bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural Coding of “Attention for Action” and “Response Selection” in Primate Anterior Cingulate Cortex
Authors: Isomura Yoshikazu , Ito Yumi , Akazawa Toshikazu , Nambu Atsushi , Takada Masahiko
Published: April 2018

Noninvasive imaging techniques showed that the anterior cingulate cortex is related to higher-order cognitive and motor-related functions in humans. To elucidate the cellular mechanism of such cingulate functions, single-unit activity was recorded from three cingulate motor areas of macaque monkeys performing delayed conditional Go/No-go discrimination tasks using spatial (location) and nonspatial (color) visual cues. Unlike prefrontal neurons, only a few neurons coded the visual information on individual features (e.g., “left” or “red”) in all of the rostral (CMAr), dorsal (CMAd), and ventral (CMAv) cingulate motor areas. Instead, many neurons in the CMAr exhibited the attention-like activity anticipating the second (conditioned) visual cues, with the specificity to visual category (“location” or “color”). In addition, there were a number of CMAr neurons specific to motor response (GoorNo-go) in relation to the second visual cues. Some of the visual category-specific neurons in the CMAr further displayed the motor response-specific activity. On the other hand, many of the task-related CMAd and CMAv neurons seemed to be implicated directly in motor functions, such as preparation and execution of movements in Go trials. The present results suggest that the CMAr neurons may participate in cognitive and motor functions of “attention for action” and “response selection” for an appropriate action according to an intention, whereas the CMAd and CMAv neurons may be involved in “motor preparation and execution”.
Are Crossed Actions of Reticulospinal and Vestibulospinal Neurons on Feline Motoneurons Mediated by the Same or Separate Commissural Neurons?
Authors: Krutki Piotr , Jankowska Elzbieta , Edgley Stephen A.
Published: April 2018

Both reticulo- and vestibulospinal neurons coordinate the activity of ipsilateral and contralateral limb muscles. The aim of this study was to investigate whether their actions on contralateral motoneurons are mediated via common interneurons. Two series of experiments were made on deeply anesthetized cats. First, the effects of stimuli applied within the lateral vestibular nucleus and to reticulospinal tract fibers within or close to the medial longitudinal fascicle in the medulla were tested on midlumbar commissural interneurons that projected to contralateral motor nuclei. EPSPs of vestibular origin were found in 16 of 20 (80%) of the interneurons, all of which were excited monosynaptically by reticulospinal fibers. These EPSPs were evoked either monosynaptically or disynaptically. Second, the effects of stimuli applied at the same two locations were tested on contralateral motoneurons, selecting motoneurons in which large disynaptic EPSPs or IPSPs were evoked by reticulospinal fibers. When stimuli that were too weak to evoke any PSPs by themselves were applied together, similar EPSPs or IPSPs were evoked in all 26 motoneurons that were tested, indicating that spatial facilitation occurred premotoneuronally. Facilitation was strongest at those intervals optimal for summation of monosynaptic and/or disynaptic EPSPs evoked in commissural neurons by the earliest reticulospinal and vestibulospinal volleys. The same interneurons thus may be used by reticulospinal and vestibulospinal neurons to influence the activity of contralateral hindlimb muscles. Separate modulation of commands from these two descending neuronal systems may occur at the level of the interneurons that mediate disynaptic excitation of commissural neurons by reticulospinal and vestibulospinal neurons, thereby increasing their flexibility.
Human Striatal Response to Salient Nonrewarding Stimuli
Authors: Zink Caroline F. , Pagnoni Giuseppe , Martin Megan E. , Dhamala Mukeshwar , Berns Gregory S.
Published: April 2018

Although one proposed function of both the striatum and its major dopamine inputs is related to coding rewards and reward-related stimuli, an alternative view suggests a more general role of the striatum in processing salient events, regardless of their reward value. Here we define saliency as an event that both is unexpected and elicits an attentional-behavioral switch (i.e., arousing). In the present study, human striatal responses to nonrewarding salient stimuli were investigated. Using functional magnetic resonance imaging (fMRI), the blood oxygenation level-dependent signal was measured in response to flickering visual distractors presented in the background of an ongoing task. Distractor salience was manipulated by altering the frequency of distractor occurrence. Infrequently presented distractors were considered more salient than frequently presented distractors. We also investigated whether behavioral relevance of the distractors was a necessary component of saliency for eliciting striatal responses. In the first experiment (19 subjects), the distractors were made behaviorally relevant by defining a subset of them as targets requiring a button press. In the second experiment (17 subjects), the distractors were not behaviorally relevant (i.e., they did not require any response). The fMRI results revealed increased activation in the nucleus accumbens after infrequent (high salience) relative to frequent (low salience) presentation of distractors in both experiments. Caudate activity increased only when the distractors were behaviorally relevant. These results demonstrate a role of the striatum in coding nonrewarding salient events. In addition, a functional subdivision of the striatum according to the behavioral relevance of the stimuli is suggested.
Dissociation of Extinction and Behavioral Disinhibition: The Role of NMDA Receptors in the Pigeon Associative Forebrain during Extinction
Authors: Lissek Silke , Güntürkün Onur
Published: April 2018

Extinction is a unique learning process that requires the alteration of stimulus-response associations such that the organism ceases to respond to a previously rewarded stimulus. Extinction is mostly studied with fear conditioning and is impaired by lesions of the prefrontal cortex as well as by blockade of NMDA receptors in the amygdala. Because previous tasks could not clearly disambiguate extinction from behavioral disinhibition, the underlying process was difficult to define. In this study, we examined the possible role of NMDA receptors and the pigeon “prefrontal cortex,” the neostriatum caudolaterale (NCL), for extinction of appetitive instrumental conditioning. We used a new design that discerns extinction from behavioral disinhibition. Our results demonstrate that NCL lesions cause deficits neither in extinction learning nor in extinction recall. However, blockade of NMDA receptors in the pigeon NCL bydl-AP-5 drastically impairs extinction learning without producing behavioral disinhibition or deficits in extinction recall. We suggest that NMDA receptors in the NCL contribute to the establishment of a learning process that selectively signals the change in value of the instrumental stimulus. Although NCL plays a key role for extinction learning, other structures can subsume similar functions after postlesional regeneration.
Motion Parallax Is Computed in the Updating of Human Spatial Memory
Authors: Medendorp W. Pieter , Tweed Douglas B. , Crawford J. Douglas
Published: April 2018

As we move through space, stationary objects around us show motion parallax: their directions relative to us change at different rates, depending on their distance. Does the brain incorporate parallax when it updates its stored representations of space? We had subjects fixate a distant target and then we flashed lights, at different distances, onto the retinal periphery. Subjects translated sideways while keeping their gaze on the distant target, and then they looked to the remembered location of the flash. Their responses corrected almost perfectly for parallax: they turned their eyes farther for nearer targets, in the predicted nonlinear patterns. Computer simulations suggest a neural mechanism in which feedback about self-motion updates remembered locations of objects within an internal map of three-dimensional visual space.
Analysis of Neurons Created from Wild-Type and Alzheimer's Mutation Knock-In Embryonic Stem Cells by a Highly Efficient Differentiation Protocol
Authors: Abe Yoichiro , Kouyama Keisuke , Tomita Taisuke , Tomita Yusuke , Ban Norimitsu , Nawa Mikiro , Matsuoka Masaaki , Niikura Takako , Aiso Sadakazu , Kita Yoshiko , Iwatsubo Takeshi , Nishimoto Ikuo
Published: April 2018

It is impossible to obtain and amplify live neurons from Alzheimer's disease (AD) patients. To establish the neurons harboring AD abnormality, we constructed mouse embryonic stem (ES) cells, in which the AD-causative V642I mutation was introduced to the endogenous amyloid precursor protein (APP) gene, in combination with a protocol to efficiently differentiate ES cells into postmitotic neurons without using a cell sorter. By this protocol, ES cells differentiated into >90% of the central type of adult postmitotic neurons. Neurons derived from V642I–APP knock-in ES cells were indistinguishable from wild-type ES-derived neurons, as determined by the expression of various markers for neuronal differentiation. Notably, V642I–APP knock-in ES cell-derived neurons exhibited significantly increased secretion of Aβ42 without AD-related hyperphosphorylation of tau, indicating that the direct output of the AD-causative mutation is increased Aβ42 secretion. In this study, we analyze created neurons with wild-type and AD genotypes and propose a new strategy for generating neurons for any dominantly inherited neurodegenerative diseases. The strategy can be applied to create human neurons with AD or any other neurodegenerative disease by using human ES cells.
Supralinear Ca2+Influx into Dendritic Tufts of Layer 2/3 Neocortical Pyramidal NeuronsIn VitroandIn Vivo
Authors: Waters Jack , Larkum Matthew , Sakmann Bert , Helmchen Fritjof
Published: April 2018

Pyramidal neurons in layer 2/3 of the neocortex are central to cortical circuitry, but the intrinsic properties of their dendrites are poorly understood. Here we study layer 2/3 apical dendrites in parallel experiments in acute brain slices and in anesthetized rats using whole-cell recordings and Ca2+imaging. We find that backpropagation of action potentials into the dendritic arbor is actively supported by Na+channels bothin vitroandin vivo. Single action potentials evoke substantial Ca2+influx in the apical trunk but little or none in the dendritic tuft. Supralinear Ca2+influx is produced in the tuft, however, when an action potential is paired with synaptic input. This dendritic supralinearity enables layer 2/3 neurons to integrate ascending sensory input from layer 4 and associative input to layer 1.
Metabolic Regulation of Fertility through Presynaptic and Postsynaptic Signaling to Gonadotropin-Releasing Hormone Neurons
Authors: Sullivan Shannon D. , DeFazio R. Anthony , Moenter Suzanne M.
Published: April 2018

Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for the central regulation of reproduction and are inhibited by negative energy balance. In normal adults, these neurons maintain elevated intracellular chloride so that GABAAreceptor activation is excitatory. We hypothesized that fasting alters homeostatic mechanisms to eliminate excitatory responses to GABA but rejected this hypothesis when brief, local GABA application elicited action currents in GnRH neurons from fed and fasted mice. This response was specific to GABAAreceptors, because glycine elicited no response. We next found that fasting reduced the frequency of spontaneous GABAergic postsynaptic currents (PSCs) and that this was reversed byin vivotreatment with leptin during the fast. In the presence of tetrodotoxin to minimize presynaptic actions, leptin also potentiated the postsynaptic response of these cells to GABAAreceptor activation. Postsynaptic effects of leptin on GABAergic miniature PSCs were eliminated by inhibiting JAK2/3 (Janus kinase), the tyrosine kinase through which leptin receptors signal. In all experiments, elimination of PSCs at EClor by treatment with the GABAAreceptor antagonist bicuculline confirmed that PSCs were specifically mediated by GABAAreceptor chloride channels. These data demonstrate that fasting and leptin act presynaptically and postsynaptically to alter GABAergic drive to GnRH neurons, providing evidence for GABAergic communication of metabolic cues to GnRH neurons, and suggest the possibility for functional leptin receptors on GnRH neurons. They further demonstrate cytokine modulation of the postsynaptic response to GABA in mammals, which may be important to central neural regulation in both healthy and diseased states.
Enhanced Oligodendrocyte Survival after Spinal Cord Injury in Bax-Deficient Mice and Mice with Delayed Wallerian Degeneration
Authors: Dong Hongxin , Fazzaro Alicia , Xiang Chuanxi , Korsmeyer Stanley J. , Jacquin Mark F. , McDonald John W.
Published: April 2018

Mechanisms of oligodendrocyte death after spinal cord injury (SCI) were evaluated by T9 cord level hemisection in wild-type mice (C57BL/6J andBax+/+ mice), Wldsmice in which severed axons remain viable for 2 weeks, and mice deficient in the proapoptotic protein Bax (Bax-/-). In the lateral white-matter tracts, substantial oligodendrocyte death was evident in the ipsilateral white matter 3-7 mm rostral and caudal to the hemisection site 8 d after injury. Ultrastructural analysis and expression of anti-activated caspase-3 characterized the ongoing oligodendrocyte death at 8 d as primarily apoptotic. Oligodendrocytes were selectively preserved in Wldsmice compared with C57BL/6J mice at 8 d after injury, when severed axons remained viable as verified by antereograde labeling of the lateral vestibular spinal tract. However, 30 d after injury when the severed axons in Wldsanimals were already degenerated, the oligodendrocytes preserved at 8 d were lost, and numbers were then equivalent to control C57BL/6J mice.

In contrast, oligodendrocyte death was prevented at both time points inBax-/- mice. When cultured oligodendrocytes were exposed to staurosporine or cyclosporin A, drugs known to stimulate apoptosis in oligodendrocytes, those fromBax-/- mice but not fromBax+/+ orBax+/- mice were resistant to the apoptotic death. In contrast, the three groups were equally vulnerable to excitotoxic necrosis death induced by kainate. On the basis of these data, we hypothesize that the Wallerian degeneration of white matter axons that follows SCI removes axonal support and induces apoptotic death in oligodendrocytes by triggering Bax expression.
Interleukin-1β Enhances NMDA Receptor-Mediated Intracellular Calcium Increase through Activation of the Src Family of Kinases
Authors: Viviani B. , Bartesaghi S. , Gardoni F. , Vezzani A. , Behrens M. M. , Bartfai T. , Binaglia M. , Corsini E. , Di Luca M. , Galli C. L. , Marinovich M.
Published: April 2018

Interleukin (IL)-1β is a proinflammatory cytokine implicated in various pathophysiological conditions of the CNS involving NMDA receptor activation. Circumstantial evidence suggests that IL-1β and NMDA receptors can functionally interact. Using primary cultures of rat hippocampal neurons, we investigated whether IL-1β affects NMDA receptor function(s) by studying (1) NMDA receptor-induced [Ca2+]iincrease and (2) NMDA-mediated neurotoxicity. IL1β (0.01-0.1 ng/ml) dose-dependently enhances NMDA-induced [Ca2+]iincreases with a maximal effect of ∼45%. This effect occurred only when neurons were pretreated with IL-1β, whereas it was absent if IL-1β and NMDA were applied simultaneously, and it was abolished by IL-1 receptor antagonist (50 ng/ml). Facilitation of NMDA-induced [Ca2+]iincrease by IL-1β was prevented by both lavendustin (LAV) A (500 nm) and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) (1 μm), suggesting an involvement of tyrosine kinases. Increased tyrosine phosphorylation of NMDA receptor subunits 2A and 2B and coimmunoprecipitation of activated Src tyrosine kinase with these subunits was observed after exposure of hippocampal neurons to 0.05 ng/ml IL-1β. Finally, 0.05 ng/ml IL-1β increased by ∼30% neuronal cell death induced by NMDA, and this effect was blocked by both lavendustin A and PP2.

These data suggest that IL-1β increases NMDA receptor function through activation of tyrosine kinases and subsequent NR2A/B subunit phosphorylation. These effects may contribute to glutamate-mediated neurodegeneration.
Chronic Neurotrophin-3 Strengthens Synaptic Connections to Motoneurons in the Neonatal Rat
Authors: Arvanian Victor L. , Horner Philip J. , Gage Fred H. , Mendell Lorne M.
Published: April 2018

We report that neurotrophin-3 (NT-3), delivered chronically via fibroblasts implanted intrathecally into neonatal rats, can facilitate synaptic transmission in the spinal cord. A small collagen plug containing NT-3-secreting fibroblasts was placed on the exposed dorsal surface of the spinal cord (L1) of 2-d-old rats; controls received β-galactosidase-secreting fibroblasts. After 6 hr to 12 d of survival, synaptic potentials (EPSP) elicited by two synaptic inputs, L5 dorsal root and ventrolateral funiculus (VLF), were recorded intracellularly in L5 motoneuronsin vitro. Preparations treated with NT-3 implants exhibited enhanced monosynaptic synaptic transmission from both inputs, which persisted over the entire testing period. Unlike acute enhancement of transmission by NT-3 (Arvanian and Mendell, 2001a), the chronic effect could occur at connections not normally eliciting an NMDA receptor-mediated response at the time of NT-3 exposure. Using susceptibility to blockade of the NMDA receptor by Mg2+and APV, we confirmed that chronic treatment with NT-3 did not enhance NMDA receptor activity at these connections. Cords treated with chronic NT-3 also transiently displayed polysynaptic components activated by VLF that were blocked by the NMDA receptor antagonist APV. These novel NMDA receptor-mediated potentials may reflect changes in interneurons near the site of fibroblast implantation. We conclude that chronic NT-3 enhances the potency of segmental and descending projections via mechanisms different from those underlying acute changes.
Proteasome Inhibition Stabilizes Tau Inclusions in Oligodendroglial Cells that Occur after Treatment with Okadaic Acid
Authors: Goldbaum Olaf , Oppermann Malte , Handschuh Melanie , Dabir Deepa , Zhang Bin , Forman Mark S. , Trojanowski John Q. , Lee Virginia M.-Y. , Richter-Landsberg Christiane
Published: April 2018

Tau-positive inclusions in oligodendrocytes are consistent neuropathological features of corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementias with Parkinsonism linked to chromosome 17. Here we show by immunohistochemistry that tau-positive oligodendroglial inclusion bodies also contain the small heat-shock protein (HSP) αB-crystallin but not HSP70. To study the molecular mechanisms underlying inclusion body formation, we engineered an oligodendroglia cell line (OLN-t40) to overexpress the longest human tau isoform. Treatment of OLN-t40 cells with okadaic acid (OA), an inhibitor of protein phosphatase 2A, caused tau hyperphosphorylation and a decrease in the binding of tau to microtubules. Simultaneously, tau-positive aggregates that also stained with the amyloid-binding dye thioflavin-S as well as with antibodies to tau and αB-crystallin were detected. However, they were only transiently expressed and were degraded within 24 hr. When the proteasomal apparatus was inhibited by carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (MG-132) after OA treatment, the aggregates were stabilized and were still detectable after 18 hr in the absence of OA. Incubation with MG-132 alone inhibited tau proteolysis and led to the induction of HSPs, including αB-crystallin and to its translocation to the perinuclear region, but did not induce the formation of thioflavin-S-positive aggregates. Hence, although tau hyperphosphorylation induced by protein phosphatase inhibition contributes to pathological aggregate formation, only hyperphosporylation of tau followed by proteasome inhibition leads to stable fibrillary deposits of tau similar to those observed in neurodegenerative diseases.
Organization of the Visual Cortex in Human Albinism
Authors: Hoffmann Michael B. , Tolhurst David J. , Moore Anthony T. , Morland Antony B.
Published: April 2018

In albinism there is an abnormal projection of part of the temporal retina to the visual cortex contralateral to the eye. This projection, together with the normally routed fibers from nasal retina, provides a cortical hemisphere with visual input from more than the normal hemifield of visual space. In many mammalian models of albinism, a possible sensory mismatch in the visual cortex is avoided either by reorganization of the thalamocortical connections to give the abnormal input an exclusive cortical representation, or by the abnormal input being substantially suppressed. In this study we examine, with fMRI, how the human visual cortex topographically maps its input in albinism. We find that the input from temporal retina is not substantially suppressed and forms a retinotopic mapping that is superimposed on the mapping of the nasal retina in striate and extrastriate areas. The abnormal routing of temporal fibers is not total, with the line of decussation shifting to between 6 and 14° into temporal retina. Our results indicate that the abnormal input to visual cortex in human albinism does not undergo topographic reorganization between the thalamus and cortex. Furthermore, the abnormal input is not significantly suppressed in either striate or extrastriate areas. The topographic mapping that we report in human does not conform, therefore, to the commonly observed patterns in other mammals but takes the form of the “true albino” pattern that has been reported rarely in cat and in the only other individual primate studied.
Glutamate and Amyloid β-Protein Rapidly Inhibit Fast Axonal Transport in Cultured Rat Hippocampal Neurons by Different Mechanisms
Authors: Hiruma Hiromi , Katakura Takashi , Takahashi Sanae , Ichikawa Takafumi , Kawakami Tadashi
Published: April 2018

Impairment of axonal transport leads to neurodegeneration and synapse loss. Glutamate and amyloid β-protein (Aβ) have critical roles in the pathogenesis of Alzheimer's disease (AD). Here we show that both agents rapidly inhibit fast axonal transport in cultured rat hippocampal neurons. The effect of glutamate (100 μm), but not of Aβ25-35(20 μm), was reversible, was mimicked by NMDA or AMPA, and was blocked by NMDA and AMPA antagonists and by removal of extracellular Ca2+. The effect of Aβ25-35was progressive and irreversible, was prevented by the actin-depolymerizing agent latrunculin B, and was mimicked by the actin-polymerizing agent jasplakinolide. Aβ25-35induced intracellular actin aggregation, which was prevented by latrunculin B. Aβ31-35but not Aβ15-20exerted effects similar to those of Aβ25-35. Full-length Aβ1-42incubated for 7 d, which specifically contained 30-100 kDa molecular weight assemblies, also caused an inhibition of axonal transport associated with intracellular actin aggregation, whereas freshly dissolved Aβ1-40, incubated Aβ1-40, and fresh Aβ1-42had no effect. These results suggest that glutamate inhibits axonal transport via activation of NMDA and AMPA receptors and Ca2+influx, whereas Aβ exerts its inhibitory effect via actin polymerization and aggregation. The ability of Aβ to inhibit axonal transport seems to require active amino acid residues, which is probably present in the 31-35 sequence. Full-length Aβ may be effective when it represents a structure in which these active residues can access the cell membrane. Our results may provide insight into the early pathogenetic mechanisms of AD.
The β3 Nicotinic Receptor Subunit: A Component of α-Conotoxin MII-Binding Nicotinic Acetylcholine Receptors that Modulate Dopamine Release and Related Behaviors
Authors: Cui Changhai , Booker T. K. , Allen Roberta S. , Grady Sharon R. , Whiteaker Paul , Marks Michael J. , Salminen Outi , Tritto Theresa , Butt Christopher M. , Allen W. R. , Stitzel Jerry A. , McIntosh J. Michael , Boulter Jim , Collins Allan C. , Heinemann Stephen F.
Published: April 2018

Nigrostriatal dopaminergic neurons express many nicotinic acetylcholine receptor (nAChR) subunits capable of forming multiple nAChR subtypes. These subtypes are expressed differentially along the neuron and presumably mediate diverse responses. β3 subunit mRNA has restricted expression but is abundant in the substantia nigra and ventral tegmental areas. To investigate the potential role(s) of nicotinic receptors containing the β3 subunit in dopaminergic tracts, we generated mice with a null mutation in the β3 gene. We were thereby able to identify a population of β3-dependent α-conotoxin MII-binding nAChRs that modulate striatal dopamine release. Changes were also observed in locomotor activity and prepulse inhibition of acoustic startle, behaviors that are controlled, in part, by nigrostriatal and mesolimbic dopaminergic activity, respectively, suggesting that β3-containing nAChRs modulate these behaviors.
The Prefrontal Cortex Regulates Lateral Amygdala Neuronal Plasticity and Responses to Previously Conditioned Stimuli
Authors: Rosenkranz J. Amiel , Moore Holly , Grace Anthony A.
Published: April 2018

The amygdala plays a role in learning and memory processes that involve an emotional component. However, neural structures that regulate these amygdala-dependent processes are unknown. Previous studies indicate that regulation of affect may be imposed by the prefrontal cortex (PFC) and its efferents to the amygdala. The presentation of conditioned affective stimuli enhances activity of neurons in the lateral nucleus of the amygdala (LAT), which is thought to drive conditioned affective responses. Moreover, plasticity of LAT neuronal responses to stimuli during the course of conditioning is believed to underlie affective learning. This study examines the role of the PFC in the regulation of affective behaviors by evaluating how the PFC affects LAT neuronal plasticity and activity that is evoked by previously conditioned stimuli.In vivointracellular recordings were performed from the LAT of anesthetized rats during pavlovian conditioning and during the presentation of stimuli that were conditioned in the awake rat before recording. Train stimulation of the PFC suppressed LAT neuronal activity that was evoked by both previously conditioned and neutral stimuli. In addition, PFC stimulation blocked LAT neuronal plasticity associated with an affective conditioning procedure. These results indicate that the PFC has the potential to regulate affective processes by inhibition of the LAT. Patients with disruptions of the PFC-LAT interaction often display an inability to regulate affective responses. This may be attributable to the loss of PFC-imposed inhibition of the emotional response to a stimulus but may also include the formation or diminished extinction of inappropriate associations.
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Protect Cortical Neurons from Excitotoxicity
Authors: Zacco Anna , Togo James , Spence Katherine , Ellis Amanda , Lloyd Darlene , Furlong Steve , Piser Timothy
Published: April 2018

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, reduce the incidence of strokes and reduce infarct volume after cerebral ischemia in mice. Excitoxicity caused by overstimulation of glutamate receptors is a major cause of neuronal death after an ischemic brain insult. Experiments presented here explored whether statins protect cultured neurons from excitotoxic death caused by the glutamate receptor agonist NMDA. Treatment with statins preserved NMDA receptor-expressing cortical neurons and potently and substantially reduced lactate dehydrogenase release caused by exposure of embryonic mouse neocortical cultures to NMDA. The rank order of neuroprotective potency was rosuvastatin = simvastatin > atorvastatin = mevastatin > pravastatin, which is similar to the known rank order of potency for inhibition of the HMG-CoA reductase enzyme. Resistance of cultures to NMDA excitotoxicity developed after several days of statin exposure. Neuroprotection by rosuvastatin was coincident with a decrease in cell sterols and occurred with a similar potency as inhibition of cholesterol biosynthesis. Neuroprotection was substantially attenuated by cotreatment with either mevalonate or cholesterol and was mimicked by acute treatment with the cholesterol-extracting agent β-cyclodextrin, suggesting that neuroprotection was mediated by depletion of a cellular pool of cholesterol because of the inhibition of cholesterol biosynthesis. These results suggest the possibility that, in addition to effects on cerebrovascular function, statins have the potential to render cortical neurons more resistant to NMDA-induced excitotoxic death as a result of changes in cell cholesterol homeostasis.
Lesions of the Orbitofrontal but not Medial Prefrontal Cortex Disrupt Conditioned Reinforcement in Primates
Authors: Pears Andrew , Parkinson John A. , Hopewell Lucy , Everitt Barry J. , Roberts Angela C.
Published: April 2018

The ventromedial prefrontal cortex (PFC) is implicated in affective and motivated behaviors. Damage to this region, which includes the orbitofrontal cortex as well as ventral sectors of medial PFC, causes profound changes in emotional and social behavior, including impairments in certain aspects of decision making. One reinforcement mechanism that may well contribute to these behaviors is conditioned reinforcement, whereby previously neutral stimuli in the environment, by virtue of their association with primary rewards, take on reinforcing value and come to support instrumental action. Conditioned reinforcers are powerful determinants of behavior and can maintain responding over protracted periods of time in the absence of and potentially in conflict with primary reinforcers. It has already been shown that conditioned reinforcement is dependent on the amygdala, and because the amygdala projects to both the orbitofrontal cortex and the medial PFC, the present study determined whether conditioned reinforcement was also dependent on one or the other of these prefrontal regions. Comparison of the behavioral effects of selective excitotoxic lesions of the PFC in the common marmoset revealed that orbitofrontal but not medial PFC lesions disrupted two distinct measures of conditioned reinforcement: (1) acquisition of a new response and (2) sensitivity to conditioned stimulus omission on a second-order schedule. In contrast, the orbitofrontal lesion did not affect sensitivity to primary reinforcement as measured by responding on a progressive-ratio schedule and a home cage consumption test. Together, these findings demonstrate the critical and specific involvement of the orbitofrontal cortex but not the medial PFC in conditioned reinforcement.
Presynaptic Ryanodine-Sensitive Calcium Stores Contribute to Evoked Neurotransmitter Release at the Basket Cell-Purkinje Cell Synapse
Authors: Galante Micaela , Marty Alain
Published: April 2018

Presynaptic terminals of cerebellar basket cells are known to contain ryanodine-sensitive calcium stores (RyCSs); recently, it has been shown that these stores control the frequency of miniature synaptic currents in the absence of presynaptic spiking. Here, using paired recordings of basket cell-Purkinje cell synapses, we show that blocking the RyCSs with high concentration of ryanodine decreases the mean amplitude of evoked IPSCs to 70% of the control value. The paired-pulse ratio and failure rate increase, indicating that the reduction stems from a decreased probability of evoked neurotransmitter release. Various control experiments eliminate the possibility of an indirect effect of ryanodine via activation of postsynaptic receptors. Prolonged application of cyclopiazonic acid, a blocker of the endoplasmic reticulum calcium pump, totally abolishes the ryanodine action. Our results indicate that calcium released from presynaptic RyCSs enhances the amplitude of evoked GABAergic synaptic currents. The precise mechanism by which calcium released from internal stores affect action potential-dependent release is unknown; however, our results suggest that these stores do not provide additional calcium for each presynaptic action potential; rather, they appear to enhance depolarization-induced calcium signals indirectly, perhaps by increasing the basal level of cytosolic calcium concentration in the vicinity of release sites.
Control of Secretion by Temporal Patterns of Action Potentials in Adrenal Chromaffin Cells
Authors: Duan Kailai , Yu Xiao , Zhang Chen , Zhou Zhuan
Published: April 2018

Action potentials (APs) are the principal physiological stimuli for neurotransmitter secretion in neurons. Most studies on stimulus-secretion coupling have been performed under voltage clamp using artificial electrical stimuli. To investigate the modulatory effects of AP codes on neural secretion, we introduce a capacitance method to study AP-induced secretion in single cells. The action potential pattern was defined by a four-parameter “code function:”F(n, m, f, d). With this method, cell secretion evoked by stimulation with an AP code was quantified in real time by membrane capacitance (Cm) in adrenal chromaffin cells. We found, in addition to AP frequency (f), for a given number of APs, another parameter of the AP code, the number of AP bursts (m) in which the set of APs occurs, can effectively modulate cell secretion. Possible mechanisms of themeffect are depletion of the readily releasable pool and inactivation of Ca2+channels during a burst of APs. The physiologicalmeffect may play a key role in AP-mediated neural information transfer within a single neuron and among the elements of a neural network.
Distribution of Postsynaptic Density (PSD)-95 and Ca2+/Calmodulin-Dependent Protein Kinase II at the PSD
Authors: Petersen Jennifer D. , Chen Xiaobing , Vinade Lucia , Dosemeci Ayse , Lisman John E. , Reese Thomas S.
Published: April 2018

Postsynaptic densities (PSDs) contain proteins that regulate synaptic transmission. We determined the positions of calcium/calmodulin-dependent protein kinase II (CaMKII) and PSD-95 within the three-dimensional structure of isolated PSDs using immunogold labeling, rotary shadowing, and electron microscopic tomography. The results show that all PSDs contain a central mesh immediately underlying the postsynaptic membrane. Label for PSD-95 is found on both the cytoplasmic and cleft sides of this mesh, averaging 12 nm from the cleft side. All PSDs label for PSD-95. The properties of CaMKII labeling are quite different. Label is virtually absent on the cleft sides of PSDs, but can be heavy on the cytoplasmic side at a mean distance of 25 nm from the cleft. In tomograms, CaMKII holoenzymes can be visualized directly, appearing as labeled, tower-like structures reflecting the 20 nm diameter of the holoenzyme. These towers protrude from the cytoplasmic side of the central mesh. There appears to be a local organization of CaMKII, as judged by fact that the nearest-neighbor distances are nearly invariant over a wide range of labeling density for CaMKII. The average density of CaMKII holoenzymes is highly variable, ranging from zero to values approaching a tightly packed state. This variability is significantly higher than that for PSD-95 and is consistent with an information storage role for CaMKII.
A case with relapsed transient neonatal diabetes mellitus treated with sulfonylurea, ending chronic insulin requirement
Authors: Ando Akihiko , Nagasaka Shoichiro , Ishibashi Shun
Published: April 2018

We report a case of a woman with diabetes mellitus caused by a genetic defect in ABCC8-coding sulfonylurea receptor 1 (SUR1), a subunit of the ATP-sensitive potassium (KATP) channel protein. She was diagnosed with diabetes at 7 days after birth. After intravenous insulin drip for 1 month, her hyperglycaemia remitted. At the age of 13 years, her diabetes relapsed, and after that she had been treated by intensive insulin therapy for 25 years with relatively poor glycaemic control. She was switched to oral sulfonylurea therapy and attained euglycaemia. In addition, her insulin secretory capacity was ameliorated gradually.

Learning points:

Genetic testing should be considered in any individuals or family with diabetes that occurred within the first year or so of life.

Sulfonylurea can achieve good glycaemic control in patients with KATP channel mutations by restoring endogenous insulin secretion, even if they were treated with insulin for decades.

Early screening and genetic testing are important to improve the prognosis of patients with neonatal diabetes mellitus arising from ABCC8 or KCNJ11 mutation.
One too many diabetes: the combination of hyperglycaemic hyperosmolar state and central diabetes insipidus
Authors: Burmazovic Snezana , Henzen Christoph , Brander Lukas , Cioccari Luca
Published: April 2018

The combination of hyperosmolar hyperglycaemic state and central diabetes insipidus is unusual and poses unique diagnostic and therapeutic challenges for clinicians. In a patient with diabetes mellitus presenting with polyuria and polydipsia, poor glycaemic control is usually the first aetiology that is considered, and achieving glycaemic control remains the first course of action. However, severe hypernatraemia, hyperglycaemia and discordance between urine-specific gravity and urine osmolality suggest concurrent symptomatic diabetes insipidus. We report a rare case of concurrent manifestation of hyperosmolar hyperglycaemic state and central diabetes insipidus in a patient with a history of craniopharyngioma.

Learning points:

In patients with diabetes mellitus presenting with polyuria and polydipsia, poor glycaemic control is usually the first aetiology to be considered.

However, a history of craniopharyngioma, severe hypernatraemia, hyperglycaemia and discordance between urine-specific gravity and osmolality provide evidence of concurrent diabetes insipidus.

Therefore, if a patient with diabetes mellitus presents with severe hypernatraemia, hyperglycaemia, a low or low normal urinary-specific gravity and worsening polyuria despite correction of hyperglycaemia, concurrent diabetes insipidus should be sought.
Predictive score for the development or progression of Graves’ orbitopathy in patients with newly diagnosed Graves’ hyperthyroidism
Authors: Wiersinga Wilmar , Žarković Miloš , Bartalena Luigi , Donati Simone , Perros Petros , Okosieme Onyebuchi , Morris Daniel , Fichter Nicole , Lareida Jurg , von Arx Georg , Daumerie Chantal , Burlacu Maria-Christina , Kahaly George , Pitz Susanne , Beleslin Biljana , Ćirić Jasmina , Ayvaz Goksun , Konuk Onur , Törüner Füsun Balos̜ , Salvi Mario , Covelli Danila , Curro Nicola , Hegedüs Laszlo , Brix Thomas , _ _
Published: April 2018

Objective

To construct a predictive score for the development or progression of Graves’ orbitopathy (GO) in Graves’ hyperthyroidism (GH).

Design

Prospective observational study in patients with newly diagnosed GH, treated with antithyroid drugs (ATD) for 18 months at ten participating centers from EUGOGO in 8 European countries.

Methods

348 patients were included with untreated GH but without obvious GO. Mixed effects logistic regression was used to determine the best predictors. A predictive score (called PREDIGO) was constructed.

Results

GO occurred in 15% (mild in 13% and moderate to severe in 2%), predominantly at 6–12 months after start of ATD. Independent baseline determinants for the development of GO were clinical activity score (assigned 5 points if score > 0), TSH-binding inhibitory immunoglobulins (2 points if TBII 2–10 U/L, 5 points if TBII > 10 U/L), duration of hyperthyroid symptoms (1 point if 1–4 months, 3 points if >4 months) and smoking (2 points if current smoker). Based on the odds ratio of each of these four determinants, a quantitative predictive score (called PREDIGO) was constructed ranging from 0 to 15 with higher scores denoting higher risk; positive and negative predictive values were 0.28 (95% CI 0.20–0.37) and 0.91 (95% CI 0.87–0.94) respectively.

Conclusions

In patients without GO at diagnosis, 15% will develop GO (13% mild, 2% moderate to severe) during subsequent treatment with ATD for 18 months. A predictive score called PREDIGO composed of four baseline determinants was better in predicting those patients who will not develop obvious GO than who will.
LECT2 promotes inflammation and insulin resistance in adipocytes via P38 pathways
Authors: Jung Tae Woo , Chung Yoon Hee , Kim Hyoung-Chun , Abd El-Aty A M , Jeong Ji Hoon
Published: April 2018

Leukocyte cell-derived chemotaxin 2 (LECT2) is a recently identified novel hepatokine that causes insulin resistance in skeletal muscle by activating c-Jun N-terminal kinase (JNK), thereby driving atherosclerotic inflammation. However, the role of LECT2 in inflammation and insulin resistance in adipocytes has not been investigated. In this study, we report that LECT2 treatment of differentiated 3T3-L1 cells stimulates P38 phosphorylation in a dose-dependent manner. LECT2 also enhanced inflammation markers such as IκB phosphorylation, nuclear factor kappa beta (NF-κB) phosphorylation and IL-6 expression. Moreover, LECT2 treatment impaired insulin signaling in differentiated 3T3-L1 cells, as evidenced by the decreased levels of insulin receptor substrate (IRS-1) and Akt phosphorylation and reduced insulin-stimulated glucose uptake. Furthermore, LECT2 augmented lipid accumulation during 3T3-L1 cell differentiation by activating SREBP1c-mediated signaling. All these effects were significantly abrogated by siRNA-mediated silencing of P38, CD209 expression or a JNK inhibitor. Our findings suggest that LECT2 stimulates inflammation and insulin resistance in adipocytes via activation of a CD209/P38-dependent pathway. Thus, these results suggest effective therapeutic targets for treating inflammation-mediated insulin resistance.
Evaluation of an Experimental Virtual Learning Environment of Winemaking for Middle School and College Students in Chile
Authors: Fredes Claudio , Espinoza Sergio
Published: April 2018

BITWINE is a virtual learning environment (VLE) that was aimed to develop work competencies in the winemaking industry based on Chilean winemaking work standards. This paper analyzed the learning of the winemaking process as well as the likeability and functionality of BITWINE for university and technical school students. The learning with BITWINE was tested through quasi-experimental tests for groups control (with BITWINE) and experimental (without BIWINE) with written assessment. Furthermore, functionality and likeability perceptions, obtained through written surveys, are analyzed and discussed. The results showed that those students who used BITWINE improved their learning. The perception of BITWINE likeability demonstrated that it was well designed. The studied VLE also contributed to teach how to work with appropriate norms of traceability, hygiene and work safety. However, although BITWINE was quite appreciated as an e-learning tool, it still requires better information and communications technology conditions to be functional.
La evaluación externa: Un mecanismo para garantizar la calidad de la educación superior en Costa Rica
Authors: Torres-Salas María Isabel , García-Rojas Andrea , Alvarado-Arguedas Andrea
Published: April 2018

This study aims to show that the accreditation involves a dynamic and complex process. The accreditation allows the improvement of higher education because it ensures and promotes quality in all the aspects that compose this educational level. This bibliographic review article considered a range of criteria concerning the standards accrediting bodies use to have self-assessments made. These criteria are associated with different experiences carried out both in Costa Rica and in other Latin American countries. In addition, this article proposes a reflection on the different mechanisms used to evaluate the quality in higher education institutions, as well as an analysis on the role of accreditation in these public universities versus the quality systems and the ways to promote the development of an institutional culture that leads to quality processes in Costa Rica. Among the main findings, the study showed that these processes put in evidence the strengths and weaknesses of the careers or institutions that undergo the accreditation, which allows the implementation of improvement plans leading to a continuously improving process that is subject to external verification following established criteria and standards.
Wo steht der Selektivvertrieb?
Authors: Lubberger Andreas
Published: April 2018

Das Coty-Urteil des Europäischen Gerichtshofs vom Dezember 2017 wirft die Frage nach dem Spannungsverhältnis zwischen dem Selektivvertrieb und dem Kartellverbot neu auf. Für die rechtliche Ausgestaltung dieses Verhältnisses hat der heute vieldiskutierte Luxusbegriff keine Bedeutung. Maßgeblich sind die Begründungsmodelle für den Selektivvertrieb, die diesen entweder kartellrechtlich unter Kontrolle bringen oder ganz vom Kartellverbot befreien können. Auf der Grundlage dieser Modelle öffnet sich dann ein anderer Blick auf die beiden wichtigsten Fragen der Praxis nach (1) der Abgrenzung von selektiven und nicht-selektiven Absatzgebieten und (2) der Zulässigkeit von Beschränkungen des Onlinehandels.
Impulsivity traits and addiction-related behaviors in youth
Authors: Rømer Thomsen Kristine , Callesen Mette Buhl , Hesse Morten , Kvamme Timo Lehmann , Pedersen Michael Mulbjerg , Pedersen Mads Uffe , Voon Valerie
Published: April 2018

Background and aims

Impulsivity is a risk factor for addictive behaviors. The UPPS-P impulsivity model has been associated with substance addiction and gambling disorder, but its role in other non-substance addiction-related behaviors is less understood. We sought to examine associations between UPPS-P impulsivity traits and indicators of multiple substance and non-substance addiction-related behaviors in youth with varying involvement in these behaviors.

Methods

Participants (N = 109, aged 16–26 years, 69% males) were selected from a national survey based on their level of externalizing problems to achieve a broad distribution of involvement in addiction-related behaviors. Participants completed the UPPS-P Questionnaire and standardized questionnaires assessing problematic use of substances (alcohol, cannabis, and other drugs) and non-substances (Internet gaming, pornography, and food). Regression analyses were used to assess associations between impulsivity traits and indicators of addiction-related behaviors.

Results

The UPPS-P model was positively associated with indicators of all addiction-related behaviors except problematic Internet gaming. In the fully adjusted models, sensation seeking and lack of perseverance were associated with problematic use of alcohol, urgency was associated with problematic use of cannabis, and lack of perseverance was associated with problematic use of other drugs than cannabis. Furthermore, urgency and lack of perseverance were associated with binge eating and lack of perseverance was associated with problematic use of pornography.

Discussion and conclusions

We emphasize the role of trait impulsivity across multiple addiction-related behaviors. Our findings in at-risk youth highlight urgency and lack of perseverance as potential predictors for the development of addictions and as potential preventative therapeutic targets.