bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contribution of Resting Conductance, GABAA-Receptor Mediated Miniature Synaptic Currents and Neurosteroid to Chloride Homeostasis in Central Neurons
Authors: Yelhekar Tushar D. , Druzin Michael , Johansson Staffan 
Published: March 2017

AbstractMaintenance of a low intraneuronal Cl–concentration, [Cl–]i, is critical for inhibition in the CNS. Here, the contribution of passive, conductive Cl–flux to recovery of [Cl–]iafter a high load was analyzed in mature central neurons from rat. A novel method for quantifying the resting Cl–conductance, important for [Cl–]irecovery, was developed and the possible contribution of GABAAand glycine receptors and of ClC-2 channels to this conductance was analyzed. The hypothesis that spontaneous, action potential-independent release of GABA is important for [Cl–]irecovery was tested. [Cl–]iwas examined by gramicidin-perforated patch recordings in medial preoptic neurons. Cells were loaded with Cl–by combining GABA or glycine application with a depolarized voltage, and the time course of [Cl–]iwas followed by measurements of the Cl–equilibrium potential,as obtained from the current recorded during voltage ramps combined with GABA or glycine application. The results show that passive Cl–flux contributes significantly, in the same order of magnitude as does K+-Cl–cotransporter 2 (KCC2), to [Cl–]irecovery and that Cl–conductance accounts for ∼ 6% of the total resting conductance. A major fraction of this resting Cl–conductance is picrotoxin (PTX)-sensitive and likely due to open GABAAreceptors, but ClC-2 channels do not contribute. The results also show that when the decay of GABAAreceptor-mediated miniature postsynaptic currents (minis) is slowed by the neurosteroid allopregnanolone, such minis may significantly quicken [Cl–]irecovery, suggesting a possible steroid-regulated role for minis in the control of Cl–homeostasis.
Suprachiasmatic Nucleus Interaction with the Arcuate Nucleus; Essential for Organizing Physiological Rhythms
Authors: Buijs Frederik N. , Guzmán-Ruiz Mara , León-Mercado Luis , Basualdo Mari Carmen , Escobar Carolina , Kalsbeek Andries , Buijs Ruud M. 
Published: March 2017

AbstractThe suprachiasmatic nucleus (SCN) is generally considered the master clock, independently driving all circadian rhythms. We recently demonstrated the SCN receives metabolic and cardiovascular feedback adeptly altering its neuronal activity. In the present study, we show that microcuts effectively removing SCN-arcuate nucleus (ARC) interconnectivity in Wistar rats result in a loss of rhythmicity in locomotor activity, corticosterone levels, and body temperature in constant dark (DD) conditions. Elimination of these reciprocal connections did not affect SCN clock gene rhythmicity but did cause the ARC to desynchronize. Moreover, unilateral SCN lesions with contralateral retrochiasmatic microcuts resulted in identical arrhythmicity, proving that for the expression of physiological rhythms this reciprocal SCN-ARC interaction is essential. The unaltered SCN c-Fos expression following glucose administration in disconnected animals as compared to a significant decrease in controls demonstrates the importance of the ARC as metabolic modulator of SCN neuronal activity. Together, these results indicate that the SCN is more than an autonomous clock, and forms an essential component of a larger network controlling homeostasis. The present novel findings illustrate how an imbalance between SCN and ARC communication through circadian disruption could be involved in the etiology of metabolic disorders.
Secondary Ammonium Agonists Make Dual Cation-π Interactions in α4β2 Nicotinic Receptors
Authors: Post Michael R. , Tender Gabrielle S. , Lester Henry A. , Dougherty Dennis A. 
Published: March 2017

AbstractA cation-π interaction between the ammonium group of an agonist and a conserved tryptophan termed TrpB is a near universal feature of agonist binding to nicotinic acetylcholine receptors (nAChRs). TrpB is one of five residues that form the aromatic box of the agonist binding site, and for the prototype agonists ACh and nicotine, only TrpB makes a functional cation-π interaction. We report that, in addition to TrpB, a significant cation-π interaction is made to a second aromatic, TyrC2, by the agonists metanicotine, TC299423, varenicline, and nornicotine. A common structural feature of these agonists, and a distinction from ACh and nicotine, is a protonated secondary amine that provides the cation for the cation-π interaction. These results indicate a distinction in binding modes between agonists with subtly different structures that may provide guidance for the development of subtype-selective agonists of nAChRs.
tDCS-Induced Modulation of GABA Levels and Resting-State Functional Connectivity in Older Adults
Authors: Antonenko Daria , Schubert Florian , Bohm Florian , Ittermann Bernd , Aydin Semiha , Hayek Dayana , Grittner Ulrike , Flöel Agnes 
Published: March 2017

Transcranial direct current stimulation (tDCS) modulates human behavior, neuronal patterns, and metabolite concentrations, with exciting potential for neurorehabilitation. However, the understanding of tDCS-induced alterations on the neuronal level is incomplete, and conclusions from young adults, in whom the majority of studies have been conducted, cannot be easily transferred to older populations. Here, we investigated tDCS-induced effects in older adults (N= 48; age range, 50–79 years) using magnetic resonance spectroscopy to quantify GABA levels as well as resting-state functional magnetic resonance imaging to assess sensorimotor network strength and interhemispheric connectivity. In a randomized, counterbalanced, crossover design, we applied anodal tDCS (atDCS), cathodal tDCS (ctDCS), and sham tDCS (stDCS) over the left sensorimotor region. We observed a significant reduction of GABA levels after atDCS compared with stDCS, reflecting the preserved neuromodulatory effect of atDCS in older adults. Moreover, resting-state functional coupling was decreased during atDCS compared with stDCS, most likely indicating augmented efficiency in brain network functioning. Increased levels of interhemispheric connectivity with age were diminished by atDCS, suggesting stimulation-induced functional decoupling. Further, the magnitude of atDCS-induced local plasticity was related to baseline functional network strength. Our findings provide novel insight into the neuronal correlates underlying tDCS-induced neuronal plasticity in older adults and thus might help to develop tDCS interventions tailored to the aging brain.SIGNIFICANCE STATEMENTTranscranial direct current stimulation (tDCS) modulates human behavior, neuronal patterns, and metabolite concentrations, with exciting potential for neurorehabilitation. However, the understanding of tDCS-induced alterations on the neuronal level is incomplete, and conclusions from young adults cannot be easily transferred to older populations. We used a systematic multimodal imaging approach to investigate the neurophysiological effects of tDCS in older adults and found stimulation-induced effects on GABA levels, reflecting augmented local plasticity and functional connectivity, suggesting modulation of network efficiency. Our findings may help to reconcile some of the recent reports on the variability of tDCS-induced effects, not only implicating age as a crucial modulating factor, but detailing its specific impact on the functionality of neural networks.
Characterization of a Human Point Mutation of VGLUT3 (p.A211V) in the Rodent Brain Suggests a Nonuniform Distribution of the Transporter in Synaptic Vesicles
Authors: Ramet Lauriane , Zimmermann Johannes , Bersot Tiphaine , Poirel Odile , De Gois Stéphanie , Silm Katlin , Sakae Diana Yae , Mansouri-Guilani Nina , Bourque Marie-Josée , Trudeau Louis-Eric , Pietrancosta Nicolas , Daumas Stéphanie , Bernard Véronique , Rosenmund Christian , El Mestikawy Salah 
Published: March 2017

The atypical vesicular glutamate transporter type 3 (VGLUT3) is expressed by subpopulations of neurons using acetylcholine, GABA, or serotonin as neurotransmitters. In addition, VGLUT3 is expressed in the inner hair cells of the auditory system. A mutation (p.A211V) in the gene that encodes VGLUT3 is responsible for progressive deafness in two unrelated families. In this study, we investigated the consequences of the p.A211V mutation in cell cultures and in the CNS of a mutant mouse. The mutation substantially decreased VGLUT3 expression (−70%). We measured VGLUT3-p.A211V activity by vesicular uptake in BON cells, electrophysiological recording of isolated neurons, and its ability to stimulate serotonergic accumulation in cortical synaptic vesicles. Despite a marked loss of expression, the activity of the mutated isoform was only minimally altered. Furthermore, mutant mice displayed none of the behavioral alterations that have previously been reported in VGLUT3 knock-out mice. Finally, we used stimulated emission depletion microscopy to analyze how the mutation altered VGLUT3 distribution within the terminals of mice expressing the mutated isoform. The mutation appeared to reduce the expression of the VGLUT3 transporter by simultaneously decreasing the number of VGLUT3-positive synaptic vesicles and the amount of VGLUT3 per synapses. These observations suggested that VGLUT3 global activity is not linearly correlated with VGLUT3 expression. Furthermore, our data unraveled a nonuniform distribution of VGLUT3 in synaptic vesicles. Identifying the mechanisms responsible for this complex vesicular sorting will be critical to understand VGLUT's involvement in normal and pathological conditions.SIGNIFICANCE STATEMENTVGLUT3 is an atypical member of the vesicular glutamate transporter family. A point mutation of VGLUT3 (VGLUT3-p.A211V) responsible for a progressive loss of hearing has been identified in humans. We observed that this mutation dramatically reduces VGLUT3 expression in terminals (∼70%) without altering its function. Furthermore, using stimulated emission depletion microscopy, we found that reducing the expression levels of VGLUT3 diminished the number of VGLUT3-positive vesicles at synapses. These unexpected findings challenge the vision of a uniform distribution of synaptic vesicles at synapses. Therefore, the overall activity of VGLUT3 is not proportional to the level of VGLUT3 expression. These data will be key in interpreting the role of VGLUTs in human pathologies.
Respiration-Deficient Astrocytes Survive As Glycolytic CellsIn Vivo
Authors: Supplie Lotti M. , Düking Tim , Campbell Graham , Diaz Francisca , Moraes Carlos T. , Götz Magdalena , Hamprecht Bernd , Boretius Susann , Mahad Don , Nave Klaus-Armin 
Published: March 2017

Neurons and glial cells exchange energy-rich metabolites and it has been suggested, originally based onin vitrodata, that astrocytes provide lactate to glutamatergic synapses (“lactate shuttle”). Here, we have studied astrocytes that lack mitochondrial respirationin vitroandin vivo. A novel mouse mutant (GLASTCreERT2::Cox10flox/flox) was generated, in which the administration of tamoxifen causes mutant astrocytes to fail in the assembly of mitochondrial cytochromecoxidase (COX). Focusing on cerebellar Bergmann glia (BG) cells, which exhibit the highest rate of Cre-mediated recombination, we found a normal density of viable astrocytes even 1 year after tamoxifen-inducedCox10gene targeting. Our data show that BG cells, and presumably all astrocytes, can survive by aerobic glycolysis for an extended period of time in the absence of glial pathology or unspecific signs of neurodegeneration.SIGNIFICANCE STATEMENTWhen astrocytes are placed into culture, they import glucose and release lactate, an energy-rich metabolite readily metabolized by neurons. This observation led to the “glia-to-neuron lactate shuttle hypothesis,” butin vivoevidence for this hypothesis is weak. To study astroglial energy metabolism and the directionality of lactate flux, we generated conditionalCox10mouse mutants lacking mitochondrial respiration in astrocytes, which forces these cells to survive by aerobic glycolysis. Here, we report that these mice are fully viable in the absence of any signs of glial or neuronal loss, suggesting that astrocytes are naturally glycolytic cells.
Topography and Lateralized Effect of Acute Aromatase Inhibition on Auditory Processing in a Seasonal Songbird
Authors: De Groof Geert , Balthazart Jacques , Cornil Charlotte A. , Van der Linden Annemie 
Published: March 2017

It is increasingly recognized that brain-derived estrogens (neuroestrogens) can regulate brain physiology and behavior much faster than what was previously known from the transcriptional action of estrogens on nuclear receptors. One of the best examples of such neuromodulation by neuroestrogens concerns the acute regulation of sensory coding by the auditory cortex as demonstrated by electrophysiological studies of selected neurons in zebra finches. Yet, the spatial extent of such modulation by neuroestrogens is not known. Using functional magnetic resonance imaging, we demonstrate here that acute estrogen depletion alters within minutes auditory processing in male European starlings. These effects are confined to very specific but large areas of the auditory cortex. They are also specifically lateralized to the left hemisphere. Interestingly, the modulation of auditory responses by estrogens was much larger (both in amplitude and in topography) in March than in December or May/June. This effect was presumably independent from changes in circulating testosterone concentrations since levels of the steroid were controlled by subcutaneous implants, thus suggesting actions related to other aspects of the seasonal cycle or photoperiodic manipulations. Finally, we also show that estrogen production specifically modulates selectivity for behaviorally relevant vocalizations in a specific part of the caudomedial nidopallium. These findings confirm and extend previous conclusions that had been obtained by electrophysiological techniques. This approach provides a new very powerful tool to investigate auditory responsiveness in songbirds and its fast modulation by sex steroids.SIGNIFICANCE STATEMENTNeuroestrogens can acutely modulate sensory processing in a manner similar to neuromodulators. We report that acute estrogen depletion rapidly disrupts auditory processing in large areas of the male starling brain. Effects were larger in March than in December or May/June, lateralized to the left hemisphere and specific to behaviorally relevant stimuli. These findings confirm and extend previous data that identified an acute regulation of auditory neurons in zebra finches by (1) delineating the extent of the brain region affected, (2) confirming its lateralization, and (3) demonstrating that a large part of the auditory brain regions are acutely affected by estrogens. These findings provide a very powerful tool to investigate auditory responsiveness in songbirds and its fast modulation by sex steroids.
Allometric Analysis Detects Brain Size-Independent Effects of Sex and Sex Chromosome Complement on Human Cerebellar Organization
Authors: Mankiw Catherine , Park Min Tae M. , Reardon P.K. , Fish Ari M. , Clasen Liv S. , Greenstein Deanna , Giedd Jay N. , Blumenthal Jonathan D. , Lerch Jason P. , Chakravarty M. Mallar , Raznahan Armin 
Published: March 2017

The cerebellum is a large hindbrain structure that is increasingly recognized for its contribution to diverse domains of cognitive and affective processing in human health and disease. Although several of these domains are sex biased, our fundamental understanding of cerebellar sex differences—including their spatial distribution, potential biological determinants, and independence from brain volume variation—lags far behind that for the cerebrum. Here, we harness automated neuroimaging methods for cerebellar morphometrics in 417 individuals to (1) localize normative male–female differences in raw cerebellar volume, (2) compare these to sex chromosome effects estimated across five rare sex (X/Y) chromosome aneuploidy (SCA) syndromes, and (3) clarify brain size-independent effects of sex and SCA on cerebellar anatomy using a generalizable allometric approach that considers scaling relationships between regional cerebellar volume and brain volume in health. The integration of these approaches shows that (1) sex and SCA effects on raw cerebellar volume are large and distributed, but regionally heterogeneous, (2) human cerebellar volume scales with brain volume in a highly nonlinear and regionally heterogeneous fashion that departs from documented patterns of cerebellar scaling in phylogeny, and (3) cerebellar organization is modified in a brain size-independent manner by sex (relative expansion of total cerebellum, flocculus, and Crus II-lobule VIIIB volumes in males) and SCA (contraction of total cerebellar, lobule IV, and Crus I volumes with additional X- or Y-chromosomes; X-specific contraction of Crus II-lobule VIIIB). Our methods and results clarify the shifts in human cerebellar organization that accompany interwoven variations in sex, sex chromosome complement, and brain size.SIGNIFICANCE STATEMENTCerebellar systems are implicated in diverse domains of sex-biased behavior and pathology, but we lack a basic understanding of how sex differences in the human cerebellum are distributed and determined. We leverage a rare neuroimaging dataset to deconvolve the interwoven effects of sex, sex chromosome complement, and brain size on human cerebellar organization. We reveal topographically variegated scaling relationships between regional cerebellar volume and brain size in humans, which (1) are distinct from those observed in phylogeny, (2) invalidate a traditional neuroimaging method for brain volume correction, and (3) allow more valid and accurate resolution of which cerebellar subcomponents are sensitive to sex and sex chromosome complement. These findings advance understanding of cerebellar organization in health and sex chromosome aneuploidy.
An ATR‐dependent function for the Ddx19 RNA helicase in nuclear R‐loop metabolism
Authors: Hodroj Dana , Recolin Bénédicte , Serhal Kamar , Martinez Susan , Tsanov Nikolay , Abou Merhi Raghida , Maiorano Domenico 
Published: March 2017

AbstractCoordination between transcription and replication is crucial in the maintenance of genome integrity. Disturbance of these processes leads to accumulation of aberrant DNA:RNA hybrids (R‐loops) that, if unresolved, generate DNA damage and genomic instability. Here we report a novel, unexpected role for the nucleopore‐associated mRNA export factor Ddx19 in removing nuclear R‐loops formed upon replication stress or DNA damage. We show, in live cells, that Ddx19 transiently relocalizes from the nucleopore to the nucleus upon DNA damage, in an ATR/Chk1‐dependent manner, and that Ddx19 nuclear relocalization is required to clear R‐loops. Ddx19 depletion induces R‐loop accumulation, proliferation‐dependent DNA damage and defects in replication fork progression. Further, we show that Ddx19 resolves R‐loops in vitro via its helicase activity. Furthermore, mutation of a residue phosphorylated by Chk1 in Ddx19 disrupts its interaction with Nup214 and allows its nuclear relocalization. Finally, we show that Ddx19 operates in resolving R‐loops independently of the RNA helicase senataxin. Altogether these observations put forward a novel, ATR‐dependent function for Ddx19 in R‐loop metabolism to preserve genome integrity in mammalian cells.
Sex‐specific, reciprocal regulation of ERα and miR‐22 controls muscle lipid metabolism in male mice
Authors: Schweisgut Judith , Schutt Christian , Wüst Stas , Wietelmann Astrid , Ghesquière Bart , Carmeliet Peter , Dröse Stefan , Korach Kenneth S , Braun Thomas , Boettger Thomas 
Published: March 2017

AbstractControl of energy homeostasis and metabolism is achieved by integrating numerous pathways, and miRNAs are involved in this process by regulating expression of multiple target genes. However, relatively little is known about the posttranscriptional processing of miRNAs and a potential role for the precursors they derive from. Here, we demonstrate that mature miRNA‐22 is more abundant in muscle from male mice relative to females and that this enables sex‐specific regulation of muscular lipid metabolism and body weight by repressing estrogen receptor alpha (ERα) expression. We found that the ERα adjusts its own activity by preventing processing of miR‐22 via direct binding to a conserved ERα‐binding element within the primary miR‐22 precursor. Mutation of the ERα binding site within the pri‐miR‐22 in vivo eliminates sex‐specific differences in miR‐22 expression. We reason that the resulting tissue selective negative feedback regulation is essential to establish sex‐specific differences in muscle metabolism and body weight development.
Changes in the viability of Strongyloides ransomi larvae (Nematoda, Rhabditida) under the influence of synthetic flavourings
Authors: Boyko A. A. , Brygadyrenko V. V. 
Published: March 2017

One of the most common nematodes of pigs globally is Strongyloides ransomi Schwartz and Alicata 1930. It usually causes aggravation of physiological indicators of its hosts and damage to their immune system. Also it is a good modelling object for the evaluation of the antiparasitic activity of new antihelminthic drugs. We conducted laboratory experiments to assess the effect of flavouring additives with flower odour (benzaldehyde, citral, D-limonene and β-ionone) upon the viability of S. ransomi larvae. The mortality rate was calculated for 24 hours exposure at four concentrations of each substance (10, 1, 0.1 и 0.01 g/l) with eight replications. The lowest LD50 values were obtained for citral (97 mg/l) and benzaldehyde (142 mg/l). These substances are recommended for further evaluation of their antihelminthic effect in experiments using laboratory animals. Unlike other substances, the effect of β-ionone and D-limonene even at a concentration of 10 g/l after 24 hours caused the death of <50% of S. ransomi larvae. The study of flavouring additives with flowery odour, which are permitted to be used in food for humans and also to be used in cosmetics, is a promising field for research aimed at the development of new antiparasitic drugs.
Stepping back to advance: Why IGD needs an intensified debate instead of a consensus
Authors: Quandt Thorsten 
Published: March 2017

Based on their analysis of Internet gaming disorder (IGD) criteria, Kuss, Griffiths, and Pontes (2017) come to the conclusion that the current situation can be described as “chaos and confusion.” Their assessment is not an exaggeration. It can be argued that there are even more issues, on logical/definitional and political/social levels: (a) the IGD diagnosis is lacking a well-defined object, (b) the cause and effect cannot be differentiated outside lab conditions, (c) the social and political effects of declaring a social behavior as a disease are worrying, and (d) a rushed diagnosis may construct an addiction with potentially harmful effects on (formerly) healthy populations. Instead of closing the debate by declaring a consensus and codifying IGD in the DSM, an undogmatic, intensified, and broader discussion is needed.