bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain Stem Circuit Operations during Baroreceptor Modulation of the Motor Pattern for Breathing
Authors: Lindsey Bruce G. , Nuding Sarah C. , Segers Lauren S. , Morris Kendall F. 
Published: June 2021

Circuit operations in the raphe‐pontomedullary network for breathing remain incompletely understood (Nuding et al. J Neurophysiol 101: 2943, 2009; Lindsey et al., Physiology, 33: 281, 2018). Current models for baroreceptor tuning of the respiratory motor pattern include parallel raphe‐ventral respiratory column (VRC) “push‐pull” circuits for regulation of respiratory phase timing and inspiratory drive (Lindsey et al. J Physiol, 512: 863, 1998; Segers et al. J Neurophysiol 113: 352, 2015). To extend prior work, we tested the hypothesis that inter‐regional loop circuits among neurons of the VRC, pons, and raphe nuclei have altered activities appropriate for roles in the tuning of respiratory drive and rhythm during changes in systemic arterial blood pressure. In 7 decerebrate vagotomized neuromuscular‐blocked cats, we used multi‐electrode arrays to record the activities of VRC (n=88), pontine (n=87), and raphe (n=188) neurons during baroreceptor‐evoked perturbations of breathing, as measured by altered peak activity in integrated efferent phrenic nerve activity and changes in respiratory phase durations. Blood pressure was transiently (30 sec.) elevated or reduced by inflations of an embolectomy catheter in the descending aorta or vena cava, respectively. Trials were separated by 1.5‐min intervals to allow the mean systemic arterial pressure to return to pre‐stimulus levels. Spike trains of 10,530 pairs of neurons were evaluated for changes in firing rate and short‐time scale correlational signatures indicative of functional connectivity. The results include evidence for: (i) baroreceptor modulation of a VRC‐pontine inspiratory off‐switch loop; (ii) a VRC inspiratory neuron chain disinhibitory microcircuit for baroreceptor tuning of the drive to breathe that operates in parallel with VRC tonic expiratory (t‐E) “hub” neurons; (iii) multiple push‐pull control pathways between baroresponsive raphe assemblies and the VRC t‐E neurons; (iv) divergent paths from the VRC to raphe circuits, including routes through the pons. Overall, the results provide additional support for parallel chain and loop operations in the brain stem network that controls breathing (Morris et al. J Neurophysiol 119:700, 2018).Support or Funding InformationSupport: NIH Grant NS19814 and Common Fund OT2OD023854.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Chronic Alcohol Administration Induces Inflammasome Activation in Mouse Lungs
Authors: Yeligar Samantha , Cingolani Francesca , Li Juan , Bedi Brahmchetna , Sadikot Ruxana , Czaja Mark 
Published: June 2021

ObjectiveExcessive alcohol misusers are 2–4 times more likely to develop respiratory infections and acute respiratory distress syndrome as compared to non‐alcoholics. Alcohol misuse enhances oxidative stress in the lung, leading to impaired lung immunity. The molecular mechanisms by which this lung immune dysfunction occurs remain poorly defined. Inflammasome activation occurs in alcoholic steatohepatitis and functions in oxidative stress and host defense. Autophagy is critical for the engulfment and degradation of intracellular pathogens and regulates inflammasome activation. Thus, we hypothesized that autophagy prevents oxidative stress and inflammasome activation in the lung induced by alcohol.MethodsLungs were collected from littermate Atg5F/F control or LysM‐Cre‐Atg5F/F mice with a macrophage‐specific knockout of the autophagy gene Atg5 that were fed either a control or ethanol‐containing (5% vol/vol) Lieber‐DeCarli diet for 5 weeks. Markers of oxidative stress and inflammation were measured in the lungs from these mice. mRNA levels of NADPH oxidase 4 (Nox4) and transforming growth factor beta (TGFβ) were assessed by qRT‐PCR. Protein expression of NLRP3, caspase‐1 and ASC were measured by western blotting and interleukin (IL)‐1β was quantitated by ELISA.ResultsIn vivo studies demonstrated that alcohol: 1) increased the mRNA levels of Nox4 and TGFβ; 2) increased components of the inflammasome complex, namely NLRP3, ASC and caspase‐1; and 3) elevated IL‐1β expression, indicative of inflammasome activation. Knockdown of Atg5 enhanced inflammasome activation and exacerbated the oxidative stress and inflammatory effects of alcohol.ConclusionsMacrophage autophagy likely plays a critical role in regulating lung oxidative stress and inflammasome activation during chronic alcohol ingestion. Inactivation of the autophagic pathway exacerbates the deleterious effects of alcohol. Therapeutic targeting of autophagy or inflammasome activation pathways could mitigate alcohol's detrimental effects on the lung and improve lung host immune defense.Support or Funding InformationResearch Funding Source: Department of Veterans Affairs 2I01BX001786 (RTS), and National Institute of Alcohol Abuse and Alcoholism 4R00AA021803 (SMY) and 5R01AA022601 (MJC).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Release of a contractile factor and reduced nitric oxide from isolated pulmonary resistance vessels from BalB/CJ mice cause higher reactivity to angiotensin II compared to C57BL/6J mice
Authors: Becirovic‐Agic Mediha , Hultström Michael 
Published: June 2021

Pulmonary arterial hypertension (PAH) is caused by increased pulmonary vascular resistance that can develop as part of other pathologies such as pulmonary embolism and heart failure, or because of pulmonary vascular remodeling. The role of angiotensin II in pulmonary hypertension has not been extensively studied, and some conflicting results have been presented.We have seen that Balb/CJ mice treated with angiotensin II and high salt diet (AngII+Salt) develop increased pulmonary vascular resistance and right ventricle systolic pressure already 24 hours following treatment initiation. Within the following 6 days, Balb/CJ mice develop massive edema and heart failure. C57Bl/6J mice on the other hand are resistant to this treatment. We hypothesized that pulmonary vessels in Balb/CJ mice are more reactive to angiotensin II than in C57BL/6J mice. The aim of present study was to investigate isolated pulmonary resistance vessel reactivity in Balb/CJ and C57BL/6J mice using wire myography.The results show that pulmonary resistance vessels from Balb/CJ mice have enhanced vascular reactivity to angiotensin II, which abolished in denuded vessels. Pulmonary resistance vessels from C57BL/6J mice on the other hand show little or no response to angiotensin II. However, transfer of bath solution from Balb/CJ pulmonary vessels to C57BL/6J pulmonary vessels induces as strong contraction as in Balb/CJ mice. This indicates that angiotensin II causes increased vascular contraction in Balb/CJ mice, mainly by stimulating release of a secondary substance from the endothelium which in turn causes strong contraction. Further, acetylcholine induced relaxation is weaker in pulmonary arteries from Balb/CJ mice compared to C57BL/6J mice, while sodium nitroprusside induced relaxation does not differ between the strains indicating a difference in endothelial nitric oxide production as well.In conclusion, pulmonary artery endothelial function is different between Balb/CJ and C57BL/6J mice, causing increased vascular reactivity to angiotensin II, by stimulating release of a substance that in turn causes contraction both in BalB/CJ mice and C57BL/6J mice. In addition, Balb/CJ show reduced relaxation after acetylcholine. These results may increase the understanding of the role of angiotensin II in pulmonary hypertension, as well as shed some light on increased susceptibility to pulmonary hypertension in patients with a reactive phenotype.Support or Funding InformationSwedish Society of Medical Research, and the Swedish Heart‐Lung Foundation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
NIH's Consortium on Molecular Transducers of Physical Activity (MoTrPAC)
Authors: Williams John P. , Joseph Lyndon , Consortium MoTrPAC 
Published: June 2021

Physical activity is beneficial to human health and well being across the lifespan. Regular physical activity brings about numerous health benefits, however most of the current studies are correlative and the molecular mechanisms that are the basis for these beneficial effects remain obscure.The NIH Common Fund initiated the Molecular Transducers of Physical Activity Consortium (MoTrPAC) in December 2016 by issuing 19 grants to 37 Principal Investigators from 23 institutions. The goals of MoTrPAC are to:

Aim 1: Assemble a comprehensive map of the molecular changes that occur in response to exercise and provide insights into how they are altered by age, sex, body composition and fitness level.
Aim 2: Develop a user‐friendly database to facilitate investigator‐initiated studies and catalyze the field of physical activity research whereby researchers can develop hypotheses exploring novel mechanisms by which physical activity improves or preserves health.
MoTrPAC is a large discovery project that will explore and document molecular signatures/markers of the exercise response to physical activity in humans and animals. The human studies are a multi‐center clinical trial cohort of people from 10–80 years of age. Animal studies have been conducted and tissues harvested from 6 and 18‐month old F344 rats before and at seven time points post acute exercise. Other rats underwent a training regime ranging from one to eight weeks and tissues harvested 48 hours after the last bought. Three of the animal tissues harvested are the same as those harvested from human subjects. A total of 18 tissues were harvested from rats. Multiple state of art and omics platforms including genomic, transcriptomic, epigenomic, proteomic and metabolomics will be employed to collect extensive data sets that will serve as a basis for future investigator initiated studies for the research community to advance our understanding of the molecular mechanisms of exercises effects. This presentation will describe various components of MoTrPAC consortium and provide information on its current activities.Support or Funding InformationNIH Common Fund; Office of the NIH DirectorThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of the ganglioglomerular nerve in response to hypoxia in juvenile rats
Authors: Coffee Gregory A , Getsy Paulina M , Lewis Stephen J 
Published: June 2021

The superior cervical ganglion (SCG) sends sympathetic input to the carotid body (CB) via the ganglioglomerular nerve (GGN) in order to modulate carotid sinus nerve (CSN) chemosensory afferent discharge via controlling vascular tone. This chemoafferent discharge is then relayed to the nucleus tractus solitarius (NTS) where the information is processed resulting in a compensatory increase in respiration. Hypoxic gas challenge stimulates the GGN. However, little is known as to the effects of ganglioglomerular nerve transection (GGNx) on carotid body chemosensory afferent response to hypoxia (HX).Our objective was to determine the effect of unilateral GGNx on the ventilatory responses elicited by HX (10% O2, 90% N2) gas challenge (5 episodes of 5 min in duration separated by 15 min) in freely‐moving juvenile (P25) Sprague‐Dawley rats.Male rats postnatal (P) 21 were subjected to sham or unilateral (right or left) GGNx and were allowed 4 days to recover. On the day of the experiment, P25 rats were placed in whole‐body plethysmography chambers and subjected to the hypoxic gas exposure. Ventilatory parameters included frequency of breathing, tidal volume, minute ventilation (= frequency x tidal volume), inspiratory and expiatory times, end inspiratory and expiratory pauses, peak inspiratory and expiratory flows, inspiratory and expiratory drive, EF50 (expiratory flow at 50% expired tidal volume) and rejection index (percentage of abnormal breaths).The HX challenge elicited altered ventilatory responses in sham‐operated rats compared to unilateral GGNx. Rejection Index (%) was diminished in unilateral (left and right) GGNx rats compared to sham, in addition to Rpef in only the right GGNx rats. Peak inspiratory flow (mL/s) was increased in only left GGNx rats, while the peak expiratory flow (mL/s) rates were increased in both the right and left GGNx subjects. Minute ventilation (mL/min) exhibited ventilatory roll‐off in sham animals while no such trend was observed in left GGNx rats. Although peak inspiratory flow, inspiratory drive (mL/s), and expiratory drive (mL/s) reached similar plateaus in right GGNx, the onset of the responses was delayed when compared to their sham counterparts. End expiratory pause (msec) showed a more robust response following hypoxic challenge in right GGNx when viewed against the sham. These findings follow a similar trend to those previously demonstrated from unilateral SCG removal, but still possess characteristics that are unique to the GGN alone. This which suggests the role the SCG has in modulating the hypoxic response is through the GGN and the CB, as well as other yet unknown mechanisms.Support or Funding InformationNIH SPARC 1OT2OD023860‐02 SJLewisThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Persistent HIF‐1 Activation by Long‐Term Intermittent Hypoxia
Authors: Nanduri Jayasri , Wang Ning , Khan Shakil A , Semenza Gregg L , Prabhakar Nanduri R 
Published: June 2021

Long‐term (30 days) exposure of rats to intermittent hypoxia (LT‐IH) results in persistent elevation of reactive oxygen species levels in central and peripheral nervous system (J. Nanduri et al., J. Physiol.2016,2018). HIF‐ regulates pro‐oxidant enzyme (POE) genes during IH. Present study examined the effect of LT‐IH on HIF‐1α protein and NADPH oxidase (Nox) 4 mRNA abundances in the carotid body (CB) and adrenal medullae (AM) of LT‐IH treated rats. CB and AM of LT‐IH treated rats exhibited robust increase in HIF‐1α protein, Nox4 mRNA and ROS levels. Remarkably, these effects persisted after recovery in room air for 30d. The effects of LT‐IH on HIF‐1α, Nox 4 mRNA, and ROS abundance were absent in rats treated with digoxin, an inhibitor of HIF‐1α during LT‐IH as well as in mice with partial deficiency of HIF‐1a (HIF‐1α heterozygote mice). These findings suggest that HIF‐1 dependent upregulation of POE genes contributes to LT‐IH induced persistent oxidative stress in the CB and AM.Support or Funding InformationSupported by NIH‐ HL‐90554.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Differential Effects of Continuous versus Intermittent Dietary Fat Intake on Markers of Serotonin Signaling in the Circumvallate Papillae of the Tongue
Authors: Primeaux Stefany , El‐Desoky Dalia 
Published: June 2021

Taste is a primary sensory modality that guides organisms in their determination of food preferences. Previous studies suggest that orosensory fat sensing may contribute to the intake and preference of dietary fat leading to the development of obesity. CD36 is the proposed fat taste receptor on the circumvallate papillae (CV) of the tongue and mediates fat sensing. Fat signaling via CD36 on the CV involves the regulation of serotonin (5‐HT) in taste receptor cells and activation of gustatory afferent nerves. The aim of these experiments was to investigate the effects of dietary fat intake on 5‐HT signaling in the CV using two feeding paradigms: continuous access to high fat diet (HFD) vs. limited access to dietary fat. We hypothesized that consumption of dietary fat, in specific patterns, contributes to the decreased sensitivity (i.e. hyposensitivity) of fat sensing through 5‐HT signaling dysregulation. The first experiment investigated the effects of continuous access to either a HFD or a low fat diet (LFD) for 1, 3 or 14 days on 5‐HT signaling in the CV. The second experiment investigated the effects of limited daily and intermittent access to dietary fat on 5‐HT signaling in the CV. Body weight and kilocalorie intake were assessed. In the CV, expression levels of CD36, 5‐HT1A, SERT, TPH1, and TPH2 mRNA were determined by Real Time PCR. Continuous HFD consumption for 14 days increased CD36, 5‐HT1A and SERT mRNA expression on the CV, suggesting reduced lingual fat sensing via decreased gustatory signaling from taste receptor cells. Limited, daily access to dietary fat increased CD36 and TPH1 mRNA expression on the CV suggesting enhanced lingual fat sensing compared to chow fed controls. Limited, intermittent access to dietary led to an escalation of fat intake without significant alterations in lingual expression of 5‐HT signaling. These data suggest that different patterns of fat consumption differentially affect 5‐HT signaling in the CV and that continuous access to HFD may lead to decreased orosensory fat perception by altering 5‐HT signaling in taste receptors cells.Support or Funding InformationLSUHSC to SDPThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Early Postnatal Intermittent Hypoxia Increases Rat Microglial Anti‐inflammatory Gene expression, Effects that Are Sex‐specific and Last into Adulthood
Authors: Kiernan Elizabeth A , Wang Tao A , Watters Jyoti J 
Published: June 2021

Chronic intermittent hypoxia (IH), a hallmark of sleep‐disordered breathing (SDB), is prevalent in pediatric and pre‐term infant populations, and is often comorbid with infection. IH increases reactive oxygen species formation, causes neuronal apoptosis, promotes peripheral and CNS inflammation, and results in long‐term neurocognitive deficits in males. However, in the developing brain, little is known about how IH impacts the acute or long‐term inflammatory activities of microglia (CNS resident innate immune cells), or whether these responses differ by sex. Since inflammation impacts cognitive development, we tested the hypothesis that early life IH exposure will sex‐dependently alter microglial inflammatory gene responses and that these effects would last into adulthood. We exposed rat pups to 8 nights of IH beginning on the first postnatal day (P1) and assessed microglial responses to a peripheral lipopolysaccharide (LPS 1mg/kg, 3 hrs) challenge either the day after the last IH exposure (P9), or 6 weeks later (adult). Using RNA sequencing and qRT‐PCR, we first found that IH increased basal expression levels of the anti‐inflammatory cytokines interleukin‐4 (IL‐4) and interferon‐beta (IFNβ) in P9 microglia of both sexes. As expected, LPS‐stimulated inflammatory cytokine expression was decreased after postnatal IH, suggesting that IH may acutely skew neonatal microglia of both sexes towards an anti‐inflammatory phenotype. At P9, there were also sexual dimorphisms in non‐inflammatory microglial genes, both in basal and LPS‐stimulated conditions. For example, multiple genes involved in impaired cognition were upregulated in male microglia, potentially playing a role in the SDB‐induced cognitive impairments that are more prominent in males. Motif analyses to detect the transcription factors that may be driving these male‐specific differences in cognitive genes surprisingly identified the androgen receptor as the top transcriptional driver. Lastly, in adults exposed to neonatal IH, enhanced basal anti‐inflammatory cytokine gene expression was evident only in male microglia, even though their inflammatory gene responses to LPS did not appear to differ at this later time. Ongoing studies are investigating the consequences of persistent increases in anti‐inflammatory cytokines in male microglia on cognitive outcomes since they are known to alter neuroplasticity.Support or Funding InformationSupported by NIH R01 NS085226 and F31 NS100229This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Prenatal Exposure to Bisphenol A and Diethylhexyl Phthalate Induces Hyperprolactinemia in Female offspring
Authors: Al Mansi Maryam H , MohanKumar Sheba M. J. , Mohankumar Puliyur 
Published: June 2021

Exposure to endocrine disrupting chemicals (EDC) such as Bisphenol A (BPA) and Diethylhexyl Phthalate (DEHP) are widespread affecting people of all ages. Pregnant women who are exposed to these chemicals through the use of personal care products and plastics invariably expose their fetus to these chemicals as well. Female offspring are then exposed to endogenous estrogens from menarche till menopause and usually, in their prime years, they are also exposed to estrogens through oral contraceptives. This places them at increased risk of developing hyperprolactinemia which causes infertility. In order to mimic real‐life exposures, we developed the “dual exposure paradigm” where we administered saline, 5μg/Kg BW of BPA, 7.5mg/kg BW of DEHP or a combination of BPA+DEHP to pregnant Sprague Dawley rats from day 6–21 of gestation. Female offspring were sham implanted or implanted with slow release estradiol‐17β (E2) pellets for 90 days when they were 3 months old. At the end of E2 treatment, animals were sacrificed, and the brain was removed, frozen and sectioned. We hypothesized that the dual exposure to EDCs and E2 would decrease dopamine (DA) levels in the median eminence of the hypothalamus to increase prolactin levels. The median eminence was microdissected from the brains and DA levels were measured using HPLC‐EC. Serum prolactin levels were assessed by EIA. DA levels in E2‐treated control rats were significantly reduced compared to sham‐implanted rats (p<0.001). Prenatal exposure to EDCs produced a modest reduction in DA levels in sham implanted rats (p<0.05) but decreased further with E2 treatment (p<0.001). Prolactin levels in control animals were significantly higher in E2 implanted rats compared to sham(p<0.05). Prolactin levels in EDC‐exposed rats were variable and were higher than normal in both sham and E2 treated animals. These results indicate that dual exposure to EDC and E2 is able to affect TIDA activity and induce hyperprolactinemia in female offspring. This could have implications in the development of mammary and pituitary tumors.Support or Funding InformationSupported by UGA research foundation and startup funds.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.