bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammation-related differences in mucosa-associated microbiota and intestinal barrier function in colonic Crohn’s disease
Authors: Libertucci Josie , Dutta Usha , Kaur Sandeep , Jury Jennifer , Rossi Laura , Fontes Michelle E. , Shajib M. Sharif , Khan Waliul I. , Surette Michael G. , Verdu Elena F. , Armstrong David
Published: May 2018

Crohn’s disease (CD), characterized by discontinuous intestinal injury and inflammation, has been associated with changes in luminal microbial composition and impaired barrier function. The relationships between visual features of intestinal injury, permeability, and the mucosa-associated microbiota are unclear. Individuals undergoing routine colonoscopy (controls) and patients with CD were evaluated by clinical parameters and confocal laser scanning endomicroscopic colonoscopy (CLE). Patients with CD were categorized as either CD with no injury (CD-NI) or CD with injury (CD-I). Colonic biopsies were taken from adjacent matched sites in all individuals, and CLE images from these sites were analyzed for vascular permeability. Microbial composition was evaluated by 16S rRNA gene sequencing of the V3 region, and the mycome was identified through internal transcribed spacer 2 sequencing. Subgroup analyses were performed for histology, paracellular permeability (Ussing chamber), and encroachment of bacteria (fluorescent in situ hybridization). CD-I patients showed an altered microbial community compared with both controls and CD-NI patients, with enrichment in Escherichia and a decrease in Firmicutes, including Lachnospira, Faecalibacterium, and Blautia. In CD-I patients, bacterial encroachment to host epithelial cells was greater in sites of injury than in matched biopsy sites. Biopsies from sites of injury also demonstrated greater vascular and paracellular permeability. Overall, CD-I patients showed an altered mucosal microbial community compared with CD-NI patients and controls. Matched biopsy samples in CD-I patients revealed that sites of injury, identified endoscopically, are characterized by increased encroachment of bacteria to host epithelial cells, associated with increased paracellular and vascular permeability, which may drive inflammation in CD.

NEW & NOTEWORTHY Patients with Crohn’s disease (CD) with areas of colonic injury have an altered microbial community compared with patients who have no endoscopic evidence of injury or active disease. Although matched biopsies from patients with colonic injury show no differences in the mucosa-associated microbiota, injured sites are associated with increased permeability and increased encroachment. Our results support the notion that dysbiotic communities within patients with colonic injury cause or permit disruption of the mucosal and endothelial layers in CD.
Pressure-volume analysis reveals characteristic sex-related differences in cardiac function in a rat model of aortic banding-induced myocardial hypertrophy
Authors: Ruppert Mihály , Korkmaz-Icöz Sevil , Loganathan Sivakkanan , Jiang Weipeng , Lehmann Lorenz , Oláh Attila , Sayour Alex Ali , Barta Bálint András , Merkely Béla , Karck Matthias , Radovits Tamás , Szabó Gábor
Published: May 2018

Sex differences in pressure overload (PO)-induced left ventricular (LV) myocardial hypertrophy (LVH) have been intensely investigated. Nevertheless, sex-related disparities of LV hemodynamics in LVH were not examined in detail. Therefore, we aimed to provide a detailed characterization of distinct aspects of LV function in male and female rats during different stages of LVH. Banding of the abdominal aorta (AB) was performed to induce PO for 6 or 12 wk in male and female rats. Control animals underwent sham operation. The development of LVH was followed by serial echocardiography. Cardiac function was assessed by pressure-volume analysis. Cardiomyocyte hypertrophy and fibrosis were evaluated by histology. At week 6, increased LV mass index, heart weight-to-tibial length, cardiomyocyte diameter, concentric LV geometry, and moderate interstitial fibrosis were detected in both male and female AB rats, indicating the development of an early stage of LVH. Functionally, at this time, impaired active relaxation, increased contractility, and preserved ventricular-arterial coupling were observed in the AB groups in both sexes. In contrast, at week 12, progressive deterioration of LVH-associated structural and functional alterations occurred in male but not female animals with sustained PO. Accordingly, at this later stage, LVH was associated with eccentric remodeling, exacerbated fibrosis, and increased chamber stiffness in male AB rats. Furthermore, augmented contractility declined in male but not female AB animals, resulting in contractility-afterload mismatch. Maintained contractility augmentation, preserved ventricular-arterial coupling, and better myocardial compliance in female rats contribute to sex differences in LV function during the progression of PO-induced LVH.

NEW & NOTEWORTHY We investigated sex differences in pressure overload-induced left ventricular myocardial hypertrophy for the first time on the functional level by pressure-volume analysis. We found that left ventricular hypertrophy was initially characterized by prolonged active relaxation, increased contractility, and maintained ventricular-arterial coupling in both sexes. However, at a later stage, augmented contractility declined in mate but not female rats, resulting in contractility-afterload mismatch. Furthermore, in male rats, increased myocardial stiffness also contributed to hypertrophy-associated diastolic dysfunction.
Activated naïve B cells promote development of malignant pleural effusion by differential regulation of TH1 and TH17 response
Authors: Wu Xiu-Zhi , Shi Xin-Yu , Zhai Kan , Yi Feng-Shuang , Wang Zhen , Wang Wen , Pei Xue-Bin , Xu Li-Li , Wang Zheng , Shi Huan-Zhong
Published: May 2018

Inflammatory signaling networks between tumor cells and immune cells contribute to the development of malignant pleural effusion (MPE). B cells have been found in MPE; however, little is known about their roles there. In the present study, by using mouse MPE models, we noted that although the total B cells in MPE were decreased as compared with the corresponding blood and spleen, the percentage of activated naïve B cells expressing higher levels of CD80, CD86, myosin heavy chain-II, CD44, CD69, and programmed cell death-ligand 1 (PD-L1) molecules were increased in wild-type mouse MPE. Compared with wild-type mice, decreased T helper (TH)1 cells and increased TH17 cells were present in B cell-deficient mouse MPE, which paralleled to the reduced MPE volume and longer survival time. Adoptive transfer of activated naïve B cells into B cell-deficient mice was able to increase TH1 cells and decrease TH17 cells in MPE and shorten the survival of mice bearing MPE. Furthermore, we demonstrated that activated naïve B cells inhibited TH17-cell expansion via the PD-1/PD-L1 pathway and promoted naïve CD4+T-cell differentiation into TH1/TH17 cells through secreting IL-27/IL-6 independent of the PD-1/PD-L1 pathway. Collectively, our data uncovered a mechanism by which naïve B cells promote MPE formation by regulating TH1/TH17 cell responses, making these B cells an attractive target for therapeutic intervention in the fight against cancer.
Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats
Authors: Krieger Jean-Philippe , Santos da Conceição Ellen Paula , Sanchez-Watts Graciela , Arnold Myrtha , Pettersen Klaus G. , Mohammed Mazher , Modica Salvatore , Lossel Pius , Morrison Shaun F. , Madden Christopher J. , Watts Alan G. , Langhans Wolfgang , Lee Shin J.
Published: May 2018

Endogenous intestinal glucagon-like peptide-1 (GLP-1) controls satiation and glucose metabolism via vagal afferent neurons (VANs). Recently, VANs have received increasing attention for their role in brown adipose tissue (BAT) thermogenesis. It is, however, unclear whether VAN GLP-1 receptor (GLP-1R) signaling affects BAT thermogenesis and energy expenditure (EE) and whether this VAN mechanism contributes to energy balance. First, we tested the effect of the GLP-1R agonist exendin-4 (Ex4, 0.3 μg/kg ip) on EE and BAT thermogenesis and whether these effects require VAN GLP-1R signaling using a rat model with a selective Glp1r knockdown (kd) in VANs. Second, we examined the role of VAN GLP-1R in energy balance during chronic high-fat diet (HFD) feeding in VAN Glp1r kd rats. Finally, we used viral transsynaptic tracers to identify the possible neuronal substrates of such a gut-BAT interaction. VAN Glp1r kd attenuated the acute suppressive effects of Ex4 on EE and BAT thermogenesis. Consistent with this finding, the VAN Glp1r kd increased EE and BAT activity, diminished body weight gain, and improved insulin sensitivity compared with HFD-fed controls. Anterograde transsynaptic viral tracing of VANs infected major hypothalamic and hindbrain areas involved in BAT sympathetic regulation. Moreover, retrograde tracing from BAT combined with laser capture microdissection revealed that a population of VANs expressing Glp1r is synaptically connected to the BAT. Our findings reveal a novel role of VAN GLP-1R signaling in the regulation of EE and BAT thermogenesis and imply that through this gut-brain-BAT connection, intestinal GLP-1 plays a role in HFD-induced metabolic syndrome.
Colonic indole, gut bacteria metabolite of tryptophan, increases portal blood pressure in rats
Authors: Huc Tomasz , Konop Marek , Onyszkiewicz Maksymilian , Podsadni Piotr , Szczepańska Agnieszka , Turło Jadwiga , Ufnal Marcin
Published: May 2018

Portal hypertension (PH) is a potentially life-threatening condition. We investigated the effects of indole and dietary tryptophan, a substrate for gut bacterial production of indole, on portal blood pressure (PBP), portal blood flow (PBF), and arterial blood pressure (ABP) in Sprague-Dawley rats (SD) and SD with PH induced by liver cirrhosis (SD-PH). Hemodynamics were recorded in anesthetized male 28-wk-old SD and SD-PH at baseline and after the administration of either a vehicle or indole into the colon. Blood levels of tryptophan and its bacterial metabolites were evaluated using chromatography coupled with mass spectrometry. Indole at lower doses increased PBP and PBF. Indole at higher doses produced a transient increase in PBP, which was accompanied by a decrease in ABP. Portal blood levels of indole, indole-3-propionic, indole-3-lactic, and indole-3-acetic acids were higher in SD-PH, suggesting an increased gut-blood barrier permeability. Rats on a tryptophan-rich diet showed a significantly higher PBP and portal blood level of indoles than rats on a tryptophan-free diet. In conclusion, a tryptophan-rich diet and intracolonic indole increase PBP and portal blood level of indole. Rats with PH show an increased penetration of indoles from the colon to the circulation. Intracolonic indole production may be of therapeutic importance in PH.
Short-term thermoneutral housing alters glucose metabolism and markers of adipose tissue browning in response to a high-fat diet in lean mice
Authors: Clayton Zachary S. , McCurdy Carrie E.
Published: May 2018

Systemic insulin resistance and glucose intolerance occur with as little as 3 days of a high-fat diet (HFD) in mice and humans; the mechanisms that initiate acute insulin resistance are unknown. Most laboratories house mice at 22°C, which is below their thermoneutral temperature (~30°C). Cold stress has been shown to increase white adipose tissue (WAT) browning, alter lipid trafficking, and impair immune function, whereas energy intake and expenditure decrease with increasing ambient temperature; importantly, dysregulation of these parameters has been strongly linked to obesity-induced insulin resistance. Therefore, we compared acute changes in glucose metabolism and the metabolic phenotype in lean mice in response to a control diet or HFD housed at standard vivarium (22°C) and thermoneutral (30°C) temperatures. Glucose intolerance occurred following 1 or 5 days of HFD and was independent of housing temperature or adiposity; however, the reduction in tissue-specific glucose clearance with HFD diverged by temperature with reduced brown adipose tissue (BAT) glucose uptake at 22°C but reduced soleus glucose uptake at 30°C. Fasting glucose, food intake, and energy expenditure were significantly lower at 30°C, independent of diet. Additionally, markers of browning in both BAT and inguinal subcutaneous WAT, but not perigonadal epididymal WAT, decreased at 30°C. Together, we find housing temperature has a significant impact on the cellular pathways that regulate glucose tolerance in response to an acute HFD exposure. Thus, even short-term changes in housing temperature should be highly considered in interpretation of metabolic studies in mice.
Neutrophil exocytosis induces podocyte cytoskeletal reorganization and proteinuria in experimental glomerulonephritis
Authors: Caster Dawn J. , Korte Erik A. , Tan Min , Barati Michelle T. , Tandon Shweta , Creed T. Michael , Salant David J. , Hata Jessica L. , Epstein Paul N. , Huang Hui , Powell David W. , McLeish Kenneth R.
Published: May 2018

Acute glomerulonephritis is characterized by rapid glomerular neutrophil recruitment, proteinuria, and glomerular hypercellularity. The current study tested the hypothesis that the release of neutrophil granule contents plays a role in both the loss of filtration barrier leading to proteinuria and the increase in glomerular cells. Inhibition of neutrophil exocytosis with a peptide inhibitor prevented proteinuria and attenuated podocyte and endothelial cell injury but had no effect on glomerular hypercellularity in an experimental acute glomerulonephritis model in mice. Cultivation of podocytes with neutrophil granule contents disrupted cytoskeletal organization, an in vitro model for podocyte effacement and loss of filtration barrier. Activated, cultured podocytes released cytokines that stimulated neutrophil chemotaxis, primed respiratory burst activity, and stimulated neutrophil exocytosis. We conclude that crosstalk between podocytes and neutrophils contributes to disruption of the glomerular filtration barrier in acute glomerulonephritis. Neutrophil granule products induce podocyte injury but do not participate in the proliferative response of intrinsic glomerular cells.
Graft function assessment in mouse models of single- and dual-kidney transplantation
Authors: Wang Lei , Wang Ximing , Jiang Shan , Wei Jin , Buggs Jacentha , Fu Liying , Zhang Jie , Liu Ruisheng
Published: May 2018

Animal models of kidney transplantation (KTX) are widely used in studying immune response of hosts to implanted grafts. Additionally, KTX can be used in generating kidney-specific knockout animal models by transplantation of kidneys from donors with global knockout of a gene to wild-type recipients or vice versa. Dual-kidney transplantation (DKT) provides a more physiological environment for recipients than single-kidney transplantation (SKT). However, DKT in mice is rare due to technical challenges. In this study, we successfully performed DKT in mice and compared the hemodynamic response and graft function with SKT. The surgical time, complications, and survival rate of DKT were not significantly different from SKT, where survival rates were above 85%. Mice with DKT showed less injury and quicker recovery with lower plasma creatinine (Pcr) and higher glomerular filtration rate (GFR) than SKT mice (Pcr = 0.34 and 0.17 mg/dl in DKT vs. 0.50 and 0.36 mg/dl in SKT at 1 and 3 days, respectively; GFR = 215 and 131 µl/min for DKT and SKT, respectively). In addition, the DKT exhibited better renal functional reserve and long-term outcome of renal graft function than SKT based on the response to acute volume expansion. In conclusion, we have successfully generated a mouse DKT model. The hemodynamic responses of DKT better mimic physiological situations with less kidney injury and better recovery than SKT because of reduced confounding factors such as single nephron hyperfiltration. We anticipate DKT in mice will provide an additional tool for evaluation of renal significance in physiology and disease.
5-HT1F receptor regulates mitochondrial homeostasis and its loss potentiates acute kidney injury and impairs renal recovery
Authors: Gibbs Whitney S. , Collier Justin B. , Morris Morgan , Beeson Craig C. , Megyesi Judit , Schnellmann Rick G.
Published: May 2018

Our laboratory previously reported that agonists of the 5-hydoxytryptamine 1F (5-HT1F) receptor induce renal mitochondrial biogenesis (MB) and that stimulation of the 5-HT1F receptor following ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) accelerated the recovery of renal function in mice. The goal of this study was to examine the contribution of the 5-HT1F receptor in the regulation of renal mitochondrial homeostasis and renal function in naïve and injured mice. Although 5-HT1F receptor knockout (KO) mice were healthy and fertile, and did not exhibit renal dysfunction, renal mitochondrial DNA copy number and mitochondrial fission gene expression increased at 10 wk of age. The 5-HT1F receptor KO mice exhibited greater proximal tubular injury and diminished renal recovery after I/R-induced AKI compared with wild-type mice. These findings were associated with persistent suppression of renal cortical MB and ATP levels after injury. In summary, the 5-HT1F receptor is a component of physiological MB regulation in the kidney, and its absence potentiates renal injury and impedes recovery.
Collecting duct principal, but not intercalated, cell prorenin receptor regulates renal sodium and water excretion
Authors: Ramkumar Nirupama , Stuart Deborah , Mironova Elena , Abraham Nikita , Gao Yang , Wang Shuping , Lakshmipathi Jayalakshmi , Stockand James D. , Kohan Donald E.
Published: May 2018

The collecting duct is the predominant nephron site of prorenin and prorenin receptor (PRR) expression. We previously demonstrated that the collecting duct PRR regulates epithelial Na+ channel (ENaC) activity and water transport; however, which cell type is involved remains unclear. Herein, we examined the effects of principal cell (PC) or intercalated cell (IC) PRR deletion on renal Na+ and water handling. PC or IC PRR knockout (KO) mice were obtained by crossing floxed PRR mice with mice harboring Cre recombinase under the control of the AQP2 or B1 subunit of the H+ ATPase promoters, respectively. PC KO mice had reduced renal medullary ENaC-α abundance and increased urinary Na+ losses on a low-Na+ diet compared with controls. Conversely, IC KO mice had no apparent differences in Na+ balance or ENaC abundance compared with controls. Acute treatment with prorenin increased ENaC channel number and open probability in acutely isolated cortical collecting ducts from control and IC PRR KO, but not PC PRR KO, mice. Furthermore, compared with controls, PC KO, but not IC KO mice, had increased urine volume, reduced urine osmolality, and reduced abundance of renal medullary AQP2. Taken together, these findings indicate that PC, but not IC, PRR modulates ENaC activity, urinary Na+ excretion, and water transport.
Kidney dysfunction in the low-birth weight murine adult: implications of oxidative stress
Authors: Abdulmahdi Wasan , Rabadi May M. , Jules Edson , Marghani Yara , Marji Noor , Leung Jessica , Zhang Frank , Siani Avi , Siskind Tamar , Vedovino Kiara , Chowdhury Nazrul , Sekulic Miroslav , Ratliff Brian B.
Published: May 2018

Maternal undernutrition (MUN) during pregnancy leads to low-birth weight (LBW) neonates that have a reduced kidney nephron endowment and higher morbidity as adults. Using a severe combined caloric and protein-restricted mouse model of MUN to generate LBW mice, we examined the progression of renal insufficiency in LBW adults. Through 6 mo of age, LBW males experienced greater albuminuria (ELISA analysis), a more rapid onset of glomerular hypertrophy, and a worse survival rate than LBW females. In contrast, both sexes experienced a comparable progressive decline in renal vascular density (immunofluorescence analysis), renal blood flow (Laser-Doppler flowmetry analysis), glomerular filtration rate (FITC-sinistrin clearance analysis), and a progressive increase in systemic blood pressure (measured via tail-cuff method). Isolated aortas from both LBW sexes demonstrated reduced vasodilation in response to ACh, indicative of reduced nitric oxide bioavailability and endothelial dysfunction. ELISA and immunofluorescence analysis revealed a significant increase of circulating reactive oxygen species and NADPH oxidase type 4 (NOX4) expression in both LBW sexes, although these increases were more pronounced in males. Although more effective in males, chronic tempol treatment did improve all observed pathologies in both sexes of LBW mice. Chronic NOX4 inhibition with GKT137831 was more effective than tempol in preventing pathologies in LBW males. In conclusion, despite some minor differences, LBW female and male adults have a reduced nephron endowment comparable with progressive renal and vascular dysfunction, which is associated with increased oxidative stress and subsequent endothelial dysfunction. Tempol treatment and/or NOX4 inhibition attenuates renal and vascular dysfunction in LBW adults.
Mechanistic target of rapamycin: integrating growth factor and nutrient signaling in the collecting duct
Authors: Brown Aaron L. , Fluitt Maurice B. , Ecelbarger Carolyn M.
Published: May 2018

The renal collecting duct and other postmacula densa sites are the primary tubular regions for fine-tuning of electrolyte homeostasis in the body. A role for the mechanistic target of rapamycin (mTOR), a serine-threonine kinase, has recently been appreciated in this regulation. mTOR exists in two distinct multiprotein functional complexes, i.e., mTORC1 and mTORC2. Upregulation of mTORC1, by growth factors and amino acids, is associated with cell cycle regulation and hypertrophic changes. In contrast, mTORC2 has been demonstrated to have a role in regulating Na+ and K+ reabsorptive processes, including those downstream of insulin and serum- and glucocorticoid-regulated kinase (SGK). In addition, mTORC2 can upregulate mTORC1. A number of elegant in vitro and in vivo studies using cell systems and genetically modified mice have revealed mechanisms underlying activation of the epithelial Na+ channel (ENaC) and the renal outer medullary K+ channel (ROMK) by mTORC2. Overall, mTOR in its systematic integration of phosphorylative signaling facilitates the delicate balance of whole body electrolyte homeostasis in the face of changes in metabolic status. Thus, inappropriate regulation of renal mTOR has the potential to result in electrolyte disturbances, such as acidosis/alkalosis, hyponatremia, and hypertension. The goal of this minireview is to highlight the physiological role of mTOR in its complexes in regulating electrolyte homeostasis in the aldosterone-sensitive distal nephron.
Kidney outer medulla mitochondria are more efficient compared with cortex mitochondria as a strategy to sustain ATP production in a suboptimal environment
Authors: Schiffer Tomas A. , Gustafsson Håkan , Palm Fredrik
Published: May 2018

The kidneys receive ~25% of cardiac output, which is a prerequisite to maintain sufficient glomerular filtration rate. However, both intrarenal regional renal blood flow and tissue oxygen levels are heterogeneous with decreasing levels in the inner part of the medulla. These differences, in combination with the heterogeneous metabolic activity of the different nephron segment located in the different parts of the kidney, may constitute a functional problem when challenged. The proximal tubule and the medullary thick ascending limb of Henle are considered to have the highest metabolic rate, which is related to the high mitochondria content needed to sustain sufficient ATP production from oxidative phosphorylation to support high electrolyte transport activity in these nephron segments. Interestingly, the cells located in kidney medulla function at the verge of hypoxia, and the mitochondria may have adapted to the surrounding environment. However, little is known about intrarenal differences in mitochondria function. We therefore investigated functional differences between mitochondria isolated from kidney cortex and medulla of healthy normoglycemic rats by using high-resolution respirometry. The results demonstrate that medullary mitochondria had a higher degree of coupling, are more efficient, and have higher oxygen affinity, which would make them more suitable to function in an environment with limited oxygen supply. Furthermore, these results support the hypothesis that mitochondria of medullary cells have adapted to the normal hypoxic in vivo situation as a strategy of sustaining ATP production in a suboptimal environment.
Effect of acetazolamide and methazolamide on diaphragm and dorsiflexor fatigue: a randomized controlled trial
Authors: Dominelli Paolo B. , McNeil Chris J. , Vermeulen Tyler D. , Stuckless Troy J. R. , Brown Courtney V. , Dominelli Giulio S. , Swenson Erik R. , Teppema Lucas J. , Foster Glen E.
Published: May 2018

Acetazolamide, a carbonic anhydrase (CA) inhibitor used clinically and to prevent acute mountain sickness, worsens skeletal muscle fatigue in animals and humans. In animals, methazolamide, a methylated analog of acetazolamide and an equally potent CA inhibitor, reportedly exacerbates fatigue less than acetazolamide. Accordingly, we sought to determine, in humans, if methazolamide would attenuate diaphragm and dorsiflexor fatigue compared with acetazolamide. Healthy men (dorsiflexor: n = 12; diaphragm: n = 7) performed fatiguing exercise on three occasions, after ingesting acetazolamide (250 mg three times a day) and then in random order, methazolamide (100 mg twice a day) or placebo for 48 h. For both muscles, subjects exercised at a fixed intensity until exhaustion on acetazolamide, with subsequent iso-time and -workload trials. Diaphragm exercise was performed using a threshold-loading device, while dorsiflexor exercise was isometric. Neuromuscular function was determined pre- and postexercise by potentiated transdiaphragmatic twitch pressure and dorsiflexor torque in response to stimulation of the phrenic and fibular nerve, respectively. Diaphragm contractility 3–10 min postexercise was impaired more for acetazolamide than methazolamide or placebo (82 ± 10, 87 ± 9, and 91 ± 8% of pre-exercise value; P < 0.05). Similarly, dorsiflexor fatigue was greater for acetazolamide than methazolamide (mean twitch torque of 61 ± 11 vs. 57 ± 13% of baseline, P < 0.05). In normoxia, methazolamide leads to less neuromuscular fatigue than acetazolamide, indicating a possible benefit for clinical use or in the prophylaxis of acute mountain sickness.

NEW & NOTEWORTHY Acetazolamide, a carbonic anhydrase inhibitor, may worsen diaphragm and locomotor muscle fatigue after exercise; whereas, in animals, methazolamide does not impair diaphragm function. Compared with both methazolamide and the placebo, acetazolamide significantly compromised dorsiflexor function at rest and after exhaustive exercise. Similarly, diaphragm function was most compromised on acetazolamide followed by methazolamide and placebo. Methazolamide may be preferable over acetazolamide for clinical use and altitude illness prophylaxis to avoid skeletal muscle dysfunction.
Immobilization rapidly induces thioredoxin-interacting protein gene expression together with insulin resistance in rat skeletal muscle
Authors: Kawamoto Emi , Tamakoshi Keigo , Ra Song-Gyu , Masuda Hiroyuki , Kawanaka Kentaro
Published: May 2018

Acute short duration of disuse induces the development of insulin resistance for glucose uptake in rodent skeletal muscle. Because thioredoxin-interacting protein (TXNIP) has been implicated in the downregulation of insulin signaling and glucose uptake, we examined the possibility that muscle disuse rapidly induces insulin resistance via increased TXNIP mRNA and protein expression. Male Wistar rats were subjected to unilateral 6-h hindlimb immobilization by plaster cast. At the end of this period, the soleus muscles from both immobilized and contralateral nonimmobilized hindlimbs were excised and examined. The 6-h immobilization resulted in an increase in TXNIP mRNA and protein expressions together with a decrease in insulin-stimulated 2-deoxyglucose uptake in the rat soleus muscle. Additionally, in the rats euthanized 6 h after the plaster cast removal, TXNIP protein expression and insulin-stimulated glucose uptake in the immobilized muscle had both been restored to a normal level. Various interventions (pretreatment with transcription inhibitor actinomycin D or AMP-dependent protein kinase activator 5-aminoimidazole-4-carboxamide ribonucleotide) also suppressed the increase in TXNIP protein expression in 6-h-immobilized muscle together with partial prevention of insulin resistance for glucose uptake. These results suggested the possibility that increased TXNIP protein expression in immobilized rat soleus muscles was associated with the rapid induction of insulin resistance for glucose uptake in that tissue.

NEW & NOTEWORTHY The cellular mechanism by which disuse rapidly induces muscle insulin resistance for glucose uptake remains to be identified. Using a rat hindlimb immobilization model, our findings suggest the possibility that transcriptional upregulation of thioredoxin-interacting protein is associated with the immobilization-induced rapid development of insulin resistance in skeletal muscle.
Tuning for rate and duration of frequency-modulated sweeps in the mammalian inferior colliculus
Authors: Morrison James A. , Valdizón-Rodríguez Roberto , Goldreich Daniel , Faure Paul A.
Published: May 2018

Responses of auditory duration-tuned neurons (DTNs) are selective for stimulus duration. We used single-unit extracellular recording to investigate how the inferior colliculus (IC) encodes frequency-modulated (FM) sweeps in the big brown bat. It was unclear whether the responses of so-called “FM DTNs” encode signal duration, like classic pure-tone DTNs, or the FM sweep rate. Most FM cells had spiking responses selective for downward FM sweeps. We presented cells with linear FM sweeps whose center frequency (CEF) was set to the best excitatory frequency and whose bandwidth (BW) maximized the spike count. With these baseline parameters, we stimulated cells with linear FM sweeps randomly varied in duration to measure the range of excitatory FM durations and/or sweep rates. To separate FM rate and FM duration tuning, we doubled (and halved) the BW of the baseline FM stimulus while keeping the CEF constant and then recollected each cell’s FM duration tuning curve. If the cell was tuned to FM duration, then the best duration (or range of excitatory durations) should remain constant despite changes in signal BW; however, if the cell was tuned to the FM rate, then the best duration should covary with the same FM rate at each BW. A Bayesian model comparison revealed that the majority of neurons were tuned to the FM sweep rate, although a few cells showed tuning for FM duration. We conclude that the dominant parameter for temporal tuning of FM neurons in the IC is FM sweep rate and not FM duration.

NEW & NOTEWORTHY Reports of inferior colliculus neurons with response selectivity to the duration of frequency-modulated (FM) stimuli exist, yet it remains unclear whether such cells are tuned to the FM duration or the FM sweep rate. To disambiguate these hypotheses, we presented neurons with variable-duration FM signals that were systematically manipulated in bandwidth. A Bayesian model comparison revealed that most temporally selective midbrain cells were tuned to the FM sweep rate and not the FM duration.
Crossed corticospinal facilitation between arm and trunk muscles in humans
Authors: Chiou Shin-Yi , Strutton Paul H. , Perez Monica A.
Published: May 2018

A voluntary contraction of muscles with one arm increases the excitability of corticospinal projections to the contralateral resting arm, a phenomenon known as crossed facilitation. Although many motor tasks engage simultaneous activation of the arm and trunk, interactions between corticospinal projections targeting these segments remain largely unknown. Using transcranial magnetic stimulation over the trunk representation of the primary motor cortex, we examined motor-evoked potentials (MEPs) in the resting erector spinae (ES) muscle when the contralateral arm remained at rest or performed 20% of isometric maximal voluntary contraction (MVC) into index finger abduction, thumb abduction, elbow flexion, and elbow extension. We found that MEP size in the ES increased during all voluntary contractions, with greater facilitation occurring during elbow flexion and index finger abduction. To further examine the origin of changes in MEP size, we measured short-interval intracortical inhibition (SICI) and cervicomedullary MEPs (CMEPs) in the ES muscle during elbow flexion and index finger abduction and when the arm remained at rest. Notably, SICI decreased and CMEPs remained unchanged in the ES during both voluntary contractions compared with rest, suggesting a cortical origin for the effects. Our findings reveal crossed facilitatory interactions between trunk extensor and proximal and distal arm muscles, particularly for elbow flexor and index finger muscles, likely involving cortical mechanisms. These interactions might reflect the different role of these muscles during functionally relevant arm and trunk movements.

NEW & NOTEWORTHY Many of the tasks of daily life involve simultaneous activation of the arm and trunk. We found that responses in the erector spinae muscles evoked by motor cortical stimulation increased in size during elbow flexion and extension and during index finger abduction and thumb abduction. Crossed facilitation with the trunk was more pronounced during elbow flexion and index finger abduction. These results might reflect the different role of these muscles during arm and trunk movements.
Combining biophysical modeling and deep learning for multielectrode array neuron localization and classification
Authors: Buccino Alessio P. , Kordovan Michael , Ness Torbjørn V. , Merkt Benjamin , Häfliger Philipp D. , Fyhn Marianne , Cauwenberghs Gert , Rotter Stefan , Einevoll Gaute T.
Published: May 2018

Neural circuits typically consist of many different types of neurons, and one faces a challenge in disentangling their individual contributions in measured neural activity. Classification of cells into inhibitory and excitatory neurons and localization of neurons on the basis of extracellular recordings are frequently employed procedures. Current approaches, however, need a lot of human intervention, which makes them slow, biased, and unreliable. In light of recent advances in deep learning techniques and exploiting the availability of neuron models with quasi-realistic three-dimensional morphology and physiological properties, we present a framework for automatized and objective classification and localization of cells based on the spatiotemporal profiles of the extracellular action potentials recorded by multielectrode arrays. We train convolutional neural networks on simulated signals from a large set of cell models and show that our framework can predict the position of neurons with high accuracy, more precisely than current state-of-the-art methods. Our method is also able to classify whether a neuron is excitatory or inhibitory with very high accuracy, substantially improving on commonly used clustering techniques. Furthermore, our new method seems to have the potential to separate certain subtypes of excitatory and inhibitory neurons. The possibility of automatically localizing and classifying all neurons recorded with large high-density extracellular electrodes contributes to a more accurate and more reliable mapping of neural circuits.

NEW & NOTEWORTHY We propose a novel approach to localize and classify neurons from their extracellularly recorded action potentials with a combination of biophysically detailed neuron models and deep learning techniques. Applied to simulated data, this new combination of forward modeling and machine learning yields higher performance compared with state-of-the-art localization and classification methods.
Minocycline promotes posthemorrhagic neurogenesis via M2 microglia polarization via upregulation of the TrkB/BDNF pathway in rats
Authors: Miao Hongsheng , Li Runming , Han Cong , Lu Xiuzhen , Zhang Hang
Published: May 2018

Intracerebral hemorrhage (ICH) is a devastating disease worldwide with increasing mortality. The present study investigated whether minocycline was neuroprotective and induced M2 microglial polarization via upregulation of the TrkB/BDNF pathway after ICH. ICH was induced via injection of autologous blood into 150 Sprague-Dawley rats. A selective TrkB antagonist [N2–2-2-oxoazepan-3-yl amino] carbonyl phenyl benzo (b) thiophene-2-carboxamide (ANA 12)] and agonist [ N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC)] were used to investigate the mechanism of minocycline-induced neuroprotection. Minocycline improved ICH-induced neurological deficits and reduced M1 microglia marker protein (CD68, CD16) expression as well as M2 microglial polarization (CD206 and arginase 1 protein). Minocycline administration enhanced microglia-neuron cross talk and promoted the proliferation of neuronal progenitor cells, such as DCX- and Tuj-1-positive cells, 24 h after ICH. Minocycline also increased M2 microglia-derived brain-derived neurotrophic factors (BDNF) and the upstream TrkB pathway. ANA 12 reversed the neuroprotective effects of minocycline. HIOC exhibited the same effects as minocycline and accelerated neurogenesis after ICH. This study demonstrated for the first time that minocycline promoted M2 microglia polarization via upregulation of the TrkB/BDNF pathway and promoted neurogenesis after ICH. This study contributes to our understanding of the therapeutic potential of minocycline in ICH.

NEW & NOTEWORTHY The present study gives several novel points: 1) Minocycline promotes neurogenesis after intracerebral hemorrhage in rats. 2) Minocycline induces activated M1 microglia into M2 neurotrophic phenotype. 3) M2 microglia secreting BDNF remodel the damaged neurocircuit.
Developmental nicotine exposure alters glycinergic neurotransmission to hypoglossal motoneurons in neonatal rats
Authors: Wollman Lila Buls , Levine Richard B. , Fregosi Ralph F.
Published: May 2018

We tested the hypothesis that nicotine exposure in utero and after birth [developmental nicotine exposure (DNE)] disrupts development of glycinergic synaptic transmission to hypoglossal motoneurons (XIIMNs). Glycinergic spontaneous and miniature inhibitory postsynaptic currents (sIPSC/mIPSC) were recorded from XIIMNs in brain stem slices from 1- to 5-day-old rat pups of either sex, under baseline conditions and following stimulation of nicotinic acetylcholine (ACh) receptors with nicotine (i.e., an acute nicotine challenge). Under baseline conditions, there were no significant effects of DNE on the amplitude or frequency of either sIPSCs or mIPSCs. In addition, DNE did not alter the magnitude of the whole cell current evoked by bath application of glycine, consistent with an absence of change in postsynaptic glycine-mediated conductance. An acute nicotine challenge (bath application of 0.5 μM nicotine) increased sIPSC frequency in the DNE cells, but not control cells. In contrast, nicotine challenge did not change mIPSC frequency in either control or DNE cells. In addition, there were no significant changes in the amplitude of either sIPSCs or mIPSCs in response to nicotine challenge. The increased frequency of sIPSCs in response to an acute nicotine challenge in DNE cells reflects an enhancement of action potential-mediated input from glycinergic interneurons to hypoglossal motoneurons. This could lead to more intense inhibition of hypoglossal motoneurons in response to exogenous nicotine or endogenous ACh. The former would occur with smoking or e-cigarette use while the latter occurs with changes in sleep state and with hypercapnia.

NEW & NOTEWORTHY Here we show that perinatal nicotine exposure does not impact baseline glycinergic neurotransmission to hypoglossal motoneurons but enhances glycinergic inputs to hypoglossal motoneurons in response to activation of nicotinic acetylcholine (ACh) receptors with acute nicotine. Given that ACh is the endogenous ligand for nicotinic ACh receptors, the latter reveals a potential mechanism whereby perinatal nicotine exposure alters motor function under conditions where ACh release increases, such as the transition from non-rapid-eye movement to rapid-eye movement sleep, and during hypercapnia.
Dynamics of corticospinal motor control during overground and treadmill walking in humans
Authors: Roeder Luisa , Boonstra Tjeerd W. , Smith Simon S. , Kerr Graham K.
Published: May 2018

Increasing evidence suggests cortical involvement in the control of human gait. However, the nature of corticospinal interactions remains poorly understood. We performed time-frequency analysis of electrophysiological activity acquired during treadmill and overground walking in 22 healthy, young adults. Participants walked at their preferred speed (4.2, SD 0.4 km/h), which was matched across both gait conditions. Event-related power, corticomuscular coherence (CMC), and intertrial coherence (ITC) were assessed for EEG from bilateral sensorimotor cortices and EMG from the bilateral tibialis anterior (TA) muscles. Cortical power, CMC, and ITC at theta, alpha, beta, and gamma frequencies (4–45 Hz) increased during the double support phase of the gait cycle for both overground and treadmill walking. High beta (21–30 Hz) CMC and ITC of EMG was significantly increased during overground compared with treadmill walking, as well as EEG power in theta band (4–7 Hz). The phase spectra revealed positive time lags at alpha, beta, and gamma frequencies, indicating that the EEG response preceded the EMG response. The parallel increases in power, CMC, and ITC during double support suggest evoked responses at spinal and cortical populations rather than a modulation of ongoing corticospinal oscillatory interactions. The evoked responses are not consistent with the idea of synchronization of ongoing corticospinal oscillations but instead suggest coordinated cortical and spinal inputs during the double support phase. Frequency-band dependent differences in power, CMC, and ITC between overground and treadmill walking suggest differing neural control for the two gait modalities, emphasizing the task-dependent nature of neural processes during human walking.

NEW & NOTEWORTHY We investigated cortical and spinal activity during overground and treadmill walking in healthy adults. Parallel increases in power, corticomuscular coherence, and intertrial coherence during double support suggest evoked responses at spinal and cortical populations rather than a modulation of ongoing corticospinal oscillatory interactions. These findings identify neurophysiological mechanisms that are important for understanding cortical control of human gait in health and disease.
Modulation of spinal motor networks by astrocyte-derived adenosine is dependent on D1-like dopamine receptor signaling
Authors: Acton David , Broadhead Matthew J. , Miles Gareth B.
Published: May 2018

Astrocytes modulate many neuronal networks, including spinal networks responsible for the generation of locomotor behavior. Astrocytic modulation of spinal motor circuits involves release of ATP from astrocytes, hydrolysis of ATP to adenosine, and subsequent activation of neuronal A1 adenosine receptors (A1Rs). The net effect of this pathway is a reduction in the frequency of locomotor-related activity. Recently, it was proposed that A1Rs modulate burst frequency by blocking the D1-like dopamine receptor (D1LR) signaling pathway; however, adenosine also modulates ventral horn circuits by dopamine-independent pathways. Here, we demonstrate that adenosine produced upon astrocytic stimulation modulates locomotor-related activity by counteracting the excitatory effects of D1LR signaling and does not act by previously described dopamine-independent pathways. In spinal cord preparations from postnatal mice, a D1LR agonist, SKF 38393, increased the frequency of locomotor-related bursting induced by 5-hydroxytryptamine and N-methyl-d-aspartate. Bath-applied adenosine reduced burst frequency only in the presence of SKF 38393, as did adenosine produced after activation of protease-activated receptor-1 to stimulate astrocytes. Furthermore, the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine enhanced burst frequency only in the presence of SKF 38393, indicating that endogenous adenosine produced by astrocytes during network activity also acts by modulating D1LR signaling. Finally, modulation of bursting by adenosine released upon stimulation of astrocytes was blocked by protein kinase inhibitor-(14–22) amide, a protein kinase A (PKA) inhibitor, consistent with A1R-mediated antagonism of the D1LR/adenylyl cyclase/PKA pathway. Together, these findings support a novel, astrocytic mechanism of metamodulation within the mammalian spinal cord, highlighting the complexity of the molecular interactions that specify motor output.

NEW & NOTEWORTHY Astrocytes within the spinal cord produce adenosine during ongoing locomotor-related activity or when experimentally stimulated. Here, we show that adenosine derived from astrocytes acts at A1 receptors to inhibit a pathway by which D1-like receptors enhance the frequency of locomotor-related bursting. These data support a novel form of metamodulation within the mammalian spinal cord, enhancing our understanding of neuron-astrocyte interactions and their importance in shaping network activity.
Dopamine D1 receptor activation contributes to light-adapted changes in retinal inhibition to rod bipolar cells
Authors: Flood Michael D. , Moore-Dotson Johnnie M. , Eggers Erika D.
Published: May 2018

Dopamine modulation of retinal signaling has been shown to be an important part of retinal adaptation to increased background light levels, but the role of dopamine modulation of retinal inhibition is not clear. We previously showed that light adaptation causes a large reduction in inhibition to rod bipolar cells, potentially to match the decrease in excitation after rod saturation. In this study, we determined how dopamine D1 receptors in the inner retina contribute to this modulation. We found that D1 receptor activation significantly decreased the magnitude of inhibitory light responses from rod bipolar cells, whereas D1 receptor blockade during light adaptation partially prevented this decline. To determine what mechanisms were involved in the modulation of inhibitory light responses, we measured the effect of D1 receptor activation on spontaneous currents and currents evoked from electrically stimulating amacrine cell inputs to rod bipolar cells. D1 receptor activation decreased the frequency of spontaneous inhibition with no change in event amplitudes, suggesting a presynaptic change in amacrine cell activity in agreement with previous reports that rod bipolar cells lack D1 receptors. Additionally, we found that D1 receptor activation reduced the amplitude of electrically evoked responses, showing that D1 receptors can modulate amacrine cells directly. Our results suggest that D1 receptor activation can replicate a large portion but not all of the effects of light adaptation, likely by modulating release from amacrine cells onto rod bipolar cells.

NEW & NOTEWORTHY We demonstrated a new aspect of dopaminergic signaling that is involved in mediating light adaptation of retinal inhibition. This D1 receptor-dependent mechanism likely acts through receptors located directly on amacrine cells, in addition to its potential role in modulating the strength of serial inhibition between amacrine cells. Our results also suggest that another D2/D4 receptor-dependent or dopamine-independent mechanism must also be involved in light adaptation of inhibition to rod bipolar cells.