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Section: Discussionmentioning

confidence: 99%

Magnitude and Mechanism of Phrenic Long-term Facilitation Shift Between Daily Rest Versus Active Phase

et al. 2023

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“…Decreases in p38MAP kinase gene expression suggest the possibility of decreased neuroinflammation and, thus, Q pathway inhibition (Agosto-Marlin et al, 2018). Counterintuitively, decreased Pde4b expression in younger females is consistent with increased PKA activation and (possibly) greater S-Q cross talk inhibition; if the change in Pde4b is sufficient, it may activate EPAC sufficiently to drive the S pathway in response to AIH, consistent with the apparent contribution of the S pathway to enhanced phrenic LTF in rats exposed to repetitive AIH (3x per week, four weeks (MacFarlane et al, 2018;Perim et al, 2020); or daily for 14 days, (Perim, Sunshine, et al, 2021). The functional impact of dAIH-reduced Pde4b expression is of considerable interest but is unknown at this time.…”

Section: Age-dependent Sexual Dimorphism and S Pathway Gene Expressionmentioning

confidence: 66%

Daily Acute Intermittent Hypoxia Elicits Age & Sex-Dependent Changes in Molecules Regulating Phrenic Motor Plasticity

Nair,

Marciante,

Lurk

et al. 2024

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Acute intermittent hypoxia (AIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (LTF). Repetitive daily AIH (dAIH) exposure enhances phrenic LTF, demonstrating a form of metaplasticity. Two additional factors impacting phrenic LTF are age and sex. For example, moderate AIH-induced phrenic LTF decreases with age in males, but increases in middle-aged females. However, little is known concerning cellular mechanisms of dAIH effects or age-dependent sexual dimorphism in phrenic LTF. Moderate AIH elicits distinct signaling cascades within phrenic motor neurons initiated by 5HT2 receptors (Q pathway) versus adenosine 2A or 5HT7 receptors (S pathway), respectively. The Q and S pathways interact via mutual crosstalk inhibition, a powerful regulator of phrenic LTF. To test the hypothesis that dAIH, age and sex effects on phrenic LTF are associated with differential expression of molecules known to regulate the Q and S pathways, we assessed mRNA of key regulatory molecules in ventral cervical homogenates from spinal segments containing the phrenic motor nucleus from young (3 month) and middle-aged (12 month) male and female Sprague-Dawley rats. Since CNS estrogen levels impact molecules regulating the Q and/or S pathways, mRNA was correlated with serum estradiol. Rats (n=8/group) were exposed to sham (21% O2) or dAIH (15, 1 min episodes of 10.5% inspired O2 per day) for 14 days, and sacrificed 24 hours post-dAIH. mRNA for molecules known to regulate phrenic LTF were assessed via RT PCR, including: brain derived neurotrophic factor (Bdnf); serotonin 2A (Htr2a); 2B (Htr2b); and (Htr7) receptors; adenosine 2a (Adora2a) receptors; exchange protein activated by cAMP (Epac1); p38 MAP kinase [Mapk14 (α) & Mapk11 (β)]; PKA catalytic subunit (Prkaa1); PKA regulatory subunit (Prkar1a); fractalkine (Cx3cl1); phosphodiesterase type 4 (Pde4b); NAPDH-gp91 (Cybb) and p47 (ncf1); and the PKCδ isoform (Prkcd). Significantly higher Pde4b, Adora2a, and Prkcd mRNA were found in young and middle-aged females versus age-matched males; Epac1 was elevated, but only in young females (p<0.001). Ncf1 was increased in middle-aged versus young adult rats of both sexes (p<0.01). Ncf1, Cx3cl1, Adora2a and Prkcd mRNA were reduced by dAIH in middle-aged females (p<0.01), but not other groups. Serum estradiol levels positively correlated with Epac1 (r2=0.29, p=0.002), Mapk14 (r2=0.31, p=0.001), Mapk11 (r2=0.20, p=0.014), and Prkar1a (r2=0.20 p=0.013) mRNA. With higher serum estradiol levels, dAIH decreased Mapk14 mRNA (slope difference p=0.001). Thus, age, sex and dAIH preconditioning influence molecules known to regulate the Q and S pathways to phrenic motor facilitation. These novel findings advance our understanding of phrenic LTF, and inform translational research concerning the therapeutic potential of dAIH to treat breathing deficits in individuals of different ages or sex.

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“…End-tidal CO 2 adjustments were made based on visual inspection of phrenic neurogram by an experienced investigator; (2) Normocapnia: end-tidal CO 2 was maintained ∼41 mmHg throughout experiments. This level, based on previous studies, is ∼2 mmHg above the CO 2 recruitment threshold (Perim et al, , 2020a; (3) Hypercapnia: end-tidal CO 2 was maintained ≥48 mmHg throughout experiments, corresponding to an average PaCO 2 of ∼50 mmHg.…”

Section: Experimental Designmentioning

confidence: 91%

“…All surgical procedures have been previously described (Perim et al, 2018(Perim et al, , 2020a. Rats were anesthetized in an acrylic chamber with 3% isoflurane in 3 L/min O 2 .…”

Section: Surgical Proceduresmentioning

confidence: 99%

Baseline Arterial CO2 Pressure Regulates Acute Intermittent Hypoxia-Induced Phrenic Long-Term Facilitation in Rats

et al. 2021

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Moderate acute intermittent hypoxia (mAIH) elicits a progressive increase in phrenic motor output lasting hours post-mAIH, a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). mAIH-induced pLTF is initiated by activation of spinally-projecting raphe serotonergic neurons during hypoxia and subsequent serotonin release near phrenic motor neurons. Since raphe serotonergic neurons are also sensitive to pH and CO2, the prevailing arterial CO2 pressure (PaCO2) may modulate their activity (and serotonin release) during hypoxic episodes. Thus, we hypothesized that changes in background PaCO2 directly influence the magnitude of mAIH-induced pLTF. mAIH-induced pLTF was evaluated in anesthetized, vagotomized, paralyzed and ventilated rats, with end-tidal CO2 (i.e., a PaCO2 surrogate) maintained at: (1) ≤39 mmHg (hypocapnia); (2) ∼41 mmHg (normocapnia); or (3) ≥48 mmHg (hypercapnia) throughout experimental protocols. Although baseline phrenic nerve activity tended to be lower in hypocapnia, short-term hypoxic phrenic response, i.e., burst amplitude (Δ = 5.1 ± 1.1 μV) and frequency responses (Δ = 21 ± 4 bpm), was greater than in normocapnic (Δ = 3.6 ± 0.6 μV and 8 ± 4, respectively) or hypercapnic rats (Δ = 2.0 ± 0.6 μV and −2 ± 2, respectively), followed by a progressive increase in phrenic burst amplitude (i.e., pLTF) for at least 60 min post mAIH. pLTF in the hypocapnic group (Δ = 4.9 ± 0.6 μV) was significantly greater than in normocapnic (Δ = 2.8 ± 0.7 μV) or hypercapnic rats (Δ = 1.7 ± 0.4 μV). In contrast, although hypercapnic rats also exhibited significant pLTF, it was attenuated versus hypocapnic rats. When pLTF was expressed as percent change from maximal chemoreflex stimulation, all pairwise comparisons were found to be statistically significant (p < 0.05). We conclude that elevated PaCO2 undermines mAIH-induced pLTF in anesthetized rats. These findings contrast with well-documented effects of PaCO2 on ventilatory LTF in awake humans.

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Spinal AMP kinase activity differentially regulates phrenic motor plasticity

Cited by 10 publications

References 47 publications

Magnitude and Mechanism of Phrenic Long-term Facilitation Shift Between Daily Rest Versus Active Phase

Magnitude and Mechanism of Phrenic Long-term Facilitation Shift Between Daily Rest Versus Active Phase

Daily Acute Intermittent Hypoxia Elicits Age & Sex-Dependent Changes in Molecules Regulating Phrenic Motor Plasticity

Baseline Arterial CO2 Pressure Regulates Acute Intermittent Hypoxia-Induced Phrenic Long-Term Facilitation in Rats

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