bluuebunny/crossref_metadata_2025_split huggingface dataset:
Motor neuron loss and neuromuscular transmission failure following chemogenetic inhibition of BDNF/TrkB signaling in adult rats
Authors: Fogarty Matthew , Khurram Obaid , Mantilla Carlos , Sieck Gary 
Published: May 2023

Brain derived neurotrophic factor (BDNF) signaling through its high-affinity tropomyosin receptor kinase B (TrkB) is known to have potent effects on motor neuron survival and morphology during development and in neurodegenerative diseases. However, the specific effects of reduced BDNF/TrkB signaling on neuromuscular structure and function in adult mammals are not as well known. In this study, we employed a novel 1NMPP1 sensitive TrkBF616 rat model to evaluate the effect of 14 days inhibition of BDNF/TrkB signaling on the number and morphology of phrenic motor neurons (PhMNs) and diaphragm muscle (DIAm) neurotransmission in adult animals. We hypothesized that reduced BDNF/TrkB signaling results in PhMN loss and impaired DIAm neuromuscular transmission. Adult female and male TrkBF616 rats were divided into 1NMPP1 or vehicle treated groups. Three days prior to treatment, PhMNs in both groups were labeled via intrapleural injection of Alexa-Fluor647 cholera toxin B (CTB). After 11 days of treatment, retrograde axonal transport was assessed by secondary labeling of PhMNs by intrapleural injection of Alexa-Fluor488 CTB. After 14 days of treatment, the spinal cord was excised and 100 μm thick spinal sections containing PhMNs were imaged in 3D using two-channel confocal microscopy. Phrenic nerve and DIAm was excised en bloc, and the extent of neuromuscular transmission failure (NMTF) was assessed by comparing DIAm isometric forces evoked by nerve (40 Hz in 330 ms duration trains repeated each s) compared to direct muscle stimulation (40 Hz 330 ms duration train) superimposed every 15 s. Presynaptic (synaptophysin immunoreactivity) and postsynaptic (α-Bungarotoxin) compartments of neuromuscular junctions (NMJs) were labeled and imaged in 3D by confocal microscopy and the extent of pre- and postsynaptic apposition assessed. 1NMPP1-induced BDNF/TrkB inhibition reduced the total number of PhMNs by ~16%, reduced the mean PhMN somal surface areas by ~25%, reduced PhMN dendritic surface area by ~38%, impaired secondary CTB uptake by 2.5-fold and impaired neuromuscular transmission by ~33%, with no overt evidence of NMJ derangement. We conclude that inhibition of BDNF/TrkB signaling in adult TrkBF616 rats is sufficient to lead to PhMN loss, morphological degeneration, deficits in retrograde axonal transport and impaired DIAm neurotransmission. Supported by NIH: R01-AG44615 and R01-HL146114 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Dose-dependent effects of fentanyl on pulmonary ventilation and arterial blood gases in adult awake goats
Authors: Neumueller Suzanne , Forster Hubert , Grams Kirstyn , Pan Lawrence , Buiter Nicole , Hilbert Grace , Lewis Stephen , Hodges Matthew 
Published: May 2023

Synthetic opioids, such as fentanyl, typically suppress breathing frequency (f) and tidal volume (VT) in rodents but decrease and increase f and VT in humans, respectively. In this and the three adjoining posters we present data on the physiologic and behavioral dose-dependent effects of intravenous (IV) fentanyl in adult awake female goats. Here we tested the hypothesis that like humans, goats would show dose-dependent decreases in f and increases in VT and corresponding changes in blood gases and pH. Pulmonary ventilation (VI), f, VT and arterial blood gases were measured for 30 minutes (min) before, during and up to 90 min after IV injection (2 min) of 0, 25, 50, 75, 100, and 125 mcg/kg fentanyl. Ventilatory measures were expressed as a percent of control (room air breathing) in 30 sec intervals for 15 min pre- and post-injection and averaged over longer time intervals (5 or 15 min) thereafter. While we observed no changes in breathing measures over 30 min before and 90 min after saline injection, the responses to IV fentanyl were highly variable and individual- and dose-dependent. However, most goats showed transient decreases in f (20-30%) where the duration of f suppression was dose-dependent (2-10 min), whereas VT increased (25-50%) for 60 min or more without an apparent dose-dependence. As a result, VI was only transiently decreased (2-4 min) and instead was above control for up to 90 min post-injection. Arterial blood was drawn (~3 ml; 30 sec) in duplicate at ~15 and 25 min into the 30 min control period, and then individual samples were obtained continuously during and immediately following the injection and in duplicate at 10, 15, 30, 45, 60, 75 and 90 min post-injection. While some goats showed transient hypoventilation (decreased PaO2/O2 saturation) immediately after fentanyl injection, on average blood gas analyses suggested modest hyperventilation (decreased PaCO2/increased pH) 60-90 min post-injection consistent with the overall effects on VI. The calculated difference in the alveolar to arterial oxygen gradient (A-a gradient) was unaffected with saline or 25 mcg/kg fentanyl, but was increased with higher doses of fentanyl peaking 15-30 min after injection in a dose-dependent manner suggesting increased V/Q mismatch. We conclude that in awake goats, fentanyl has opposite effects on f and VT similar to that in humans. However, individual variation in timing and nature of the ventilatory responses to fentanyl over the dose range tested herein suggests that the compensatory f and VT changes allowed for the maintenance of arterial blood gas and pH status. NIH DA050571 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Cough sensory mechanism -- Multiple sensor theory in airway mechanosensory units
Authors: Yu Jerry 
Published: May 2023

Two doctrines: one-sensor theory (OST) and line-labeled theory (LLT) significantly influences our data interpretation in lung sensory field. In OST, one afferent axon connects to a single sensor. In LLT, different sensors send signals to different brain regions to evoke reflex. Thus, lung inflation activates slowly adapting receptors (SARs) and send signals to inhibit breathing (inhibitory line), causing Hering-Breuer reflex. The inflation and deflation stimulate rapidly adapting receptors (RARs) to send signals to stimulate breathing (excitatory line), producing the Hering-Breuer deflation reflex. Our physiological and morphological studies demonstrate numerous sensors up to 4 different types may be housed within a unit, i.e., an axon connects to many heterogeneous sensors (multiple-sensor theory, MST). In addition to SARs and RARs, there are deflation-activated slowly adapting (dSARs) or rapidly adapting receptors (dRARs). They work together to determine the unit behavior. For example, SAR or RAR units may respond to deflation if they house dSARs responsible for the Hering-Breuer deflation reflex. MST requires a conceptual shift because different types of information carried in an afferent axon violates conventional doctrines. Data generated over last eight decades under OST require re-interpretation. For example, based on LLT scientists believe “SARs do not cause cough”: their activation on deep lung inflation does not evoke cough. Similarly, deep inspiration and expiration activate RARs, but not cough. Therefore, SARs and RARs are excluded from the cough initiation mechanism. MST posits discharge pattern and timing dictates reflex response. It follows that, in the mechanosensory afferent pathway, continuous discharge (during sustained inflation) produces apnea and cyclic discharge facilitates respiratory rate. Therefore, there is no reason to exclude punctate-associated irregular surging discharge from cough initiation. Indeed, mechanosensors have highest density in large airways, punctate stimulation activates all four types of sensors and their coactivation significantly enhances afferent input. These thick myelinated afferents have the highest conduction velocity and discharge frequency and connect to inspiratory and expiratory neurons monosynaptically to perform effective cough action. Decades of research data support activation of this system can evoke powerful inspiratory and expiratory muscle responses. Blocking it eliminates cough response. While punctate stimulation also activates C fiber and high threshold Ad fiber sensors and may produce cough, the mechanosensory units are most important for punctate-induced cough. (Supported by a VA Merit Review Award (PULM-024-17S) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Vasoactive properties of hepatokines using mesenteric resistance arteries in male Wistar rats
Authors: Nielson Andrew , Costa Tiago , Wood Emily , Wenceslau Camilla , McCarthy Cameron 
Published: May 2023

Hepatokines, defined as proteins or protein-like substances secreted mainly or exclusively by the liver in an endocrine or paracrine way, play an essential role in modulating the metabolic progress and pathological conditions of the body. While it is well known that hepatokines play a major pro-inflammatory role in the body, it is still unclear as to whether their actions specifically affect vascular function. We hypothesized that some, if not all, hepatokines would play a role in vasoconstriction in mesenteric resistance arteries (MRA) of male Wistar rats (12 weeks old, n=4-17). To test this hypothesis, we isolated and mounted MRA with endothelium in a wire myography. After evaluating vascular viability, arteries were treated with hepatokine (1 μg/mL) or vehicle for 30 minutes. This was done for a total of 15 different hepatokines: ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, Fetuin-A, FGF21, Follistatin, GDF-15, Hepassocin, IGF-1, LECT2, Lipocalin-13, SEPP1, SMOC-1, and Tsukushi. Subsequently, we performed concentration-response curves to phenylephrine (10-9 to 10-4 M) and used maximal response and LogEC50 to compare the contraction response curve of the MRA bathed in hepatokine to the control (vehicle). Interestingly, the hepatokines ANGPTL3 [% KCl 120mM, Vehicle: 132.1±3.2 vs. ANGPTL3: 141.6±3.9, p=0.0540] (figure a), FGF21 [% KCl 120mM, Vehicle: 123.3±5.8 vs. FGF21: 139.7±4.8, p=0.0355] (figure d), and ANGPTL4 [% KCl 120mM, Vehicle: 130.2±3.6 vs. ANGPTL4: 141.7±3.7, p=0.0282] (figure b) increased maximum contraction, while the hepatokines SMOC-1 [LogEC50, Vehicle: -5.7±0.1 vs. SMOC-1: -6.0±0.1, p=0.0134] (figure e) and ANGPTL6 [LogEC50, Vehicle: -5.7±0.1 vs. ANGPTL6: -6.0±0.1, p=0.0103] (figure c) increased the sensitivity of phenylephrine compared to the control. On the other hand, the hepatokines ANGPTL8, Fetuin-A, Follistatin, GDF-15, Hepassocin, IGF-1, LECT2, Lipocalin-13, SEPP1, and Tsukushi did not change vascular function. These data show that the vascular system senses the presence of hepatokines. Based on these findings, we suggest that hepatokines could be novel therapeutic targets in vascular disease. NHLBI (R00HL151889), NIGMS (1P20GM103641 - Pilot Project), UofSC SOM (Startup funds) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Amylin receptor agonism protects against metabolic side effects of acute olanzapine
Authors: Medak Kyle , Jeromson Stewart , Belluci Annalaura , Arbeau Meagan , Wright David 
Published: May 2023

Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and several on- and off-label conditions. While effective in reducing psychoses, acute olanzapine treatment causes rapid hyperglycemia, insulin resistance, and dyslipidemia and these perturbations are linked to an increased risk of developing cardiometabolic disease. Increases in glucagon are central to the metabolic side effects of olanzapine. Amylin receptor activation has been shown to reduce circulating glucagon but it is unclear if targeting amylin signaling would be an effective approach to lessen olanzapine-induced hyperglycemia alone or as an adjunct with other glucose lowering medications such as glucagon-like peptide-1 (GLP1) receptor agonist liraglutide. The purpose of this study was to 1) determine if treatment with recombinant amylin or the amylin receptor agonist pramlintide is sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis and 2) if there are synergistic effects of combining pramlintide and liraglutide. We hypothesized that amylin and pramlintide would confer protection against olanzapine-induced perturbations in glucose homeostasis and that these effects would be additive with liraglutide. We found that pramlintide co-treatment lowered olanzapine-induced increases in glucagon:insulin. There was an additive effect of pramlintide and liraglutide in protecting against olanzapine-induced hyperglycemia and a synergistic effect on markers of dyslipidemia. Our findings provide evidence that pramlintide, while moderately protective against some aspects of olanzapine-induced metabolic dysfunction, can be used to enhance other interventions which protect against olanzapine-induced hyperglycemia. This research was supported by a Project Grant (PJT 159538) from the Canadian Institutes of Health Research to DCW. KDM was supported by a Postgraduate Scholarship from the Natural Sciences and Engineering Research Council (NSERC) of Canada. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Renal denervation modulates neurohormonal activity and inflammation in heart failure with preserved ejection fraction
Authors: Pushpakumar Sathnur , Juin Subir Kumar , Smolenkova Irina , Tyagi Suresh , Sen Utpal 
Published: May 2023

Heart failure with preserved ejection fraction (HFpEF) accounts for >50% of cases with heart failure (HF) and is often accompanied by derangements in several organs including kidney. Under normal conditions, the heart and kidney functions are reciprocally regulated by several bidirectional pathways that include neurohormonal, hemodynamic, and endocrine signaling, however, the underlying renal mechanisms during HFpEF remains largely unknown. Current evidence postulates that sympathetic nervous system (SNS) hyperactivation and low-grade inflammation play a key role in HFpEF, however, whether these mechanisms are cause or effect of HFpEF remains unknown. The kidney responds to volume overload in HFpEF via modulation of glomerular function, RAAS activation and norepinephrine release. Separately, selective denervation has been shown to reduce immune activation in hypertension, post myocardial infarction, and inflammatory arthritis, Therefore, the purpose of the study was to investigate whether renal denervation (RDN) in HFpEF modulates SNS activity thus RAAS, to reduce stress, and inflammation. Methods: C57BL/6J (WT, 50-52 wks) mice w/o and with HFpEF, and w/o and with RDN were used in the study. Aorto-vena cava fistula (AVF) was created as a model of diastolic dysfunction and serial ECHO was done to denote HFpEF (ejection fraction, EF > 50%). Results: AVF mice showed exercise intolerance, increased plasma catecholamines and low levels of atrial and brain natriuretic peptides (ANP and BNP resp.) but increased C-type natriuretic peptide (CNP) compared to WT groups. RDN improved exercise ability, increased ANP and BNP, and decreased plasma catecholamines in RDN+ AVF group. AVF hearts showed increased inflammatory cell infiltration and cytokine expression; RDN abrogated these changes. Further, RDN attenuated abnormal cardiac indices (Ejection fraction, fractional shortening, E/A ratio, and E/e’ ratio) and SNS activity following AVF. GFR was increased and renal resistive index (RI) decreased in RDN and RDN+AVF mice. In AVF mice, cardiac vasculature showed rarefaction and reduction of septal branches that improved following RDN. Conclusion: Taken together, our results suggest that RDN enhances cardiac regeneration by modulating SNS activity, improving renal function, and reduction of inflammation. NIH grant: DK116591, AR071789 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The effect of Akt-induced skeletal muscle hypertrophy on the UBR family of E3 ubiquitin ligases
Authors: Hughes David , Baehr Leslie , Sharples Adam , Waddell David , Bodine Sue 
Published: May 2023

Introduction: The N-degron pathway contributes to proteolysis by targeting N-terminal residues of destabilized proteins via E3 ligases that contain a UBR-box domain. Emerging evidence suggests this UBR family of E3 ubiquitin ligases are important in the regulation of skeletal muscle mass. We sought to investigate the response of E3 ubiquitin ligases in the UBR family to a hypertrophic stimulus via Akt overexpression in skeletal muscle. Methodology: Male C57BL/6 mice (5 to 6-months old) were subjected to in vivo electroporation with either a wild-type Akt (Akt-WT) or constitutively active Akt (Akt-CA) plasmid (20ug) in the tibialis anterior (TA) muscle with the contralateral leg serving as an empty vector control (EV). After 7 days, TA muscles were collected, weighed, and processed for biochemical and histochemical analyses. Western blotting was performed to determine levels of puromycin incorporation, Akt/mTORC/S6K1 signalling, ubiquitin, and UBR-related E3 ligases (e.g., UBR2, UBR4, and UBR5). RNA was isolated from frozen muscle powder and qPCR performed to assess mRNA expression for UBR2, UBR4, UBR5, UBR7, MuRF1 and MAFbx. Results: Akt overexpression led to significant increases in TA muscle mass for the Akt-WT (+5%) and Akt-CA (+11%) transfected muscles after 7 days. We observed significant increases in puromycin labelling in the Akt-CA transfected muscles, indicative of elevations in nascent polypeptides. UBR4, UBR5 and UBR7 protein was significantly increased with Akt-CA overexpression. Interestingly, mRNA expression for UBR5 did not change across groups, yet UBR2, UBR4 and UBR7 displayed increased expression in Akt-CA transfected muscles. No change was observed for MuRF1 or MAFbx mRNA expression, but we did observe a significant increase in total ubiquitin levels following Akt-CA overexpression. Conclusion: The increased level of UBR E3 ubiquitin ligases in hypertrophied skeletal muscle provides further evidence for a possible important role for this family of E3 ligases in muscle growth. Future studies will seek to understand the translational control of the UBR E3 ubiquitin ligases and their potential role towards protein quality control in skeletal muscle plasticity. D.C.H. was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number K01AR077684. A.P.S. was supported by The Research Council of Norway (RCN or Norges forskningsrèfâ¥d/NFR) project number: 314157. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Tonic GABAergic signaling from prostaglandin EP3 receptor-expressing preoptic neurons bidirectionally controls body temperature
Authors: Nakamura Kazuhiro , Nakamura Yoshiko , Yahiro Takaki , Fukushima Akihiro , Kataoka Naoya , Hioki Hiroyuki 
Published: May 2023

The principal controller neurons of the thermoregulatory center in the preoptic area (POA) have yet to be determined. In the present study using rats, we discovered that prostaglandin EP3 receptor-expressing POA neurons (POAEP3R neurons) are a pivotal bidirectional controller in the central thermoregulatory circuit mechanism. POAEP3R neurons were activated in response to elevated ambient temperature, but inhibited by prostaglandin E2, a pyrogenic mediator. In newly generated Ptger3 (EP3R)-tTA transgenic rats, chemogenetic stimulation of POAEP3R neurons at room temperature reduced body temperature by eliciting skin vasodilation (enhancing heat dissipation), whereas inhibition of them elicited hyperthermia involving brown adipose tissue thermogenesis and tachycardia, mimicking fever. Furthermore, we revealed that POAEP3R neurons innervate sympathoexcitatory neurons in the dorsomedial hypothalamus (DMH) via tonic inhibitory signaling. Although many POAEP3R neuronal cell bodies expressed a glutamatergic mRNA marker, paradoxically, most of their axons in the DMH contained GABAergic synaptic proteins. Interestingly, such GABAergic terminals of POAEP3R→DMH axons were increased by chronic heat exposure of rats, indicating a synaptic alteration to enhance heat tolerance. Consistent with the anatomical observation, slice patch-clamp recordings from DMH neurons combined with optogenetic stimulation of POAEP3R→DMH axon terminals showed that these terminals predominantly form GABAergic synapses onto DMH neurons. These findings demonstrate that tonic GABAergic inhibitory signaling from POAEP3R neurons is a fundamental determinant of body temperature for thermal homeostasis and fever. NEXT Program from JSPS (LS070 to K.N.); MEXT KAKENHI (JP21K06767, JP17K08568, JP26860159, JP23790271 to Y.N.; JP22K06844 to A.F.; JP22K06470, JP19K06954, JP16K19006 to N.K.; JP21H02592 to H.H.; JP20H03418, JP16H06276 (AdAMS), JP16H05128, JP15H05932, JP26118508, JP26713009, JP22689007 to K.N.); PRESTO (JPMJPR13M9 to K.N.), FOREST (JPMJFR204D to H.H.), Moonshot R&D (JPMJMS2024 to H.H.; JPMJMS2023 to K.N.) of JST; AMED (JP21wm0525002 to N.K.; JP21dm0207112 to H.H.; JP21gm5010002 to K.N.); Hori Sciences and Arts Foundation (to Y.N.); Kato Memorial Bioscience Foundation, Foundation of Kinoshita Memorial Enterprise (to N.K.); Takeda Science Foundation (to T.Y. and K.N.); Nakajima Foundation, Uehara Memorial Foundation, Ono Medical Research Foundation, Brain Science Foundation, Kowa Life Science Foundation (to K.N.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.