bluuebunny/crossref_metadata_2025 huggingface dataset:
Zfrp8/PDCD2is required in ovarian stem cells and interacts with the piRNA pathway machinery
Authors: Minakhina Svetlana , Changela Neha , Steward Ruth
Published: December 2013

The maintenance of stem cells is central to generating diverse cell populations in many tissues throughout the life of an animal. Elucidating the mechanisms involved in how stem cells are formed and maintained is crucial to understanding both normal developmental processes and the growth of many cancers. Previously, we showed that Zfrp8/PDCD2 is essential for the maintenance of Drosophila hematopoietic stem cells. Here, we show that Zfrp8/PDCD2 is also required in both germline and follicle stem cells in the Drosophila ovary. Expression of human PDCD2 fully rescues the Zfrp8 phenotype, underlining the functional conservation of Zfrp8/PDCD2. The piRNA pathway is essential in early oogenesis, and we find that nuclear localization of Zfrp8 in germline stem cells and their offspring is regulated by some piRNA pathway genes. We also show that Zfrp8 forms a complex with the piRNA pathway protein Maelstrom and controls the accumulation of Maelstrom in the nuage. Furthermore, Zfrp8 regulates the activity of specific transposable elements also controlled by Maelstrom and Piwi. Our results suggest that Zfrp8/PDCD2 is not an integral member of the piRNA pathway, but has an overlapping function, possibly competing with Maelstrom and Piwi.
EphA/ephrin A reverse signaling promotes the migration of cortical interneurons from the medial ganglionic eminence
Authors: Steinecke André , Gampe Christin , Zimmer Geraldine , Rudolph Judith , Bolz Jürgen
Published: December 2013

Inhibitory interneurons control the flow of information and synchronization in the cerebral cortex at the circuit level. During embryonic development, multiple subtypes of cortical interneurons are generated in different regions of the ventral telencephalon, such as the medial and caudal ganglionic eminence (MGE and CGE), as well as the preoptic area (POA). These neurons then migrate over long distances towards their cortical target areas. Diverse families of diffusible and cell-bound signaling molecules, including the Eph/ephrin system, regulate and orchestrate interneuron migration. Ephrin A3 and A5, for instance, are expressed at the borders of the pathway of MGE-derived interneurons and prevent these cells from entering inappropriate regions via EphA4 forward signaling. We found that MGE-derived interneurons, in addition to EphA4, also express ephrin A and B ligands, suggesting Eph/ephrin forward and reverse signaling in the same cell. In vitro and in vivo approaches showed that EphA4-induced reverse signaling in MGE-derived interneurons promotes their migration and that this effect is mediated by ephrin A2 ligands. In EphA4 mutant mice, as well as after ephrin A2 knockdown using in utero electroporation, we found delayed interneuron migration at embryonic stages. Thus, besides functions in guiding MGE-derived interneurons to the cortex through forward signaling, here we describe a novel role of the ephrins in driving these neurons to their target via reverse signaling.
Preface. Montage principle and the semiotics of culture
Authors: Huttunen Tomi
Published: December 2013

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Метрический монтаж: к теории полиметрических композиций [Metrical montage: On the theory of polymetrical compositions]
Authors: Лотман [Lotman] Михаил [Mihhail]
Published: December 2013

Metrical montage: On the theory of polymetrical compositions.The theory of polymetrical compositions was founded as late as in the 1970s by Pyotr Rudnev, a scholar of the University of Tartu. While Rudnev approached the problem from the paradigmatic aspect, in the present paper the priority of syntagmatics over paradigmatics is emphasized: the effect of polymetricity is based on the contrast of segments, which is, in its own way, a montage with means of verse technique. Just like in the case of video montage, here as well we can distinguish between straight cut (closed polymetrics in Rudnev’s terms) and dissolve (open polymetrics in Rudnev’s terms). The given types of montage use different semiotic mechanisms and have different semantic effects. The theoretical standpoints are illustrated with examples from Alexander Pushkin’s poetry.
Montage in Russian Imaginism: Poetry, theatre and theory
Authors: Huttunen Tomi
Published: December 2013

The article discusses the concept of montage as used by the Russian Imaginist poetic group: the montage principle in their poetry, theoretical writings and theatre articles. The leading Imaginist figures Vadim Shershenevich and Anatolij Mariengof were active both in theorizing and practising montage in their oeuvre at the beginning of the 1920s. Shershenevich’s application of the principle in poetry was called “image catalogue”, a radical poetic experiment in the spirit of both Walt Whitman and Sergei Eisenstein. Mariengof ’s main contribution to the montage poetics was his first fictional novel The Cynics (1928). The article also discusses the Imaginists’ writings on the essence of theatre as an autonomous art form – Shershenevich’s actitivy in the OGT (Experimental Heroic Theatre) and Mariengof ’s participation in the work of the MKT (Moscow Kamerny Theatre).
The ideological aspect of intersemiotic translation and montage
Authors: Torop Peeter
Published: December 2013

The Estonian film The Last Relic offers an interesting case of ideological intersemiotic translation. At the same time, it is an innovative film from the point of view of text composition as well as combination of traditional montage with intersemiotic montage in which the speech of the heroes, the messages of the songs and repetition of visual and musical motifs are juxtaposed to create historical and ideological ambiguity. The specificity of this film is very close to later tendencies in using montage: the movement from a temporal understanding of montage to spatial montage in contemporary new media and 3D-movies. A new understanding of montage is also fruitful for the new interpretation of the chronotopical structure of narrative texts. The traditional theory of montage is rooted in classical literature, while new media experience opens up new possibilities for understanding mechanisms of montage. On a very general level, contemporary tendencies of montage can be analysed as chronotopical montage.
The place of language among sign systems: Juri Lotman and Émile Benveniste
Authors: Gramigna Remo
Published: December 2013

This paper seeks to shed light on an unwritten chapter in the history of Tartu semiotics, that is, to draw a parallel between Juri Lotman and Émile Benveniste on the status of natural language among other systems of signs. The tenet that language works as a ‘primary modelling system’ represents one of the trademarks of the Tartu-Moscow school. For Lotman, the primacy assigned to natural language in respect to other systems of signs lied in the fact that the former functions as a ‘model’ for the latter thus regarded as ‘secondary modelling systems’. Yet how does language carry out its function of being a model for other sign systems? Is language the only primary modelling system? This paper seeks to foster the abovementioned claim of the primacy of natural language and argues that this issue deserves a closer inspection. In order to follow this route, it suggests a parallel between Lotman and Benveniste arguing that there exist several points in common that lead to a convergence of positions between these two remarkable scholars. The paper explores such a possibility, arguing that Lotman’s and Benveniste’s positions open up an interesting debate with specific reference to the relations laid down between language and other system of signs.
On the dynamics of culture
Authors: Lotman Juri
Published: December 2013

First published as Лотман, Ю. М. 1992. О динамике культуры. Труды по знаковым системам (Sign Systems Studies) 25: 5–22.
Canonical art as informational paradox
Authors: Lotman Juri
Published: December 2013

Originally published as Лотман, Ю. М. 1973. Каноническое искусство как информа цион- ный парадокс. In: Муриан, Инна Федоровна (ed.), Проблема канона в древнем и средневековом искусстве Азии и Африки. Москва: Наука, 16–22.
Autocommunication in semiotic systems: 40 years after the Theses on the Semiotic Study of Cultures (Tartu Summer School in Semiotics 2013)
Authors: Randviir Anti
Published: December 2013

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Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT1ASerotonin Receptor
Authors: Bouaziz Elodie , Emerit Michel Boris , Vodjdani Guilan , Gautheron Vanessa , Hamon Michel , Darmon Michèle , Masson Justine
Published: December 2013

Selective serotonin reuptake inhibitors (SSRI) are aimed at increasing brain 5-HT tone; however, this expected effect has a slow onset after starting SSRI treatment because of initial activation of 5-HT1Aautoreceptor-mediated negative feedback of 5-HT release. After chronic SSRI treatment, 5-HT1Aautoreceptors desensitize, which allows 5-HT tone elevation. Because 5-HT1Areceptor (5-HT1AR) internalization has been proposed as a possible mechanism underlying 5-HT1Aautoreceptor desensitization, we examined whether this receptor could internalize under well controlledin vitroconditions in the LLC-CPK1 cell line and in raphe or hippocampal neurons from rat embryos. To this goal, cells were transfected with recombinant lentiviral vectors encoding N-terminal tagged 5-HT1AR, and exposed to various pharmacological conditions. Constitutive endocytosis and plasma membrane recycling of tagged-5-HT1AR was observed in LLC-PK1 cells as well as in neurons. Acute exposure (for 1 h) to the full 5-HT1AR agonists, 5-HT and 5-carboxamido-tryptamine, but not the partial agonist 8-OH-DPAT, triggered internalization of tagged 5-HT1AR in serotonergic neurons only. In contrast, sustained exposure (for 24 h) to all agonists induced tagged-5-HT1AR endocytosis in raphe serotonergic neurons and a portion of hippocampal neurons, but not LLC-PK1 cells and partial agonist displayed an effect only in serotonergic neurons. In all cases, agonist-induced tagged 5-HT1AR endocytosis was prevented by the 5-HT1AR antagonist, WAY-100635, which was inactive on its own. These data showed that agonist-induced 5-HT1AR internalization does exist in neurons and depends on agonist efficacy and neuronal phenotype. Its differential occurrence in serotonergic neurons supports the idea that 5-HT1AR internalization might underlie 5-HT1Aautoreceptor desensitization under SSRI antidepressant therapy.
Intracranial Cortical Responses during Visual–Tactile Integration in Humans
Authors: Quinn Brian T. , Carlson Chad , Doyle Werner , Cash Sydney S. , Devinsky Orrin , Spence Charles , Halgren Eric , Thesen Thomas
Published: December 2013

Sensory integration of touch and sight is crucial to perceiving and navigating the environment. While recent evidence from other sensory modality combinations suggests that low-level sensory areas integrate multisensory information at early processing stages, little is known about how the brain combines visual and tactile information. We investigated the dynamics of multisensory integration between vision and touch using the high spatial and temporal resolution of intracranial electrocorticography in humans. We present a novel, two-step metric for defining multisensory integration. The first step compares the sum of the unisensory responses to the bimodal response as multisensory responses. The second step eliminates the possibility that double addition of sensory responses could be misinterpreted as interactions. Using these criteria, averaged local field potentials and high-gamma-band power demonstrate a functional processing cascade whereby sensory integration occurs late, both anatomically and temporally, in the temporo–parieto–occipital junction (TPOJ) and dorsolateral prefrontal cortex. Results further suggest two neurophysiologically distinct and temporally separated integration mechanisms in TPOJ, while providing direct evidence for local suppression as a dominant mechanism for synthesizing visual and tactile input. These results tend to support earlier concepts of multisensory integration as relatively late and centered in tertiary multimodal association cortices.
Dual Effects of 5-HT1aReceptor Activation on Breathing in Neonatal Mice
Authors: Corcoran Andrea E. , Commons Kathryn G. , Wu Yuanming , Smith Jeffrey C. , Harris Michael B. , Richerson George B.
Published: December 2013

Inhibitory 5-HT1areceptors are located on serotonin (5-HT) neurons (autoreceptors) as well as neurons of the respiratory network (heteroreceptors). Thus, effects on breathing of 5-HT1aagonists, such as (R)-(+)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), could either be due to decreased firing of 5-HT neurons or direct effects on the respiratory network. Mice in which the transcription factor LMX1B is genetically deleted selectively inPet1-1-expressing cells (Lmx1bf/f/p) essentially have complete absence of central 5-HT neurons, providing a unique opportunity to separate the effect of activation of downstream 5-HT1aheteroreceptors from that of autoreceptors. We used rhythmically active medullary slices from wild-type (WT) andLmx1bf/f/pneonatal mice to differentiate autoreceptor versus heteroreceptor effects of 8-OH-DPAT on hypoglossal nerve respiratory output. 8-OH-DPAT transiently increased respiratory burst frequency inLmx1bf/f/ppreparations, but not in WT slices. This excitation was abolished when synaptic inhibition was blocked by GABAergic/glycinergic receptor antagonists. Conversely, after 10 min of application, frequency inLmx1bf/f/pslices was not different from baseline, whereas it was significantly depressed in WT slices. In WT micein vivo, subcutaneous injection of 8-OH-DPAT produced similar biphasic respiratory effects as inLmx1bf/f/pmice. We conclude that 5-HT1areceptor agonists have two competing effects: rapid stimulation of breathing due to excitation of the respiratory network, and delayed inhibition of breathing due to autoreceptor inhibition of 5-HT neurons. The former effect is presumably due to inhibition of inhibitory interneurons embedded in the respiratory network.
Repeating Firing Fields of CA1 Neurons Shift Forward in Response to Increasing Angular Velocity
Authors: Cowen Stephen L. , Nitz Douglas A.
Published: December 2013

Self-motion information influences spatially-specific firing patterns exhibited by hippocampal neurons. Moreover, these firing patterns can repeat across similar subsegments of an environment, provided that there is similarity of path shape and head orientations across subsegments. The influence of self-motion variables on repeating fields remains to be determined. To investigate the role of path shape and angular rotation on hippocampal activity, we recorded the activity of CA1 neurons from rats trained to run on spiral-shaped tracks. During inbound traversals of circular-spiral tracks, angular velocity increases continuously. Under this condition, most neurons (74%) exhibited repeating fields across at least three adjacent loops. Of these neurons, 86% exhibited forward shifts in the angles of field centers relative to centers on preceding loops. Shifts were absent on squared-spiral tracks, minimal and less reliable on concentric-circle tracks, and absent on outward-bound runs on circular-spiral tracks. However, outward-bound runs on the circular-spiral track in the dark were associated with backward shifts. Together, the most parsimonious interpretation of the results is that continuous increases or decreases in angular velocity are particularly effective at shifting the center of mass of repeating fields, although it is also possible that a nonlinear integration of step counts contributes to the shift. Furthermore, the unexpected absence of field shifts during outward journeys in light (but not darkness) suggests visual cues around the goal location anchored the map of space to an allocentric reference frame.
Better Get Back to Work: A Role for Motor Beta Desynchronization in Incentive Motivation
Authors: Meyniel Florent , Pessiglione Mathias
Published: December 2013

Much research has been devoted to characterizing brain representations of reward and movement. However, the mechanisms allowing expected rewards to influence motor commands remain poorly understood. Unraveling such mechanisms is crucial to providing explanations of how behavior can be driven by goals, hence accounting for apathy cases in clinics. Here, we propose that the reduction of motor beta synchrony (MBS) before movement onset could participate in this incentive motivation process. To test this hypothesis, we recorded brain activity using magnetoencenphalography (MEG) while human participants were exerting physical effort to win monetary incentives. Knowing that the payoff was proportional to the time spent above a target force, subjects spontaneously took breaks when exhausted and resumed effort production when repleted. Behavioral data indicated that the rest periods were shorter when higher incentives were at stake. MEG data showed that the amplitude of MBS reduction correlated to both incentive level and rest duration. Moreover, the time of effort initiation could be predicted by MBS reduction measured at the beginning of rest periods. Incentive effects on MBS reduction and rest duration were also correlated across subjects. Finally, Bayesian comparison between possible causal models suggested that MBS reduction mediates the impact of incentive level on rest duration. We conclude that MBS reduction could represent a neural mechanism that speeds the initiation of effort production when the effort is more rewarded.
ACF7 Is a Hair-Bundle Antecedent, Positioned to Integrate Cuticular Plate Actin and Somatic Tubulin
Authors: Antonellis Patrick J. , Pollock Lana M. , Chou Shih-Wei , Hassan Ahmed , Geng Ruishuang , Chen Xi , Fuchs Elaine , Alagramam Kumar N. , Auer Manfred , McDermott Brian M.
Published: December 2013

The precise morphology of the mechanosensitive hair bundle requires seamless integration of actin and microtubule networks. Here, we identify Acf7a (actin crosslinking family protein 7a) as a protein positioned to bridge these distinct cytoskeletal networks in hair cells. By imaging Acf7a–Citrine fusion protein in zebrafish and immunolabeling of vestibular and cochlear mouse hair cells, we show that Acf7a and ACF7 circumscribe, underlie, and are interwoven into the cuticular plate (CP), and they also encircle the basal body of the kinocilium. In cochlear hair cells, ACF7 localization is graded, with the highest concentration near each fonticulus—an area free of F-actin in the region of the CP that contains the basal body. During hair-cell development and regeneration, Acf7a precedes formation of the hair bundle and CP. Finally, electron tomography demonstrates that the ends of microtubules insert into the CP and are decorated with filamentous linkers connecting microtubules to the CP. These observations are consistent with ACF7 being a linker protein, which may shape the cytoskeleton of the hair cell early during hair-bundle genesis.
Coding of Electric Pulse Trains Presented through Cochlear Implants in the Auditory Midbrain of Awake Rabbit: Comparison with Anesthetized Preparations
Authors: Chung Yoojin , Hancock Kenneth E. , Nam Sung-Il , Delgutte Bertrand
Published: December 2013

Cochlear implant (CI) listeners show limits at high frequencies in tasks involving temporal processing such as rate pitch and interaural time difference discrimination. Similar limits have been observed in neural responses to electric stimulation in animals with CI; however, the upper limit of temporal coding of electric pulse train stimuli in the inferior colliculus (IC) of anesthetized animals is lower than the perceptual limit. We hypothesize that the upper limit of temporal neural coding has been underestimated in previous studies due to the confound of anesthesia. To test this hypothesis, we developed a chronic, awake rabbit preparation for single-unit studies of IC neurons with electric stimulation through CI. Stimuli were periodic trains of biphasic pulses with rates varying from 20 to 1280 pulses per second. We found that IC neurons in awake rabbits showed higher spontaneous activity and greater sustained responses, both excitatory and suppressive, at high pulse rates. Maximum pulse rates that elicited synchronized responses were approximately two times higher in awake rabbits than in earlier studies with anesthetized animals. Here, we demonstrate directly that anesthesia is a major factor underlying these differences by monitoring the responses of single units in one rabbit before and after injection of an ultra-short-acting barbiturate. In general, the physiological rate limits of IC neurons in the awake rabbit are more consistent with the psychophysical limits in human CI subjects compared with limits from anesthetized animals.
T-Cell Receptor Activation Decreases Excitability of Cortical Interneurons by Inhibiting α7 Nicotinic Receptors
Authors: Komal Pragya , Gudavicius Geoff , Nelson Christopher J. , Nashmi Raad
Published: December 2013

Many proteins in the immune system are also expressed in the brain. One such class of immune proteins are T-cell receptors (TCRs), whose functions in T lymphocytes in adaptive immunity are well characterized. In the brain, TCRs are confined to neocortical neurons, but their functional role has not been determined. In mouse layer 1 neocortical neurons, TCR activation inhibited α7 nicotinic currents. TCRs modulated α7 currents via tyrosine phosphorylation of α7 nicotinic receptors (nAChRs) through src tyrosine kinases because eliminating lck kinase expression, coexpressing fyn kinase dead, or mutating tyrosine to alanine in α7 blocked the effect of TCR activation. We found that TCR stimulation decreased surface α7 nAChRs and reduced single-channel conductance. These results reveal that TCRs play a major role in the modulation of cholinergic neurotransmission in the brain mediated by α7 nAChRs and that this has a profound effect on regulating neuronal excitability.
α-Synuclein Is Localized to Mitochondria-Associated ER Membranes
Authors: Guardia-Laguarta Cristina , Area-Gomez Estela , Rüb Cornelia , Liu Yuhui , Magrané Jordi , Becker Dorothea , Voos Wolfgang , Schon Eric A. , Przedborski Serge
Published: December 2013

Familial Parkinson disease is associated with mutations in α-synuclein (α-syn), a presynaptic protein that has been localized not only to the cytosol, but also to mitochondria. We report here that wild-type α-syn from cell lines, and brain tissue from humans and mice, is present not in mitochondria but rather in mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), a structurally and functionally distinct subdomain of the ER. Remarkably, we found that pathogenic point mutations in human α-syn result in its reduced association with MAM, coincident with a lower degree of apposition of ER with mitochondria, a decrease in MAM function, and an increase in mitochondrial fragmentation compared with wild-type. Although overexpression of wild-type α-syn in mutant α-syn-expressing cells reverted the fragmentation phenotype, neither overexpression of the mitochondrial fusion/MAM-tethering protein MFN2 nor inhibition/ablation of the mitochondrial fission protein DRP1 was able to do so, implying that α-syn operates downstream of the mitochondrial fusion/fission machinery. These novel results indicate that wild-type α-syn localizes to the MAM and modulates mitochondrial morphology, and that these behaviors are impaired by pathogenic mutations in α-syn. We believe that our results have far-reaching implications for both our understanding of α-syn biology and the treatment of synucleinopathies.
Heterogeneous Single-Unit Selectivity in an fMRI-Defined Body-Selective Patch
Authors: Popivanov Ivo D. , Jastorff Jan , Vanduffel Wim , Vogels Rufin
Published: December 2013

Although the visual representation of bodies is essential for reproduction, survival, and social communication, little is known about the mechanisms of body recognition at the single neuron level. Imaging studies showed body-category selective regions in the primate occipitotemporal cortex, but it is difficult to infer the stimulus selectivities of the neurons from the population activity measured in these fMRI studies. To overcome this, we recorded single unit activity and local field potentials (LFPs) in the middle superior temporal sulcus body patch, defined by fMRI in the same rhesus monkeys. Both the spiking activity, averaged across single neurons, and LFP gamma power in this body patch was greater for bodies (including monkey bodies, human bodies, mammals, and birds) compared with other objects, which fits the fMRI activation. Single neurons responded to a small proportion of body images. Thus, the category selectivity at the population level resulted from averaging responses of a heterogeneous population of single units. Despite such strong within-category selectivity at the single unit level, two distinct clusters, bodies and nonbodies, were present when analyzing the responses at the population level, and a classifier that was trained using the responses to a subset of images was able to classify novel images of bodies with high accuracy. The body-patch neurons showed strong selectivity for individual body parts at different orientations. Overall, these data suggest that single units in the fMRI-defined body patch are biased to prefer bodies over nonbody objects, including faces, with a strong selectivity for individual body images.
Causal Evidence for a Privileged Working Memory State in Early Visual Cortex
Authors: Zokaei Nahid , Manohar Sanjay , Husain Masud , Feredoes Eva
Published: December 2013

Emerging evidence suggests that items held in working memory (WM) might not all be in the same representational state. One item might be privileged over others, making it more accessible and thereby recalled with greater precision. Here, using transcranial magnetic stimulation (TMS), we provide causal evidence in human participants that items in WM are differentially susceptible to disruptive TMS, depending on their state, determined either by task relevance or serial position. Across two experiments, we applied TMS to area MT+ during the WM retention of two motion directions. In Experiment 1, we used an “incidental cue” to bring one of the two targets into a privileged state. In Experiment 2, we presented the targets sequentially so that the last item was in a privileged state by virtue of recency. In both experiments, recall precision of motion direction was differentially affected by TMS, depending on the state of the memory target at the time of disruption. Privileged items were recalled with less precision, whereas nonprivileged items were recalled with higher precision. Thus, only the privileged item was susceptible to disruptive TMS over MT+. By contrast, precision of the nonprivileged item improved either directly because of facilitation by TMS or indirectly through reduced interference from the privileged item. Our results provide a unique line of evidence, as revealed by TMS over a posterior sensory brain region, for at least two different states of item representation in WM.
Presynaptic α7 Nicotinic Acetylcholine Receptors Enhance Hippocampal Mossy Fiber Glutamatergic Transmission via PKA Activation
Authors: Cheng Qing , Yakel Jerrel L.
Published: December 2013

Nicotinic acetylcholine receptors (nAChRs) are expressed widely in the CNS, and mediate both synaptic and perisynaptic activities of endogenous cholinergic inputs and pharmacological actions of exogenous compounds (e.g., nicotine and choline). Behavioral studies indicate that nicotine improves such cognitive functions as learning and memory. However, the mechanism of nicotine's action on cognitive function remains elusive. We performed patch-clamp recordings from hippocampal CA3 pyramidal neurons to determine the effect of nicotine on mossy fiber glutamatergic synaptic transmission. We found that nicotine in combination with NS1738, an α7 nAChR-positive allosteric modulator, strongly potentiated the amplitude of evoked EPSCs (eEPSCs), and reduced the EPSC paired-pulse ratio. The action of nicotine and NS1738 was mimicked by PNU-282987 (an α7 nAChR agonist), and was absent in α7 nAChR knock-out mice. These data indicate that activation of α7 nAChRs was both necessary and sufficient to enhance the amplitude of eEPSCs. BAPTA applied postsynaptically failed to block the action of nicotine and NS1738, suggesting again a presynaptic action of the α7 nAChRs. We also observed α7 nAChR-mediated calcium rises at mossy fiber giant terminals, indicating the presence of functional α7 nAChRs at presynaptic terminals. Furthermore, the addition of PNU-282987 enhanced action potential-dependent calcium transient at these terminals. Last, the potentiating effect of PNU-282987 on eEPSCs was abolished by inhibition of protein kinase A (PKA). Our findings indicate that activation of α7 nAChRs at presynaptic sites, via a mechanism involving PKA, plays a critical role in enhancing synaptic efficiency of hippocampal mossy fiber transmission.
Action Potential Energetics at the Organismal Level Reveal a Trade-Off in Efficiency at High Firing Rates
Authors: Lewis John E. , Gilmour Kathleen M. , Moorhead Mayron J. , Perry Steve F. , Markham Michael R.
Published: December 2013

The energetic costs of action potential (AP) production constrain the evolution of neural codes and brain networks. Cellular-level estimates of AP-related costs are typically based on voltage-dependent Na+currents that drive active transport by the Na+/K+ATPase to maintain the Na+and K+ion concentration gradients necessary for AP production. However, these estimates of AP cost have not been verified at the organismal level. Electric signaling in the weakly electric fishEigenmannia virescensrequires that specialized cells in an electric organ generate APs with large Na+currents at high rates (200–600 Hz). We measured these currents using a voltage-clamp protocol and then estimated the energetic cost at the cellular level using standard methods. We then used this energy-intensive signaling behavior to measure changes in whole-animal energetics for small changes in electric discharge rate. At low rates, the whole-animal measure of AP cost was similar to our cellular-level estimates. However, AP cost increased nonlinearly with increasing firing rates. We show, with a biophysical model, that this nonlinearity can arise from the increasing cost of maintaining AP amplitude at high rates. Our results confirm that estimates of energetic costs based on Na+influx are appropriate for low baseline firing rates, but that extrapolating to high firing rates may underestimate true costs in cases in which AP amplitude does not decrease. Moreover, the trade-off between energetic cost and firing rate suggests an additional constraint on the evolution of high-frequency signaling in neuronal systems.
CGRP Inhibits Neurons of the Bed Nucleus of the Stria Terminalis: Implications for the Regulation of Fear and Anxiety
Authors: Gungor Nur Zeynep , Pare Denis
Published: December 2013

The bed nucleus of the stria terminalis (BNST) is thought to generate anxiety-like states via its projections to autonomic and neuroendocrine regulatory structures of the brain. However, because most BNST cells are GABAergic, they are expected to inhibit target neurons. In contrast with this, infusion of calcitonin gene-related peptide (CGRP) into BNST was reported to potentiate anxiety while activating BNST targets. The present study aimed to shed light on this paradox. The CGRP innervation of BNST originates in the pontine parabrachial nucleus and targets its anterolateral sector (BNST-AL). Thus, we investigated the effects of CGRP on BNST-AL neurons using patch recordingsin vitroin male rats. CGRP did not alter the passive properties of BNST-AL cells but increased the amplitude of IPSPs evoked by stimulation of the stria terminalis (ST). However, IPSP paired-pulse ratios were unchanged by CGRP, and there was no correlation between IPSP potentiation and variance, suggesting that CGRP acts postsynaptically. Consistent with this, CGRP hyperpolarized the GABA-A reversal of BNST-AL cells. These results indicate that CGRP increases ST-evoked GABA-A IPSPs and hyperpolarizes their reversal potential through a postsynaptic change in Cl−homeostasis. Overall, our findings suggest that CGRP potentiates anxiety-like behaviors and increases neural activity in BNST targets, by inhibiting BNST-AL cells, supporting the conclusion that BNST-AL exerts anxiolytic effects.
Modulation of Neurotransmission by GPCRs Is Dependent upon the Microarchitecture of the Primed Vesicle Complex
Authors: Hamid Edaeni , Church Emily , Wells Christopher A. , Zurawski Zack , Hamm Heidi E. , Alford Simon
Published: December 2013

Gi/o-protein-coupled receptors (GPCRs) ubiquitously inhibit neurotransmission, principally via Gβγ, which acts via a number of possible effectors. GPCR effector specificity has traditionally been attributed to Gα, based on Gα's preferential effector targetingin vitrocompared with Gβγ's promiscuous targeting of various effectors. In synapses, however, Gβγ clearly targets unique effectors in a receptor-dependent way to modulate synaptic transmission. It remains unknown whether Gβγ specificityin vivois due to specific Gβγ isoform-receptor associations or to spatial separation of distinct Gβγ pathways through macromolecular interactions. We thus sought to determine how Gβγ signaling pathways within axons remain distinct from one another. In rat hippocampal CA1 axons, GABABreceptors (GABABRs) inhibit presynaptic Ca2+entry, and we have now demonstrated that 5-HT1Breceptors (5-HT1BRs) liberate Gβγ to interact with SNARE complex C terminals with no effect on Ca2+entry. Both GABABRs and 5-HT1BRs inhibit Ca2+-evoked neurotransmitter release, but 5-HT1BRs have no effect on Sr2+-evoked release. Sr2+, unlike Ca2+, does not cause synaptotagmin to compete with Gβγ binding to SNARE complexes. 5-HT1BRs also fail to inhibit release following cleavage of the C terminus of the SNARE complex protein SNAP-25 with botulinum A toxin. Thus, GABABRs and 5-HT1BRs both localize to presynaptic terminals, but target distinct effectors. We demonstrate that disruption of SNARE complexes and vesicle priming with botulinum C toxin eliminates this selectivity, allowing 5-HT1BR inhibition of Ca2+entry. We conclude that receptor-effector specificity requires a microarchitecture provided by the SNARE complex during vesicle priming.
When Norepinephrine Becomes a Driver of Breathing Irregularities: How Intermittent Hypoxia Fundamentally Alters the Modulatory Response of the Respiratory Network
Authors: Zanella Sébastien , Doi Atsushi , Garcia Alfredo J. , Elsen Frank , Kirsch Sarah , Wei Aguan D. , Ramirez Jan-Marino
Published: December 2013

Neuronal networks are endogenously modulated by aminergic and peptidergic substances. These modulatory processes are critical for maintaining normal activity and adapting networks to changes in metabolic, behavioral, and environmental conditions. However, disturbances in neuromodulation have also been associated with pathologies. Using whole animals (in vivo) and functional brainstem slices (in vitro) from mice, we demonstrate that exposure to acute intermittent hypoxia (AIH) leads to fundamental changes in the neuromodulatory response of the respiratory network located within the preBötzinger complex (preBötC), an area critical for breathing. Norepinephrine, which normally regularizes respiratory activity, renders respiratory activity irregular after AIH. Respiratory irregularities are caused bothin vitroandin vivoby AIH, which increases synaptic inhibition within the preBötC when norepinephrine is endogenously or exogenously increased. These irregularities are prevented by blocking synaptic inhibition before AIH. However, regular breathing cannot be reestablished if synaptic inhibition is blocked after AIH. We conclude that subtle changes in synaptic transmission can have dramatic consequences at the network level as endogenously released neuromodulators that are normally adaptive become the drivers of irregularity. Moreover, irregularities in the preBötC result in irregularities in the motor outputin vivoand in incomplete transmission of inspiratory activity to the hypoglossus motor nucleus. Our finding has basic science implications for understanding network functions in general, and it may be clinically relevant for understanding pathological disturbances associated with hypoxic episodes such as those associated with myocardial infarcts, obstructive sleep apneas, apneas of prematurity, Rett syndrome, and sudden infant death syndrome.
Changing the Spatial Scope of Attention Alters Patterns of Neural Gain in Human Cortex
Authors: Itthipuripat Sirawaj , Garcia Javier O. , Rungratsameetaweemana Nuttida , Sprague Thomas C. , Serences John T.
Published: December 2013

Over the last several decades, spatial attention has been shown to influence the activity of neurons in visual cortex in various ways. These conflicting observations have inspired competing models to account for the influence of attention on perception and behavior. Here, we used electroencephalography (EEG) to assess steady-state visual evoked potentials (SSVEP) in human subjects and showed that highly focused spatial attention primarily enhanced neural responses to high-contrast stimuli (response gain), whereas distributed attention primarily enhanced responses to medium-contrast stimuli (contrast gain). Together, these data suggest that different patterns of neural modulation do not reflect fundamentally different neural mechanisms, but instead reflect changes in the spatial extent of attention.
Dynamic Range Adaptation to Spectral Stimulus Statistics in Human Auditory Cortex
Authors: Herrmann Björn , Schlichting Nadine , Obleser Jonas
Published: December 2013

Classically, neural adaptation refers to a reduction in response magnitude by sustained stimulation. In human electroencephalography (EEG), neural adaptation has been measured, for example, as frequency-specific response decrease by previous stimulation. Only recently and mainly based on animal studies, it has been suggested that statistical properties in the stimulation lead to adjustments of neural sensitivity and affect neural response adaptation. However, it is thus far unresolved which statistical parameters in the acoustic stimulation spectrum affect frequency-specific neural adaptation, and on which time scales the effects take place. The present human EEG study investigated the potential influence of the overall spectral range as well as the spectral spacing of the acoustic stimulation spectrum on frequency-specific neural adaptation. Tones randomly varying in frequency were presented passively and computational modeling of frequency-specific neural adaptation was used. Frequency-specific adaptation was observed for all presentation conditions. Critically, however, the spread of adaptation (i.e., degree of coadaptation) in tonotopically organized regions of auditory cortex changed with the spectral range of the acoustic stimulation. In contrast, spectral spacing did not affect the spread of frequency-specific adaptation. Therefore, changes in neural sensitivity in auditory cortex are directly coupled to the overall spectral range of the acoustic stimulation, which suggests that neural adjustments to spectral stimulus statistics occur over a time scale of multiple seconds.
Perceptual Color Map in Macaque Visual Area V4
Authors: Li Ming , Liu Fang , Juusola Mikko , Tang Shiming
Published: December 2013

Colors distinguishable with trichromatic vision can be defined by a 3D color space, such as red-green-blue or hue-saturation-lightness (HSL) space, but it remains unclear how the cortex represents colors along these dimensions. Using intrinsic optical imaging and electrophysiology, and systematically choosing color stimuli from HSL coordinates, we examined how perceptual colors are mapped in visual area V4 in behaving macaques. We show that any color activates 1–4 separate cortical patches within “globs,” millimeter-sized color-preferring modules. Most patches belong to different hue or lightness clusters, in which sequential representations follow the color order in HSL space. Some patches overlap greatly with those of related colors, forming stacks, possibly representing invariable features, whereas few seem positioned irregularly. However, for any color, saturation increases the activity of all its patches. These results reveal how the color map in V4 is organized along the framework of the perceptual HSL space, whereupon different multipatch activity patterns represent different colors. We propose that such distributed and combinatorial representations may expand the encodable color space of small cortical maps and facilitate binding color information to other image features.
Early Features in Neuroimaging of Two Siblings With Molybdenum Cofactor Deficiency
Authors: Higuchi Ryuzo , Sugimoto Takuya , Tamura Akira , Kioka Naomi , Tsuno Yoshinobu , Higa Asumi , Yoshikawa Norishige
Published: December 2013

We report the features of neuroimaging within 24 hours after birth in 2 siblings with molybdenum cofactor deficiency. The first sibling was delivered by emergency cesarean section because of fetal distress and showed pedaling and crawling seizures soon after birth. Brain ultrasound revealed subcortical multicystic lesions in the frontal white matter, and brain MRI at 4 hours after birth showed restricted diffusion in the entire cortex, except for the area adjacent to the subcortical cysts. The second sibling was delivered by elective cesarean section. Cystic lesions were seen in the frontal white matter on ultrasound, and brain MRI showed low signal intensity on T1-weighted image and high signal intensity on T2-weighted image in bifrontal white matter within 24 hours after birth, at which time the infant sucked sluggishly. Clonic spasm appeared at 29 hours after birth. The corpus callosum could not be seen clearly on ultrasound or MRI in both infants. Cortical atrophy and white matter cystic lesions spread to the entire hemisphere and resulted in severe brain atrophy within ∼1 month in both infants. Subcortical multicystic lesions on ultrasound and a cortex with nonuniform, widespread, restricted diffusion on diffusion-weighted images are early features of neuroimaging in patients with molybdenum cofactor deficiency type A.
An Unusual Presentation of Denys-Drash Syndrome Due to Bigenic Disease
Authors: Eneman Benedicte , Mekahli Djalila , Audrezet Marie-Pierre , Lerut Evelyne , Van Damme-Lombaerts Rita , Van den Heuvel Lambertus , Levtchenko Elena
Published: December 2013

We report a case of Denys-Drash syndrome (DDS) in a 3-month-old girl presenting with bilateral renal cortical cysts mimicking polycystic kidney disease. Genetic analysis revealed a de novo heterozygous missense mutation c.1186G>A (p.Asp396Asn) in the WT1 gene, confirming the diagnosis of DDS. Because multiple renal cysts have never been reported in DDS, we explored several genes responsible for these renal manifestations, such as HNF-1β, PAX2, PKD1, and PKD2. Remarkably, we identified a heterozygous missense variant c.12439A>G (p.Lys4147Glu) in the PKD1 gene. The same variant was found in the patient’s mother, who had no renal cysts, and in the grandfather, who had several renal cysts. Mutation prediction programs classified the c.12439A>G variant as being “likely pathogenic.” We hypothesize that the severe cystic phenotype in the index patient could be due to the WT1 mutation, enhancing pathogenicity of the “hypomorph” PKD1 allele. A possible role for Wilms tumor suppressor 1 (WT1) in renal cyst development should be considered. From a conceptual point of view, this case shows that an unusual presentation of a known genetic syndrome might point to bigenic inheritance, with unexpected interference of mutated genes causing an uncommon clinical phenotype.
Outcomes in Hospitalized Pediatric Patients With Systemic Lupus Erythematosus
Authors: Son Mary Beth F. , Johnson Victor M. , Hersh Aimee O. , Lo Mindy S. , Costenbader Karen H.
Published: December 2013

OBJECTIVE:

Disparities in outcomes among adults with systemic lupus erythematosus (SLE) have been documented. We investigated associations between sociodemographic factors and volume of annual inpatient hospital admissions with hospitalization characteristics and poor outcomes among patients with childhood-onset SLE.

METHODS:

By using the Pediatric Health Information System, we analyzed admissions for patients aged 3 to <18 years at index admission with ≥1 International Classification of Diseases, Ninth Revision code for SLE from January 2006 to September 2011. Summary statistics and univariable analyses were used to examine demographic characteristics of hospital admissions, readmissions, and lengths of stay. We used multivariable logistic regression analyses, controlling for patient gender, age, race, ethnicity, insurance type, hospital volume, US census region, and severity of illness, to examine risk factors for poor outcomes.

RESULTS:

A total of 10 724 admissions occurred among 2775 patients over the study period. Hispanic patients had longer lengths of stay, more readmissions, and higher in-hospital mortality. In multivariable analysis, African American race was significantly associated with ICU admission. African American race and Hispanic ethnicity were associated with end-stage renal disease and death. Volume of patients with SLE per hospital and hospital location were not significantly associated with outcomes.

CONCLUSIONS:

In this cohort of hospitalized children with SLE, race and ethnicity were associated with outcomes. Further studies are needed to elucidate the relationship between sociodemographic factors and poor outcomes in patients with childhood-onset SLE.
Isotonic Versus Hypotonic Maintenance IV Fluids in Hospitalized Children: A Meta-Analysis
Authors: Wang Jingjing , Xu Erdi , Xiao Yanfeng
Published: December 2013

OBJECTIVE:

To assess evidence from randomized controlled trials (RCTs) on the safety of isotonic versus hypotonic intravenous (IV) maintenance fluids in hospitalized children.

METHODS:

We searched PubMed, Embase, Cochrane Library, and clinicaltrials.gov (up to April 11, 2013) for RCTs that compared isotonic to hypotonic maintenance IV fluid therapy in hospitalized children. Relative risk (RR), weighted mean differences, and 95% confidence intervals (CIs) were calculated based on the effects on plasma sodium (pNa). The risk of developing hyponatremia (pNa <136 mmol/L), severe hyponatremia (pNa <130 mmol/L), and hypernatremia (pNa >145 mmol/L) was evaluated. We adopted a random-effects model in all meta-analyses. Sensitivity analyses by missing data were also performed.

RESULTS:

Ten RCTs were included in this review. The meta-analysis showed significantly higher risk of hypotonic IV fluids for developing hyponatremia (RR 2.24, 95% CI 1.52 to 3.31) and severe hyponatremia (RR 5.29, 95% CI 1.74 to 16.06). There was a significantly greater fall in pNa in children who received hypotonic IV fluids (–3.49 mmol/L versus isotonic IV fluids, 95% CI –5.63 to –1.35). No significant difference was found between the 2 interventions in the risk of hypernatremia (RR 0.73, 95% CI 0.22 to 2.48). None of the findings was sensitive to imputation of missing data.

CONCLUSIONS:

Isotonic fluids are safer than hypotonic fluids in hospitalized children requiring maintenance IV fluid therapy in terms of pNa.