bluuebunny/crossref_metadata_2025_split huggingface dataset:
Persistent pain intensifies the recall of already consolidated fear memories
Authors: Dimitrov Eugene 
Published: November 2023

The deleterious impact of chronic pain on learning, memory and mood is well documented. Long‐lasting pain leads to anxiety, depression and negatively impairs learning and formation of new memories. We hypothesized that chronic pain may affect even memories that were established before the onset of pain. Mice underwent a classic auditory fear conditioning that included 30 seconds 75 dB tone as a conditioned stimulus (CS) that was paired with 2 seconds 1 mA electric foot shock as unconditioned stimulus (US). Sciatic nerve constriction by inserting a small plastic tube around the left sciatic nerve was used to induce neuropathic pain 48 hours after the fear conditioning. This nerve constriction, also called “cuffing”, reliably produced mechanical allodynia that lasted for the duration of the experiments. Fear recall was measured by exposing the mice to the CS and recording their activity for five minutes. The time mice were completely immobile (freezing time) was expressed as a percent. Two sessions of fear recall were conducted, one 14 days and second 28 days after the initiation of neuropathic pain. Mice with neuropathic pain showed an increased percent of time freezing to CS (sham group with 22.7% ± 1.4 versus an average of 38.2% ± 4.3 freezing time for the pain group, t36 =3.9, P<0.001). The cuffed mice once again spent more time freezing when retested 28 days after the beginning of pain (the average freezing time was 22.9% ± 2.9 for the shams versus 49.5% ± 4.9 of the cuffed group, t36= 4.8, P< 0.001). In the next experiment the sciatic nerve constriction was applied two weeks after fear conditioning. These mice showed increased fear response to the CS 14 days after the onset of pain or 28 days after the fear conditioning took place (the freezing time of the sham group was 44.6% ± 6.5 versus the cuffed group with 69.5% ± 5.4 freezing time, t18 = 2.9, P<0.001). When tested for anxiety and depression, the experimental groups did not display any increased anxiety‐like or depression‐like behavior in comparison to the control groups. However, the Sholl analysis of the pyramidal neurons in basolateral amygdala of mice with neuropathic pain showed increased dendritic length (the average dendritic length was 701.9 μm ± 40.1 in sham group versus 955.7 μm ± 46.2 in cuffed group, df25=2.7, P<0.02).In conclusion, our studies provide evidence for impact of persistent pain on already consolidated fear memories. Very likely the underlying mechanism for this phenomenon is increased dendritic plasticity of the pyramidal neurons brought by overall decreased inhibitory tone in basolateral amygdala during persistent pain. It is possible that the increased fear recall to already consolidated fear memory is a harbinger for a later development of anxiety and depression symptoms that are typical for chronic pain.Support or Funding InformationGrant # 5R01MH105528‐04
The Nuclear Receptor REV‐ERBα Alters Mood and Neurotransmission in the Prefrontal Cortex
Authors: Otsuka Tsuyoshi , Kohsaka Akira , Le Hue Thi , Nakao Tomomi , Thein Zaw Lin , Maeda Masanobu 
Published: November 2023

A defect in behavioral rhythms is a key feature of mood disorders such as depression, seasonal affective disorder, and bipolar disorder. Recent studies have proposed REV‐ERBα as a key circadian nuclear receptor that links behavioral rhythms to mood regulation. However, how REV‐ERBα regulates mood in the brain remains to be elucidated. Here we show that REV‐ERBα is abundantly expressed in neuronal cells and that the prefrontal cortex expresses Rev‐erbα at the highest level among mood‐controlling areas of the brain. To further explore the role of REV‐ERBα in the regulation of mood, we analyzed transcriptome in the prefrontal cortex of Rev‐erbα deficient mice. Importantly, we found marked alteration in the expression levels of a cluster of genes known to regulate mood such as Fabp7, Bdnf, and Nr4a1 in the prefrontal cortex of Rev‐erbα deficient animals. We also found that deficiency in the Rev‐erbα gene altered expression levels of genes associated with neuronal activity and plasticity in the prefrontal cortex. More importantly, a quantitative UPLC assay using tissues of the prefrontal cortex without the Rev‐erbα gene detected changes in the levels of key neurotransmitters which can directly affect mood regulation. Taken together, our results suggest that the circadian nuclear receptor REV‐ERBα plays an important role in the regulation of neurotransmission in the prefrontal cortex that coordinates mood and behaviors.Support or Funding InformationThis work was supported by JSPS KAKENHI Grant Number 16K19781
Heat Exposure Improves Cognitive Performance in Persons with Higher Levels of Spinal Cord Injury
Authors: Handrakis John P , Tittley Tishina D. , Tascione Oriana F. , Bart Jessica , Barton Christian , Bang Charlene , Spungen Ann M. , Bauman William A. 
Published: November 2023

Our previous work demonstrated that core body temperature (Tcore) is typically lower in persons with tetraplegia and that limited exposure to cool temperature results in a decline in Tcore with an associated decline in cognitive performance, while a similar cool exposure in able‐bodied (AB) individuals did not affect Tcore or cognitive performance. Because of the prior observed effect of cool exposure in those with tetraplegia, the effect of heat exposure on Tcore and cognitive performance was determined in persons with higher spinal cord lesions (above T4).Fifteen persons with spinal cord injury (SCI) (C5‐T3, AIS A‐B) and 15 age and body mass index‐matched AB controls were acclimated to 27°C at baseline (BL) before being exposed to 35°C for up to 120 minutes (Heat Challenge). Tcore (rectal temperature) was continuously measured while cognitive performance was assessed at BL and at the end of Heat Challenge using Stroop Color and Word and Wechsler Adult Intelligence Scale‐Fourth Edition (WAIS‐IV) Digit Span tests. Persons with SCI were divided into two groups based on the magnitude of change in Tcore to Heat Challenge, High Responder (HR: > 0.5°C) and Low Responder (LR: <0.5°C).At BL, average Tcore was 36.7±0.43°C in HR (9 participants with C5‐T1), 37.2±0.33°C in LR (6 participants with C5‐T3), and 37.3±0.36°C in AB controls; Tcore was different between HR and AB groups (p<0.05). After Heat Challenge, Tcore was not significantly different among the three groups with Tcore increasing 0.75±0.32°C in HR, 0.27±0.16°C in LR, and −0.05±0.25°C in AB groups; the changes in Tcore after challenge were significant only in the HR and LR groups. On measures of cognitive performance, HR group had a significantly greater percent change compared to AB group in Stroop Word (19.8±13.5% vs. 5.2±13.9%; p=0.02, respectively) and WAIS‐IV Sequence (24.1±17.2% vs. −2.2±19.5%; p=0.003, respectively); no differences in cognitive performance were found between the LR and AB groups.Those persons with higher levels of SCI who had a greater rise in Tcore after a thermal challenge and a lower Tcore at BL also demonstrated improved cognitive performance. Thus, the HR group displayed a greater impairment in thermoregulation with associated increased vulnerability to exposure to extremes in ambient temperature. Because subnormal Tcore has been demonstrated to impair cognitive performance, efforts to maintain euthermia in vulnerable persons with higher levels of SCI should be considered with the use of practical and effective strategies to accomplish this objective.Support or Funding InformationVA Rehabilitation Research and Development Service, Small Projects in Rehabilitation Research (SPiRE): Federal Award Identification Number: I21RX001734
A Triple Combination Approach Involving Nerve Transplantation, Glial Scar Digestion and Passive Exercise Promotes Cardiovascular Recovery after Spinal Cord Injury
Authors: Sachdeva Rahul , Gopaul Rayshad , Jia Mengyao , Monga Aaron , Ramer Matt , Krassioukov Andrei V. 
Published: November 2023

IntroductionCardiovascular (CV) dysfunction is the leading cause of morbidity and mortality after spinal cord injury (SCI). SCI causes CV dysfunction primarily by (a) the direct loss of critical medullary control of sympathetic pre‐ganglionic neurons and, (b) the aberrant sprouting of nociceptive afferent fibers within the spinal cord. To promote significant CV recovery after SCI, we developed a triple combination approach to simultaneously promote axonal regeneration to regain the supraspinal vasomotor control as well as to reduce aberrant sprouting of nociceptive afferent fibers in an experimental model of SCI.MethodsAdult male Wistar rats (n=40) received a complete spinal transection (Tx) at 3rd thoracic segment. The treatment group received peripheral nerve grafts (PNGs) spanning the lesion, intrathecal chondroitinase enzyme (ChABC) and cycling exercise beginning on day 5 (1 hr/day, 5 days/week). Appropriate control groups received Tx only or Tx and a single intervention. At 8 weeks post injury, CV function [i.e. resting blood pressure (BP), heart rate and pressor response to colorectal distension (CRD)] was assessed using radiotelemetry. Functional regeneration across PNGs was determined using stimulus driven units below the lesion upon electrical stimulation at cervical level. Neural tract tracing and immunohistochemistry was performed to quantify the number of regenerating neurons as well as the sprouting of nociceptive (calcitonin gene related peptide positive) afferent fibers.ResultsThe preliminary findings (n= 5/group) show that the combination approach (Tx+PNG+ChABC+Ex) leads to significant CV recovery compared to the untreated group (Tx alone). Specifically, in response to CRD, the treatment group shows 53.8% reduction in systolic BP elevation (77.8 vs. 37.7 mmHg, p<0.0001, Fig. A), 42.2% reduction in diastolic BP elevation (42.5 vs. 24.5 mmHg, p<0.001, Fig. B), 57.6% reduction in mean arterial pressure elevation (54.2 vs. 22.9 mmHg, p<0.001, Fig. C) as well as abolishment of CRD‐induced bradycardia (−80.2 vs. +14.6 bpm, p=0.056, Fig. D). Synaptically driven activity of spinal cord neurons at T4 level upon electrical stimulation above the injury confirmed the functional re‐connection of regenerating axons. Histological studies are underway to further investigate the regeneration/plasticity related mechanisms underlying recovery.ConclusionCombined neuro‐regenerative and rehabilitative approach leads to significant recovery of CV function after SCI, which is likely mediated by vasomotor regeneration and afferent plasticity manipulation.Support or Funding InformationPresent study was supported by the Rick Hansen Foundation start up funding and the Heart and Stroke Foundation of Canada (AVK).
Dapagliflozin, a Selective SGLT2 Inhibitor, Attenuated Cardiac Fibrosis by Regulating the Macrophage Polarization via STAT3 Signaling in Infarcted Rat Hearts
Authors: Lee Tsung‐Ming , Chang Tsang‐Wei , Yang Chen‐Chia 
Published: November 2023

During myocardial infarction, delayed M1 toward M2 macrophage phenotype transition is considered one of the major factors for adverse ventricular remodeling. We investigated whether dapagliflozin, a sodium‐glucose cotransporter 2 (SGLT2) inhibitor, attenuates cardiac fibrosis via regulating macrophage phenotype by a reactive oxygen and nitrogen species (RONS)/STAT3‐dependent pathway in postinfarcted rats. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline, dapagliflozin (a specific SGLT2 inhibitor), phlorizin (a nonspecific SGLT1/2 inhibitor), dapagliflozin + S3I‐201 (a STAT3 inhibitor), or phlorizin + S3I‐201 for 4 weeks. There were similar infarct sizes among the infarcted groups at the acute and chronic stages of infarction. At day 3 after infarction, post‐infarction was associated with increased RONS levels, which can be inhibited by administering either dapagliflozin or phlorizin. SGLT2 inhibitors significantly increased STAT3 activity, STAT3 nuclear translocation, myocardial IL‐10 levels and the percentage of M2 macrophage infiltration. At day 28 after infarction, SGLT2 inhibitors were associated with attenuated myofibroblast infiltration and cardiac fibrosis. Compared with phlorizin, the extent of dapagliflozin towards M2 polarization was significantly higher. The effects of SGLT2 inhibitors on M2 polarization were nullified by adding S3I‐201. Furthermore, the effects of dapagliflozin on STAT3 activity and myocardial IL‐10 levels can be reversed by 3‐morpholinosydnonimine, a peroxynitrite generator. These observations provide a novel mechanism of SGLT2 inhibitors‐mediated M2 polarization through a RONS‐dependent STAT3‐mediated pathway and selective SGLT2 inhibitors are more effective in attenuating cardiac fibrosis during postinfarction remodeling.Support or Funding Informationnil
Inhibition of Cyclophilin D During Acute and Chronic Myocardial Infarction in Rats: The Effect of Reperfusion
Authors: Parodi‐Rullán Rebecca Maria , Soto‐Prado Jadira , Vega‐Lugo Jesús , Chapa‐Dubocq Xavier , Javadov Sabzali 
Published: November 2023

BackgroundMitochondrial permeability transition pore (mPTP) opening plays a critical role in pathogenesis of myocardial infarction (MI) and cardiac ischemia‐reperfusion (IR). Cyclophilin D (CyP‐D) is the only protein which has been broadly accepted as a major regulator of the mPTP complex. Therefore, inhibition of CyP‐D is mostly used as a target for inhibition of mPTP opening and thus, prevention of mitochondria‐mediated cell death induced by MI and IR injury. In addition to mPTP regulation, CyP‐D also plays an important physiological role and controls cell metabolism through regulation of glucose uptake, fatty acid oxidation, and mitochondrial bioenergetics. Growing data on the physiological role of CyP‐D and mPTP opening as well as failure of recent CIRCUS (Cyclosporine and Prognosis in Acute Myocardial Infarction Patients) clinical trials when cyclosporin A (CsA) failed to protect the heart in STEM patients, indicates the necessity for further studies elucidating the role of CyP‐D inhibition to exert cardioprotection against IR injury. Here, we hypothesized that inhibition of CyP‐D may have different effects in non‐reperfused MI and reperfused MI (IR).MethodsMI was induced in adult female rats (200–250g) by ligation coronary artery (CAL) for 30 min followed by 2‐ and 28‐day post‐surgery with or without reperfusion. The animals were studied in the following groups: i) Sham (S, no MI, n=6 and n=11 for 2 and 28 days, respectively); ii) SS (Sham+SfA, n=5 and n=11 for 2 and 28 days, respectively); iii) MI (no reperfusion, n=4 and n=5 for 2 and 28 days, respectively); iv) MI+SfA (n=4 and n=6 for 2 and 28 days, respectively); v) MI+R (MI+reperfusion, n=4 and n=5 for 2 and 28 days, respectively); and vi) MI+RS (MI+reperfusion+SfA, n=6 and n=7 for 2 and 28 days, respectively). SfA (5mg/kg, IV) was administered at 25 min after a start of sham surgery or MI. Cardiac function was analyzed at 2 and 28 days post‐surgery by echocardiography.ResultsSfA significantly improved cardiac function (ejection fraction, EF%) (33±5 vs. 53±4, P<0.01) after 2 days, but it had no beneficial effects at 28 days (38±3 vs. 42±4). Likewise, SfA administration to permanent occluded hearts has no effect on EF% at 2 (44±9 vs. 35±9) and 28 (37±3 vs. 44±5) days. SfA administration to control animals reduces cardiac EF% at 2 (69±3 vs. 52±3, P<0.001) and 28 days (66±2 vs. 55±3, P<0.01).ConclusionOur data indicates that inhibition of CyP‐D by SfA has cardioprotective effects on MI at early reperfusion and no effect on MI without short‐ or long reperfusion.Support or Funding InformationSupported by NHLBI NIH (SC1HL118669) and NIH MBRS‐RISE Program (R25‐GM061838).
Reduced SIRT3 contributes to large elastic artery stiffness with aging
Authors: Brodjeski Alexander Lee , Schaeffer Gilbert V , Ear Po Hien , Brenner Charles , Sindler Amy L 
Published: November 2023

Age‐related increases in arterial stiffness are mediated in part by mitochondrial dysfunction. Sirtuin 3 (SIRT3) is a mitochondrial NAD+‐dependent deacetylase that regulates mitochondrial function. SIRT3 deficiency contributes to physiological dysfunction in a variety of pathological conditions. Here, we tested the hypothesis that age‐associated arterial stiffness, assessed by aortic pulse wave velocity (aPWV), would be accompanied with decreased SIRT3 expression and activity. Old (~26 mo, n = 9) C57BL/6N male mice had higher aPWV vs. young (6 mo, n = 10) (448 ±14 vs 382 ± 13, p < 0.005), which was associated with reduced arterial and renal SIRT3 protein expression (0.17 ± 0.04 n=5 vs 0.57 ± 0.11 n=7, p<0.05; 0.70 ± 0.09 n=6 vs 0.96 ± 0.08 n=6, p =0.05, respectively). Aortic SIRT3 protein expression was negatively correlated aPWV (R=−0.7798, p<0.005). Furthermore, SIRT3 KO male mice demonstrated higher aPWV compared to age‐matched control mice (480±20.77 n=6 vs. 391.3±12.3 n=7, p<0.005). Downstream markers of SIRT3 regulatory activity were examined. Taken together, these data suggest that the age‐associated decline in SIRT3 contributes to increased arterial stiffness and may be a potential target for improving vascular function.Support or Funding InformationSupported by NIH K01AG047626 and University of Iowa Department of Health and Human Physiology.
Skeletal Muscle Mitochondrial Respiratory Capacity and Function Are Diminished in Patients with Advanced Peripheral Artery Disease and Critical Limb Ischemia
Authors: Rontoyanni Victoria G , Lopez Omar Nunez , Fankhauser Grant T. , Cheema Zulfiqar F. , Cheng Charlie , Rasmussen Blake B. , Borsheim Elisabet , Porter Craig 
Published: November 2023

IntroductionPeripheral artery disease (PAD) is associated with a marked reduction in functional capacity, where progression to critical limb ischemia (CLI) is the most severe clinical presentation of the disease. Current evidence suggests diminished skeletal muscle oxidative capacity in patients with PAD. To our knowledge, no study has simultaneously assayed mitochondrial oxidative capacity and mitochondrial quality to compressively determine the role of mitochondrial dysfunction in PAD. We set out to compare mitochondrial oxidative capacity and mitochondrial quality in PAD patients with CLI versus healthy controls.MethodsTo date, we have recruited and studied 7 PAD patients with CLI undergoing revascularization procedures or amputation (56±11 y; PAD) and 7 healthy adults (62±6 y; Control). Skeletal muscle samples were collected from the leg, and mitochondrial respiratory capacity and function were determined in permeabilized myofibers by high‐resolution respirometry (Figure 1). Results are presented as means ± SD.ResultsMitochondrial respiration coupled to ATP production (State 3I+II; Figure 1) and maximal respiratory capacity (State 3u; Figure 1) were diminished in PAD patients with CLI when compared to healthy controls (18.5±12.3 vs. 41.3±12.4 pmol/s/mg, P<0.01 and 27.9±17.4 vs 51.8±16.6 pmol/s/mg, P<0.05, respectively). Respiration coupled to ATP production was highly correlated to maximal respiratory capacity in both PAD patients with CLI (r=0.94, P<0.01) and controls (r=0.97, P<0.001). The flux control ratio (State 3I+II/State 3u), a marker of mitochondrial quality, was significantly lower in PAD patients with CLI compared to controls (O.67±0.11 vs 0.80±0.06, P<0.05), indicating reduced mitochondrial efficiency in CLI.ConclusionOur preliminary results show that both skeletal muscle oxidative capacity and mitochondrial efficiency (i.e., quality) are substantially lower in muscle from PAD patients with CLI when compared to healthy controls. Collectively, reduced skeletal muscle respiratory capacity and mitochondrial quality likely contribute to impaired functional capacity in PAD patients with CLI. The mitochondrion may represent a therapeutic target to alter disease progression and/or improve functional capacity in patients with PAD.Support or Funding InformationSeed funding for this project was supplied by the Department of Surgery, UTMB. This work was also supported by the following grants: NIH RO1 AG‐033761, RO1 AR‐049877, R56 AG05126701, P30 AG024832 and SHC‐84080, and was conducted with the support of the Institute for Translational Sciences at UTMB, supported in part by a Clinical and Translational Science Award (UL1TR000071).
High Glucose Induces Vascular Contraction through Mitochondrial Membrane Potential (MMP)‐Miro‐MLC Pathway
Authors: Xu Jie , Qin Xinghua , Wang Zhen , Zhang Xing , Gao Feng 
Published: November 2023

ObjectiveAlthough vascular dysfunction is prevalent in diabetes mellitus, the directly effect of high glucose on vascular tone is unclear. This study aimed to examine whether high glucose can induces vascular contraction and the role of mitochondria in this process.MethodsVascular ultrasound was used for blood vessel diameter measurement. Wire myograph system 610M was used to record vascular response. Myosin light chain (MLC) phosphorylation and Miro expression level were detected in primary vascular smooth muscle cell isolated from thoracic aorta of rats. mitochondrial membrane potential (MMP) was measured by JC‐1 or TMRM dye.ResultsArterial blood pressure increased while brachial/abdominal aorta vascular diameter decreased during transient hyperglycemia in healthy human subjects (1.0g/kg glucose, po) and constant hyperglycemia in diabetic rats (2.0g/kg glucose, ip). High glucose (40 mmol/L) induced isolated thoracic aorta contraction which could be enhanced by insulin (10 nmol/L). Importantly, we found that MMP of vascular smooth muscle cells, which was increased by high glucose challenge, induced vascular contraction independently of endothelium. Mechanically, MMP induced vascualr contraction via ROCK‐MLC signaling rather than Ca2+ signaling. Miro, an atypical Rho GTPases located on mitochondrial membrane, serves as an upstream of ROCK signaling.ConclusionThese data show that high glucose can induces vascular contraction via increasing MMP and resulted activation Miro‐ROCK‐MLC signaling of vascular smooth muscle cells.Support or Funding InformationThis study was supported by the grants from the National Basic Research Program of China (No. 2013CB531204).