bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrical activation of phrenic afferent neurons evokes phrenic motor plasticity following cervical spinal cord injury
Authors: Streeter Kristi A. , Wollman Lila B. , Fusco Anna , Poirier Thomas , Salminen Jake , Fuller David 
Published: June 2021

Anatomical data from our laboratory indicate that phrenic afferent fibers can project across the spinal midline and neurophysiological data indicate that electrical activation of phrenic afferents can increase contralateral phrenic motor output. We have also observed that following chronic unilateral C2 hemisection (C2Hx) phrenic nerve afferent fibers undergo significant anatomical remodeling. Here we tested the hypothesis that following chronic C2Hx, activation of ipsilateral (same side as injury) phrenic afferent neurons would induce contralateral (opposite to injury) phrenic motor plasticity. Twelve weeks after unilateral C2Hx (n=9) or C2 laminectomy (n=8), adult Sprague‐Dawley rats were anesthetized, vagotomized, and ventilated to enable phrenic motor output to be studied under controlled conditions. The phrenic nerve ipsilateral to C2Hx or laminectomy was electrically stimulated using a bipolar electrode while contralateral phrenic motor output was recorded. Rats received 30 minutes of inspiratory triggered stimulation (90μA, 40pps, 1ms pulse width) and contralateral phrenic motor output was recorded for one hour. Analysis of contralateral burst amplitude using a two‐way repeated measures ANOVA revealed a significant effect of time (F3,45=9.505, P<0.0001), but not treatment (C2Hx vs. laminectomy, F1,15=0.1577, P=0.6969). Thus, phrenic burst amplitude was significantly changing over the 60 minute post‐stimulation, and both experimental groups had increased phrenic burst amplitude during this period (P<0.05 vs. pre‐stimulation baseline). These results indicate that electrical activation of phrenic nerve afferent fibers can induce a sustained increased (facilitation) of contralateral phrenic motor output after spinal cord injury. The response was not statistically different in the laminectomy group, which indicates that the phrenic afferent‐induced facilitation does not require conditions induced by the spinal cord injury. The ability of phrenic afferent neurons to evoke phrenic motor plasticity after spinal cord injury suggests that these afferent pathways could be important to rehabilitation of the diaphragm motor system post‐injury.Support or Funding InformationK99HL143207‐01 (KS), F32NS095620‐01 (KS), T32HL134621‐01A1 (LBW), SPARC OT2 OD023854 (DDF)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Glutamate Receptor Plasticity in Brainstem Respiratory Nuclei Following Chronic Hypercapnia in Goats
Authors: Burgraff Nicholas , Buchholz Kirstyn , Neumueller Suzanne , Pan Lawrence , Hodges Matthew , Forster Hubert 
Published: June 2021

Patients that retain CO2 with respiratory diseases such as chronic obstructive pulmonary disease (COPD) have worse prognoses and higher mortality rates than those with equal impairment of lung function without hypercapnia. However, little is known about the effects of chronic hypercapnia on the neurochemical mechanisms controlling brainstem respiratory nuclei (BRN). Common mechanisms of neuroplasticity involve changes in glutamate receptor expression/phosphorylation to modulate synaptic strength and network excitability, driven by changes in both AMPA (GluR) and NMDA (GluN) glutamate receptors. Accordingly, herein we tested the hypothesis that changes occur in glutamatergic signaling within the BRN during exposure to chronically elevated inspired CO2 (InCO2) induced hypercapnia. Healthy goats were euthanized after either 24 hours or 30 days of chronic exposure to 6% InCO2 or room air. The brainstems were extracted for western blot analyses to assess GluR and GluN receptor expression and phosphorylation state within the BRN. Compared to room air control goats, the following significant (P<0.05) changes were found after 24 hours of exposure to chronic hypercapnia: 1) AMPA receptor expression was greater, and NMDA receptor expression lower within the rostral solitary complex. 2) NMDA receptor expression/phosphorylation and APMA receptor phosphorylation were lower within the rostral ventrolateral medulla (VLM), while AMPA receptor expression/phosphorylation were greater in the caudal VLM. 3) AMPA receptor expression/phosphorylation were lower within the rostral retrotrapezoid nucleus. And, 4) NMDA receptor expression was greater within the caudal Raphe nucleus. The data indicate that within 24 hours of chronic hypercapnia changes have occurred in four BRN in GluR/GluN signaling which may contribute to an attenuated CO2‐induced hyperpnea and attenuated CO2 chemoreflex between 1 and 24 hours of hypercapnia (J. Physiol. 2018). GluR/GluN changes found at 24 hours of hypercapnia had returned to control levels after 30 days of hypercapnia. However, compared to room air control goats, the following significant (P<0.05) changes were found following 30 days of hypercapnia: 1) NMDA receptor phosphorylation was greater in the caudal ventral respiratory column, and 2) AMPA receptor expression was greater in the caudal RTN. The changes in GluR/GluN signaling between 24 hours and 30 days of chronic InCO2 may contribute to a sustained hyperpnea and normalization of the CO2 chemoreflex at 30 days.Support or Funding Information‐Department of Veteran Affairs ‐NIH Grant 007852This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Viral‐Induced Systemic Inflammation Undermines Respiratory Motor Plasticity
Authors: Hocker Austin D , Huxtable Adrianne G 
Published: June 2021

Systemic inflammation arises from varied stimuli and elicits distinct inflammatory profiles, yet we know little about the effects of different inflammatory stimuli on respiratory motor plasticity. Bacterial‐induced systemic inflammation undermines respiratory motor plasticity in the form of phrenic long‐term facilitation (pLTF), induced by acute intermittent hypoxia (AIH). pLTF is evoked by distinct cellular mechanisms, such as the Q‐pathway (induced by moderate AIH, PaO2 35–45 mmHg) and the S‐pathway (induced by severe AIH, PaO2 25–35 mmHg). The Q‐pathway is undermined by bacterial‐induced inflammation at 3 and 24 hours, while the S‐pathway is resistant. However, the effects of viral‐induced systemic inflammation on pLTF are unknown. Since viral‐induced inflammation is common, we tested the hypothesis that inflammation induced by a viral mimetic polyinosinic:polycitidylic acid (polyIC) would undermine Q‐pathway‐evoked pLTF, but not S‐pathway‐evoked pLTF. PolyIC dose‐response experiments (0.25 – 0.75 mg/kg, i.p.) revealed 0.75 mg/kg polyIC (i.p.) was sufficient to undermine Q‐pathway‐evoked pLTF 24 hours post‐polyIC (17 ± 15% change from baseline, n=5, p > 0.05). However, at 3 hours, polyIC (0.75 mg/kg, i.p.) was not sufficient to undermine Q‐pathway‐evoked pLTF (67 ± 21%, n=5, p < 0.0001), suggesting the temporal actions of viral‐induced systemic inflammation differ from bacterial‐induced systemic inflammation. Confirming the role of inflammatory signaling after polyIC (0.75 mg/kg, 24 hours, i.p.) in impairing pLTF, a non‐steroidal anti‐inflammatory (ketoprofen, 12.5 mg/kg, i.p., 3 hours) restored Q‐pathway‐evoked pLTF (64 ± 24%, n=5, p < 0.0001), and was not different from saline controls (55 ± 13%, n=5, p = 0.4711). Additionally, S‐pathway‐evoked pLTF was insensitive to polyIC‐induced inflammation (0.75 mg/kg, i.p.; 72 ± 25%, n=5, p < 0.0001) and was not different from saline controls (65 ± 32%, n=4, p = 0.6291). Our results suggest the inflammatory‐impairment of Q‐pathway‐evoked pLTF is not stimulus specific and confirm the inflammatory‐resistance of S‐pathway‐evoked pLTF. These data support the hypothesis that S‐pathway‐evoked plasticity could compensate for Q‐pathway impairments during inflammation. Thus, in situations where respiratory motor plasticity may be beneficial, for example, as a therapeutic tool to improve motor function after incomplete spinal cord injury, inflammation likely undermines Q‐pathway‐evoked plasticity and strategies targeting S‐pathway‐evoked plasticity may improve therapeutic outcomes.Support or Funding InformationHL141249This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mitochondrial‐targeted antioxidant drugsas therapeutically tools for apnea of prematurity: intermittent hypoxia and sex dimorphism
Authors: Soliz Jorge , Arias Christian , Marcouiller François , Laouafa Sofien , Bairam Aida , Joseph Vincent 
Published: June 2021

Immaturity of the brainstem network system that controls breathing leads to apnea of prematurity (AoP). While AoP is a developmental (and thus self‐resolving) disorder, it is not the apnea but the associated decrease of arterial oxygen levels (Intermittent Hypoxemia ‐ IH) what is detrimental for neural maturation. IH induces mitochondrial dysfunction, increased production of reactive oxygen species (ROS), and oxidative stress, thus promoting higher breathing instability, delayed neural maturation and prolonged hospitalization. We hypothesized that the mitochondrial‐targeted antioxidant drug MitoTEMPO, by restoring mitochondrial dysfunction, protects newborns against the consequences of IH induced by AoP. Moreover, keeping in mind that male sex is an important risk factor for several respiratory diseases in preterm neonates experiments were performed in male and female newborn rats exposed to IH during postnatal days (P) 3–10. During this time, animals were daily injected (i.p.) with vehicle or MitoTEMPO (10–12 pups/group). At P10 the frequency of apneas at rest were measured (as an index of respiratory dysfunction) by plethysmography. Next, the cortex tissue was collected, and a high‐resolution Oxygraph‐2k was used to evaluate the mitochondrial bioenergetics and ROS (H2O2) production using saponin‐permeabilized tissue punches of 1.5–3 mg weight. Our preliminary results obtained in male animals showed that mitoTEMPO: 1) restored the IH‐mediated increase of apneic events, 2) restored the IH‐mediated decrease of mitochondrial respiration of complex I (NADH‐linked respiration), and complex II (FADH2‐linked respiration), and 3) decreased the IH‐mediated increase of mitochondrial H2O2. Surprisingly, no impact of IH and/or the treatment with mitoTEMPO was observed in female animals. We conclude that neonatal IH leads to respiratory disturbances in male animals only. Moreover, our results suggest that antioxidant drugs may be used as new therapeutical tools for apnea of prematurity in males.Support or Funding InformationJorge Soliz is funded by the Canadian Institutes of Health Research (CIHR – Catalyst grant sex as a variable in biomedical research‐IC118777). The salary of Jorge Soliz is supported by Laval University. The Canadian Foundation for Innovations (FCI – 32986) supported the acquisition of state‐of‐the art equipment in Jorge Soliz lab.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effects of TNFα on Mitochondria Morphology are Mediated by Endoplasmic Reticulum Stress in Human Airway Smooth Muscle Cells
Authors: Yap John Qian , Chen Xujiao , Delmotte Philippe , Sieck Gary 
Published: June 2021

Airway inflammation is a key trigger for asthma, and pro‐inflammatory cytokines such as TNFα mediate the airway hyperreactivity and remodeling characteristic of asthma. In various diseases, inflammation leads to an increase in mitochondrial fission, associated with decreased expression of mitochondrial fusion proteins, such as Mfn2. Mitochondrial fission is generally coupled with mitochondrial biogenesis and cell proliferation. Some studies in other cell types suggest that mitochondrial fission may be a result of the accumulation of unfolded or misfolded proteins i.e., endoplasmic reticulum (ER) stress. ER stress activates three intracellular pathways to induce a homeostatic response to restore normal ER function. The IRE1α pathway is activated by autophosphorylation and splices XBP1 mRNA. Previous studies have shown that the XBP1 has downstream effects on mitochondrial proteins. In this study we hypothesized that TNFα induces activation of the IRE1α pathway which leads to a decrease in Mfn2 expression. hASM cells were isolated from lung specimen incidental to patient surgery. The patients were normal as evaluated by the clinical pathologist (no history of asthma or COPD). hASM cells were stimulated with TNFα (20 ng/ml) for 1, 3, 6, 12 or 24 h. Expression of total and phosphorylated IRE1α, Mfn2 and cleaved and uncleaved XBP1 were evaluated by Western blot. RNAscope® was used to measure Mfn2 mRNA expression in hASM cells transfected with non‐phosphorylatable IREα (DeltaP‐IRE1α; GFP tagged) compared to non‐transfected cells. Results were analyzed by 2‐way ANOVA with Bonferroni analysis when justified. We found that exposure of hASM cells to TNFα activated the IRE1α/XBP1 pathway and decreased Mfn2 expression in a time dependent fashion. In addition we found that TNFα exposure in cells expressing the inactive DeltaP‐IRE1α did not lead to a significant decrease in Mfn2 expression. Our results suggest that the IRE1α/XBP1 pathway may be involved in the regulation of mitochondrial fission, mitochondrial biogenesis and cell proliferation.Support or Funding InformationSupported by NIH grant HL126451 (GCS)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Novel Protease‐Activated Receptor‐2 Antagonist Blocks Allergen‐induced Airway Epithelial Cell Signaling In vitro and Asthma Symptoms In vivo
Authors: Rivas Candy Mavis , Addison Kenneth , Yee Michael , Ledford Julie , DeFea Kathryn , Price Theodore , Vagner Josef , Boitano Scott A. 
Published: June 2021

Protease‐activated receptor‐2 (PAR2) is a G protein‐coupled receptor that can self‐activate upon proteolysis of the extracellular amino terminus. Tethered ligand binding leads to receptor activation and stimulation of both β‐arrestin/MAPK and Gαq‐Ca2+ dependent signaling. PAR2 is expressed by the airway epithelium and thus is poised to encounter proteases found within asthma‐inducing environmental allergens. Studies using activating peptides or PAR2 knock out cells/animals demonstrate a key role for PAR2 in animal models of asthma. Recently, our lab has developed C391, a potent PAR2 antagonist that has shown to be effective in blocking peptidomimetic‐ and trypsin‐induced PAR2 signaling in vitro as well as inflammatory pain in vivo. Here we show that C391 competitively binds PAR2 (using a Time Resolved Fluorescence binding assay) and evaluate the ability for C391 to block the protease‐containing asthma‐associated allergen (Alternaria alternata)‐induced signaling in cultured human airway epithelial cells (16HBE14o‐) and A. alternata‐induced asthma symptoms in a murine model. We demonstrate that micromolar concentrations of C391 block A. alternata‐induced Ca2+ signaling (digital imaging microscopy), A. alternata‐induced MAPK signaling (In Cell Western) and A. alternata‐induced β‐arrestin signaling (Bioluminescence Resonance Energy Transfer). In an eight‐day murine model of A. alternaria‐sensitization and challenge, we next evaluated the ability for C391 to block asthma associated symptoms. We demonstrate that C391 effectively attenuates inflammation (bronchoalveolar lavage and histochemical analyses), mucus production and goblet cell hyperplasia (histochemical analysis) and airway hyperresponsiveness (Forced Oscillation Technique analysis with Flexivent) in both C57Bl/6 and BALB‐C mice. To our knowledge, this is the first demonstration of pharmacological block of PAR2 to block allergen‐induced asthma symptoms in vivo. These data support further development of PAR2 antagonism as a potential first‐in‐class allergic asthma drug.Support or Funding InformationAmerican Physiological Society: William Townsend Porter Pre‐doctoral Fellowship (CMR) NIH AI140257 (SB)NIH NS098826 (TP JV SB)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sex Differences in the Diameter of Extra‐parenchymal Airways in a Large Cohort of Healthy Adult Non‐smokers
Authors: Cross Troy J , Wheatley Courtney , Wentz Robert , Levin David L , Bartholmai Brian J , Johnson Bruce D 
Published: June 2021

Growing evidence suggests that the larger conducting airways are smaller in women than men; however, evidence of this sex‐difference in airway geometry is yet to be demonstrated in a large cohort of adult, healthy non‐smokers. Furthermore, it is not known whether these sex differences persist after airway size is adjusted for its allometric relationship with absolute lung size.PurposeWe examined the effect of sex on airway size in a large cohort of non‐smoking healthy adults after adjusting for the possible confounding effect of absolute lung size.MethodsA total of 133 (75 men; 58 women) non‐smoking adults (50 ± 18 yrs) with normal pulmonary function (>80% pred.) participated in this study. Full thoracic CT scans were obtained in each participant during a breath‐hold at full inflation. Commercial software was used to automatically segment airways and assign 32 anatomical labels ranging from the 0th to the 5th generation. Intraluminal hydraulic diameters (Dh) were obtained for each airway. An allometric relationship was assumed between Dh and absolute lung size, as given by: Dh = TLVβ·ek, where TLV is the total lung volume at full inflation, β is the allometric scaling exponent, and k allowed for proportional effects of confounding variables. This allometric equation was log‐log transformed such that it could be examined using linear regression: e.g., ln(Dh) = β·ln(TLV) + k. Sex, age and their interaction were allowed to contribute to both β and k as covariates. The model also included a term for reconstructed voxel size. Model averaging was used to provide parameter estimates of the log‐log transformed allometric equation.ResultsThe allometric exponent, β, assigned to TLV was significant for all 32 anatomically labelled airways (P < 0.05); neither sex nor age affected β. On the other hand, sex and age were significant mediators of k for the extra‐parenchymal airways only (Trachea, RMB, LMB, BronInt, see Figure 1, P < 0.05).ConclusionsOur findings indicate that sex differences in Dh remain present despite accounting for the allometric relationship between airway and lung size (see Figure 1). Importantly, however, this sex‐difference in airway size is seemingly confined to the extra‐parenchymal airways.Support or Funding InformationThis work was supported by NIH Grant HL71478.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Divergent effects of sex and aging on the intrinsic physiology of substantia nigra dopamine neurons
Authors: Howell Rebecca Dean , Lopez Sergio Dean Dominguez , Parikh Ishita , Beckstead Michael 
Published: June 2021

The largest population of dopamine‐producing neurons is in the ventral midbrain. Within this region, the neurons located in the substantia nigra are necessary for the initiation of voluntary movement. The degeneration of substantia nigra dopamine neurons is involved in the etiology for Parkinson's disease, a disease characterized by progressive loss of motor and cognitive functions. The biggest risk factor for Parkinson's disease is age, with most cases occurring after age 60. Moreover, Parkinson's is almost 2 times more prevalent in men than in women. While much research in Parkinson's has focused on the mechanisms underlying the dopamine neuron degeneration, very little work has considered the influence of normal aging on dopamine neurons which may contribute to disease risk and presentation.In this work, we performed whole cell patch clamp recordings in brain slices to study the changes in intrinsic firing properties of dopamine neurons in C57BL/6 mice across ages (4, 12, 18, ≥24 months) and compared between sexes. In addition, we assessed open field locomotion in these mice and performed a quantitative comparison of the numbers of substantia nigra dopamine neurons. Interestingly, we found a progressive decline in dopamine neuron function and number in males with age, while neurons in females remained largely unaffected. Behaviorally, there was a decrease in the distance travelled and speed of the mice with age, with females exhibiting higher activity levels at young ages. The effects of age and sex were further evaluated by comparing the transcriptomic profile of the substantia nigra pars compacta in these mice. The impairments in dopamine neuron function and locomotor activity in males that occurs with age may represent a vulnerability to further insults that could underlie the susceptibility to neurodegenerative processes like those seen in Parkinson's disease.Support or Funding InformationNIH grant (R01AG052606)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effects of Lavender Essential Oils on the Anxious Behavior of Zebrafish
Authors: Moore Jennifer Lindsey , Kasper Sherry Oden 
Published: June 2021

In the United States, anxiety disorders are becoming increasingly prominent, affecting as many as 30% of Americans with more cases found each year. Currently, lavender essential oils are being utilized by people to relieve anxiety symptoms although there is little research to validate the scientific basis for the relief of symptoms. Some research has indicated that lavender in essential oils can inhibit the serotonin reuptake transporter similar to the mechanism of action for many oral antidepressants. Zebrafish have become an accepted model for anxious behavior due to their visible and inherent diving behavior when presented with negative stimuli. In addition, zebrafish share 82% of the genes associated with mental disorders in humans and have similar endocrine responses such as the release of cortisol. To test the effect of lavender essential oil on the anxious behavior, zebrafish were exposed to a stressful stimulus and given varying doses of lavender oil to determine their shoaling behavior. In addition, to determine the effects on endocrine response, cortisol levels were tested in each condition. We have found that lavender essential oils decrease diving behavior in zebrafish compared with those who are untreated. Therefore, the goal of the research was to exhibit the relief of anxious symptoms with the treatment of lavender oil in zebrafish by documenting their behavioral changes when treated with lavender essential oils compared with anxious behavior in those with no treatment.Support or Funding InformationNoneThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.