bluuebunny/crossref_metadata_2025_split huggingface dataset:
AnIn VivoPharmacological Screen Identifies Cholinergic Signaling as a Therapeutic Target in Glial-Based Nervous System Disease
Authors: Wang Liqun , Hagemann Tracy L. , Messing Albee , Feany Mel B. 
Published: February 2016

The role that glia play in neurological disease is poorly understood but increasingly acknowledged to be critical in a diverse group of disorders. Here we use a simple genetic model of Alexander disease, a progressive and severe human degenerative nervous system disease caused by a primary astroglial abnormality, to perform anin vivoscreen of 1987 compounds, including many FDA-approved drugs and natural products. We identify four compounds capable of dose-dependent inhibition of nervous system toxicity. Focusing on one of these hits, glycopyrrolate, we confirm the role for muscarinic cholinergic signaling in pathogenesis using additional pharmacologic reagents and genetic approaches. We further demonstrate that muscarinic cholinergic signaling works through downstream Gαq to control oxidative stress and death of neurons and glia. Importantly, we document increased muscarinic cholinergic receptor expression in Alexander disease model mice and in postmortem brain tissue from Alexander disease patients, and that blocking muscarinic receptors in Alexander disease model mice reduces oxidative stress, emphasizing the translational significance of our findings. We have therefore identified glial muscarinic signaling as a potential therapeutic target in Alexander disease, and possibly in other gliopathic disorders as well.SIGNIFICANCE STATEMENTDespite the urgent need for better treatments for neurological diseases, drug development for these devastating disorders has been challenging. The effectiveness of traditional large-scalein vitroscreens may be limited by the lack of the appropriate molecular, cellular, and structural environment. Using a simpleDrosophilamodel of Alexander disease, we performed a moderate throughput chemical screen of FDA-approved drugs and natural compounds, and found that reducing muscarinic cholinergic signaling ameliorated clinical symptoms and oxidative stress in Alexander disease model flies and mice. Our work demonstrates that small animal models are valuable screening tools for therapeutic compound identification in complex human diseases and that existing drugs can be a valuable resource for drug discovery given their known pharmacological and safety profiles.
Cyfip1 Regulates Presynaptic Activity during Development
Authors: Hsiao Kuangfu , Harony-Nicolas Hala , Buxbaum Joseph D. , Bozdagi-Gunal Ozlem , Benson Deanna L. 
Published: February 2016

Copy number variations encompassing the gene encoding Cyfip1 have been associated with a variety of human diseases, including autism and schizophrenia. Here we show that juvenile mice hemizygous forCyfip1have altered presynaptic function, enhanced protein translation, and increased levels of F-actin. In developing hippocampus, reduced Cyfip1 levels serve to decrease paired pulse facilitation and increase miniature EPSC frequency without a change in amplitude. Higher-resolution examination shows these changes to be caused primarily by an increase in presynaptic terminal size and enhanced vesicle release probability. Short hairpin-mediated knockdown of Cyfip1 coupled with expression of mutant Cyfip1 proteins indicates that the presynaptic alterations are caused by dysregulation of the WAVE regulatory complex. Such dysregulation occurs downstream of Rac1 as acute exposure to Rac1 inhibitors rescues presynaptic responses in culture and in hippocampal slices. The data serve to highlight an early and essential role for Cyfip1 in the generation of normally functioning synapses and suggest a means by which changes in Cyfip1 levels could impact the generation of neural networks and contribute to abnormal and maladaptive behaviors.SIGNIFICANCE STATEMENTSeveral developmental brain disorders have been associated with gene duplications and deletions that serve to increase or decrease levels of encoded proteins. Cyfip1 is one such protein, but the role it plays in brain development is poorly understood. We asked whether decreased Cyfip1 levels altered the function of developing synapses. The data show that synapses with reduced Cyfip1 are larger and release neurotransmitter more rapidly. These effects are due to Cyfip1's role in actin polymerization and are reversed by expression of a Cyfip1 mutant protein retaining actin regulatory function or by inhibiting Rac1. Thus, Cyfip1 has a more prominent early role regulating presynaptic activity during a stage of development when activity helps to define neural pathways.
Behaviorally Relevant Abstract Object Identity Representation in the Human Parietal Cortex
Authors: Jeong Su Keun , Xu Yaoda 
Published: February 2016

The representation of object identity is fundamental to human vision. Using fMRI and multivoxel pattern analysis, here we report the representation of highly abstract object identity information in human parietal cortex. Specifically, in superior intraparietal sulcus (IPS), a region previously shown to track visual short-term memory capacity, we found object identity representations for famous faces varying freely in viewpoint, hairstyle, facial expression, and age; and for well known cars embedded in different scenes, and shown from different viewpoints and sizes. Critically, these parietal identity representations were behaviorally relevant as they closely tracked the perceived face-identity similarity obtained in a behavioral task. Meanwhile, the task-activated regions in prefrontal and parietal cortices (excluding superior IPS) did not exhibit such abstract object identity representations. Unlike previous studies, we also failed to observe identity representations in posterior ventral and lateral visual object-processing regions, likely due to the greater amount of identity abstraction demanded by our stimulus manipulation here. Our MRI slice coverage precluded us from examining identity representation in anterior temporal lobe, a likely region for the computing of identity information in the ventral region. Overall, we show that human parietal cortex, part of the dorsal visual processing pathway, is capable of holding abstract and complex visual representations that are behaviorally relevant. These results argue against a “content-poor” view of the role of parietal cortex in attention. Instead, the human parietal cortex seems to be “content rich” and capable of directly participating in goal-driven visual information representation in the brain.SIGNIFICANCE STATEMENTThe representation of object identity (including faces) is fundamental to human vision and shapes how we interact with the world. Although object representation has traditionally been associated with human occipital and temporal cortices, here we show, by measuring fMRI response patterns, that a region in the human parietal cortex can robustly represent task-relevant object identities. These representations are invariant to changes in a host of visual features, such as viewpoint, and reflect an abstract level of representation that has not previously been reported in the human parietal cortex. Critically, these neural representations are behaviorally relevant as they closely track the perceived object identities. Human parietal cortex thus participates in the moment-to-moment goal-directed visual information representation in the brain.
Sex Differences in GABAASignaling in the Periaqueductal Gray Induced by Persistent Inflammation
Authors: Tonsfeldt Karen J. , Suchland Katherine L. , Beeson Kathleen A. , Lowe Janet D. , Li Ming-hua , Ingram Susan L. 
Published: February 2016

The ventrolateral periaqueductal gray (vlPAG) is a key structure in the descending pain modulatory circuit. Activation of the circuit occurs via disinhibition of GABAergic inputs onto vlPAG output neurons. In these studies, we tested the hypothesis that GABAergic inhibition is increased during persistent inflammation, dampening activation of the descending circuit from the vlPAG. Our results indicate that persistent inflammation induced by Complete Freund's adjuvant (CFA) modulates GABA signaling differently in male and female rats. CFA treatment results in increased presynaptic GABA release but decreased high-affinity tonic GABAAcurrents in female vlPAG neurons. These effects are not observed in males. The tonic currents in the vlPAG are dependent on GABA transporter activity and are modulated by agonists that activate GABAAreceptors containing the δ subunit. The GABAAδ agonist THIP (gaboxadol) induced similar amplitude currents in naive and CFA-treated rats. In addition, a positive allosteric modulator of the GABAAδ subunit, DS2 (4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl]benzamide), increased tonic currents. These results indicate that GABAAδ receptors remain on the cell surface but are less active in CFA-treated female rats.In vivobehavior studies showed that morphine induced greater antinociception in CFA-treated females that was reversed with microinjections of DS2 directly into the vlPAG. DS2 did not affect morphine antinociception in naive or CFA-treated male rats. Together, these data indicate that sex-specific adaptations in GABAAreceptor signaling modulate opioid analgesia in persistent inflammation. Antagonists of GABAAδ receptors may be a viable strategy for reducing pain associated with persistent inflammation, particularly in females.SIGNIFICANCE STATEMENTThese studies demonstrate that GABA signaling is modulated in the ventrolateral periaqueductal gray by persistent inflammation differently in female and male rats. Our results indicate that antagonists or negative allosteric modulators of GABAAδ receptors may be an effective strategy to alleviate chronic inflammatory pain and promote opioid antinociception, especially in females.
Higher-Order Sensory Cortex Drives Basolateral Amygdala Activity during the Recall of Remote, but Not Recently Learned Fearful Memories
Authors: Cambiaghi Marco , Grosso Anna , Likhtik Ekaterina , Mazziotti Raffaele , Concina Giulia , Renna Annamaria , Sacco Tiziana , Gordon Joshua A. , Sacchetti Benedetto 
Published: February 2016

Negative experiences are quickly learned and long remembered. Key unresolved issues in the field of emotional memory include identifying the loci and dynamics of memory storage and retrieval. The present study examined neural activity in the higher-order auditory cortex Te2 and basolateral amygdala (BLA) and their crosstalk during the recall of recent and remote fear memories. To this end, we obtained local field potentials and multiunit activity recordings in Te2 and BLA of rats that underwent recall at 24 h and 30 d after the association of an acoustic conditioned (CS, tone) and an aversive unconditioned stimulus (US, electric shock). Here we show that, during the recall of remote auditory threat memories in rats, the activity of the Te2 and BLA is highly synchronized in the theta frequency range. This functional connectivity stems from memory consolidation processes because it is present during remote, but not recent, memory retrieval. Moreover, the observed increase in synchrony is cue and region specific. A preponderant Te2-to-BLA directionality characterizes this dialogue, and the percentage of time Te2 theta leads the BLA during remote memory recall correlates with a faster latency to freeze to the auditory conditioned stimulus. The blockade of this information transfer via Te2 inhibition with muscimol prevents any retrieval-evoked neuronal activity in the BLA and animals are unable to retrieve remote memories. We conclude that memories stored in higher-order sensory cortices drive BLA activity when distinguishing between learned threatening and neutral stimuli.SIGNIFICANCE STATEMENTHow and where in the brain do we store the affective/motivational significance of sensory stimuli acquired through life experiences? Scientists have long investigated how “limbic” structures, such as the amygdala, process affective stimuli. Here we show that retrieval of well-established threat memories requires the functional interplay between higher-order components of the auditory cortex and the amygdala via synchrony in the theta range. This functional connectivity is a result of memory consolidation processes and is characterized by a predominant cortical to amygdala direction of information transfer. This connectivity is predictive of the animals' ability to recognize auditory stimuli as aversive. In the absence of this necessary cortical activity, the amygdala is unable to distinguish between frightening and neutral stimuli.
Post-Movement Beta Activity in Sensorimotor Cortex Indexes Confidence in the Estimations from Internal Models
Authors: Tan Huiling , Wade Cian , Brown Peter 
Published: February 2016

Beta oscillations are a dominant feature of the sensorimotor system. A transient and prominent increase in beta oscillations is consistently observed across the sensorimotor cortical-basal ganglia network after cessation of voluntary movement: the post-movement beta synchronization (PMBS). Current theories about the function of the PMBS have been focused on either the closure of motor response or the processing of sensory afferance. Computational models of sensorimotor control have emphasized the importance of the integration between feedforward estimation and sensory feedback, and therefore the putative motor and sensory functions of beta oscillations may reciprocally interact with each other and in fact be indissociable. Here we show that the amplitude of sensorimotor PMBS is modulated by the history of visual feedback of task-relevant errors, and negatively correlated with the trial-to-trial exploratory adjustment in a sensorimotor adaptation task in young healthy human subjects. The PMBS also negatively correlated with the uncertainty associated with the feedforward estimation, which was recursively updated in light of new sensory feedback, as identified by a Bayesian learning model. These results reconcile the two opposing motor and sensory views of the function of PMBS, and suggest a unifying theory in which PMBS indexes the confidence in internal feedforward estimation in Bayesian sensorimotor integration. Its amplitude simultaneously reflects cortical sensory processing and signals the need for maintenance or adaptation of the motor output, and if necessary, exploration to identify an altered sensorimotor transformation.SIGNIFICANCE STATEMENTFor optimal sensorimotor control, sensory feedback and feedforward estimation of a movement's sensory consequences should be weighted by the inverse of their corresponding uncertainties, which require recursive updating in a dynamic environment. We show that post-movement beta activity (13–30 Hz) over sensorimotor cortex in young healthy subjects indexes the evaluation of uncertainty in feedforward estimation. Our work contributes to the understanding of the function of beta oscillations in sensorimotor control, and provides further insight into how aberrant beta activity can contribute to the pathophysiology of movement disorders.
Oncomodulin, an EF-Hand Ca2+Buffer, Is Critical for Maintaining Cochlear Function in Mice
Authors: Tong Benton , Hornak Aubrey J. , Maison Stéphane F. , Ohlemiller Kevin K. , Liberman M. Charles , Simmons Dwayne D. 
Published: February 2016

Oncomodulin (Ocm), a member of the parvalbumin family of calcium binding proteins, is expressed predominantly by cochlear outer hair cells in subcellular regions associated with either mechanoelectric transduction or electromotility. Targeted deletion of Ocm caused progressive cochlear dysfunction. Although sound-evoked responses are normal at 1 month, by 4 months, mutants show only minimal distortion product otoacoustic emissions and 70–80 dB threshold shifts in auditory brainstem responses. Thus, Ocm is not critical for cochlear development but does play an essential role for cochlear function in the adult mouse.SIGNIFICANCE STATEMENTNumerous proteins act as buffers, sensors, or pumps to control calcium levels in cochlear hair cells. In the inner ear, EF-hand calcium buffers may play a significant role in hair cell function but have been very difficult to study. Unlike other reports of genetic disruption of EF-hand calcium buffers, deletion of oncomodulin (Ocm), which is predominately found in outer hair cells, leads to a progressive hearing loss after 1 month, suggesting that Ocm critically protects hearing in the mature ear.
Pet-1 Switches Transcriptional Targets Postnatally to Regulate Maturation of Serotonin Neuron Excitability
Authors: Wyler Steven C. , Spencer W. Clay , Green Noah H. , Rood Benjamin D. , Crawford LaTasha , Craige Caryne , Gresch Paul , McMahon Douglas G. , Beck Sheryl G. , Deneris Evan 
Published: February 2016

Newborn neurons enter an extended maturation stage, during which they acquire excitability characteristics crucial for development of presynaptic and postsynaptic connectivity. In contrast to earlier specification programs, little is known about the regulatory mechanisms that control neuronal maturation. The Pet-1 ETS (E26 transformation-specific) factor is continuously expressed in serotonin (5-HT) neurons and initially acts in postmitotic precursors to control acquisition of 5-HT transmitter identity. Using a combination of RNA sequencing, electrophysiology, and conditional targeting approaches, we determined gene expression patterns in maturing flow-sorted 5-HT neurons and the temporal requirements for Pet-1 in shaping these patterns for functional maturation of mouse 5-HT neurons. We report a profound disruption of postmitotic expression trajectories inPet-1−/−neurons, which prevented postnatal maturation of 5-HT neuron passive and active intrinsic membrane properties, G-protein signaling, and synaptic responses to glutamatergic, lysophosphatidic, and adrenergic agonists. Unexpectedly, conditional targeting revealed a postnatal stage-specific switch in Pet-1 targets from 5-HT synthesis genes to transmitter receptor genes required for afferent modulation of 5-HT neuron excitability. 5-HT1aautoreceptor expression depended transiently on Pet-1, thus revealing an early postnatal sensitive period for control of 5-HT excitability genes. Chromatin immunoprecipitation followed by sequencing revealed that Pet-1 regulates 5-HT neuron maturation through direct gene activation and repression. Moreover, Pet-1 directly regulates the 5-HT neuron maturation factor Engrailed 1, which suggests Pet-1 orchestrates maturation through secondary postmitotic regulatory factors. The early postnatal switch in Pet-1 targets uncovers a distinct neonatal stage-specific function for Pet-1, during which it promotes maturation of 5-HT neuron excitability.SIGNIFICANCE STATEMENTThe regulatory mechanisms that control functional maturation of neurons are poorly understood. We show that in addition to inducing brain serotonin (5-HT) synthesis and reuptake, the Pet-1 ETS (E26 transformation-specific) factor subsequently globally coordinates postmitotic expression trajectories of genes necessary for maturation of 5-HT neuron excitability. Further, Pet-1 switches its transcriptional targets as 5-HT neurons mature from 5-HT synthesis genes to G-protein-coupled receptors, which are necessary for afferent synaptic modulation of 5-HT neuron excitability. Our findings uncover gene-specific switching of downstream targets as a previously unrecognized regulatory strategy through which continuously expressed transcription factors control acquisition of neuronal identity at different stages of development.
INFLUJO DE ZUBIRI1 EN LA PEDAGOGÍA2 LATINOAMERICANA: SU APORTE A UN NUEVO PROYECTO PÚBLICO DE EDUCACIÓN
Authors: Niño M. Fideligno 
Published: February 2016

<p>El balance de lo que ha sido la educación en América Latina finalizando la vigésima<br />centuria, arroja indudables conquistas, aunque también pone de presente abultadas y<br />múltiples carencias. Como si ello fuera poco, el actual proceso de globalización viene<br />afectando esenciales coordenadas de la vida, como la económica, la productiva y la<br />cultural. A consecuencia de todo ello, nuestra educación se ve puesta radicalmente en </p><p>cuestión, hasta el punto de hacer necesario un nuevo pacto educativo que nos permita<br />construir, con el aporte de todos, un renovado Proyecto público de educación. Proyecto<br />que debe estar apuntalado por una idónea concepción de hombre, sociedad y cultura.<br />En este menester el pensamiento de X. Zubiri puede brindar sustancial aporte. Aquí resalto sólo cuatro vertientes, entre otras igualmente fecundas, que su reflexión<br />antropológica puede ofrecer: el carácter integrador de su antropología, su concepción<br />de persona, su consideración genética de la subjetividad y su entendimiento de la<br />historicidad humana.</p>
SapTrap, a Toolkit for High-Throughput CRISPR/Cas9 Gene Modification in Caenorhabditis elegans
Authors: Schwartz Matthew L , Jorgensen Erik M 
Published: February 2016

Abstract
In principle, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 allows genetic tags to be inserted at any locus. However, throughput is limited by the laborious construction of repair templates and guide RNA constructs and by the identification of modified strains. We have developed a reagent toolkit and plasmid assembly pipeline, called “SapTrap,” that streamlines the production of targeting vectors for tag insertion, as well as the selection of modified Caenorhabditis elegans strains. SapTrap is a high-efficiency modular plasmid assembly pipeline that produces single plasmid targeting vectors, each of which encodes both a guide RNA transcript and a repair template for a particular tagging event. The plasmid is generated in a single tube by cutting modular components with the restriction enzyme SapI, which are then “trapped” in a fixed order by ligation to generate the targeting vector. A library of donor plasmids supplies a variety of protein tags, a selectable marker, and regulatory sequences that allow cell-specific tagging at either the N or the C termini. All site-specific sequences, such as guide RNA targeting sequences and homology arms, are supplied as annealed synthetic oligonucleotides, eliminating the need for PCR or molecular cloning during plasmid assembly. Each tag includes an embedded Cbr-unc-119 selectable marker that is positioned to allow concurrent expression of both the tag and the marker. We demonstrate that SapTrap targeting vectors direct insertion of 3- to 4-kb tags at six different loci in 10–37% of injected animals. Thus SapTrap vectors introduce the possibility for high-throughput generation of CRISPR/Cas9 genome modifications.