bluuebunny/crossref_metadata_2025 huggingface dataset:
Target-Specific Neuropeptide Y-Ergic Synaptic Inhibition and Its Network Consequences within the Mammalian Thalamus
Authors: Sun Qian-Quan , Baraban Scott C. , Prince David A. , Huguenard John R.
Published: April 2018

Neuropeptides are commonly colocalized with classical neurotransmitters, yet there is little evidence for peptidergic neurotransmission in the mammalian CNS. We performed whole-cell patch-clamp recording from rodent thalamic brain slices and repetitively stimulated corticothalamic fibers to strongly activate NPY-containing GABAergic reticular thalamic (RT) neurons. This resulted in long-lasting (∼10 sec) feedforward slow IPSPs (sIPSPs) in RT cells, which were mimicked and blocked by NPY1(Y1) receptor agonists and antagonists, respectively, and were present in wild-type mice but absent in NPY-/-mice. NPYergic sIPSPs were mediated via G-proteins and G-protein-activated, inwardly rectifying potassium channels, as evidenced by sensitivity to GDP-β-S and 0.1 mmBa2+. In rat RT neurons, NPYergic sIPSPs were also present but were surprisingly absent in the major synaptic targets of RT, thalamic relay neurons, where instead robust GABABIPSPs occurred.In vitrooscillatory network responses in rat thalamus were suppressed and augmented by Y1agonists and antagonists, respectively. These findings provide evidence for segregation of postsynaptic actions between two targets of RT cells and support a role for endogenously released NPY within RT in the regulation of oscillatory thalamic responses relevant to sleep and epilepsy.
Lmx1b, Pet-1, andNkx2.2Coordinately Specify Serotonergic Neurotransmitter Phenotype
Authors: Cheng Leping , Chen Chih-Li , Luo Ping , Tan Min , Qiu Mengsheng , Johnson Randy , Ma Qiufu
Published: April 2018

Serotonergic (5-HT) neurons in the brainstem modulate a wide range of physiological processes and behaviors. Two transcription factor genes,Pet-1andNkx2.2, are necessary but not sufficient to specify the 5-HT transmitter phenotype. Here we show that the Lim class homeobox geneLmx1bis required for proper formation of the entire 5-HT system in the hindbrain, as indicated by the loss of expression of genes necessary for serotonin synthesis and transport inLmx1bnull mice. Lmx1b and Pet1 act downstream of Nkx2.2, and their expression is independently regulated at the time when 5-HT transmitter phenotype is specified. Ectopic expression ofLmx1bplusPet-1is able to induce formation of 5-HT cells in the most ventral spinal cord, whereNkx2.2is normally expressed. Combined expression of all three genes,Lmx1b, Pet-1, andNkx2.2, drives 5-HT differentiation in the dorsal spinal cord. Our studies therefore define a molecular pathway necessary and sufficient to specify the serotonergic neurotransmitter phenotype.
The Role of the Ankyrin-Binding Protein NrCAM in Node of Ranvier Formation
Authors: Custer Andrew W. , Kazarinova-Noyes Katia , Sakurai Takeshi , Xu Xiaorong , Simon William , Grumet Martin , Shrager Peter
Published: April 2018

Molecular events involved in Na+channel clustering at the node of Ranvier have been investigated during early development. NrCAM, an ankyrinG-binding protein, precedes Na+channels at cluster sites adjacent to the tips of Schwann cell processes. Both Na+channel and ankyrinGsequestration at developing nodes are delayed in NrCAM null mutants. The action of NrCAM is manifest locally at individual nodes, rather than affecting overall neuronal expression, and is linked to glial interactions. During remyelination, Na+channel clusters at new nodes are initially labile, and anchoring to the cytoskeleton appears to grow progressively with time. The distance between Na+channel clusters across remyelinating Schwann cells (nascent internodes) increases markedly from 83 to 274 μm during node formation, arguing against schemes in which the loci of nodes are fixed in advance by the axon. A hypothesis for node formation in which axonal Na+channels move by lateral diffusion from regions of Schwann cell contact, with clustering dependent on linkage to the cytoskeleton by ankyrinG, is proposed and tested in a computational model. To match experimental measurements, this latter reaction needs fast kinetics, and the early arrival of NrCAM is postulated to contribute to this requirement.
Specific Assembly with the NMDA Receptor 3B Subunit Controls Surface Expression and Calcium Permeability of NMDA Receptors
Authors: Matsuda Keiko , Fletcher Matt , Kamiya Yoshinori , Yuzaki Michisuke
Published: April 2018

The NMDA receptor 3B (NR3B) subunit is the most recently identified member of the NMDA receptor family. In heterologous cells, it has been shown to reduce the Ca2+permeability of glutamatergic receptor complexes formed together with NR1 and NR2 subunits and to form the unique excitatory glycine receptor complex with the NR1 subunit. However, it is unclear whether NR3B protein is expressed in and exerts similar functions in neurons. In addition, it is not understood how NR3B interacts with NR1 and NR2 and how such an interaction may regulate the membrane trafficking of the NMDA receptor complex. Here we report that our analysis using an antibody specific for NR3B showed that the NR3B protein is selectively expressed in somatic motor neurons in the brainstem of adult mice. Coimmunoprecipitation and electrophysiological analyses demonstrated that NR3B, when exogenously introduced into hippocampal neurons, can coassemble with endogenous NR1 and NR2A and can reduce the Ca2+permeability of NMDA currents. In contrast, NR3B was not involved in the excitatory glycine response in neurons under our test conditions. Although NR1 or NR3B alone cannot be transported to the cell surface, coexpression of these subunits mutually supported transport of the NMDA receptor complex by interaction involving the specific regions of the C terminus of NR3B. These results indicate that NR3B may modulate the function of NMDA receptors in somatic motor neurons during adulthood by controlling membrane trafficking and by reducing Ca2+permeability.
Pathway-Specific Differences in Subunit Composition of Synaptic NMDA Receptors on Pyramidal Neurons in Neocortex
Authors: Kumar Sanjay S. , Huguenard John R.
Published: April 2018

Heterogeneity of synaptic inputs onto neocortical layer 5 pyramidal neurons could result from differences in the underlying receptors, yet previous work has shown that functional attributes of AMPA receptors are uniform among synaptic connections onto these neurons. To determine whether NMDA receptors (NMDARs) would be similarly uniform, we compared in the same pyramidal neurons pharmacologically isolated NMDAR-mediated EPSCs evoked by stimulation of two anatomically distinguishable pathways, callosal or intracortical. Based on differences in voltage dependence, decay kinetics, apparent Mg2+sensitivity, and subunit-specific (NR2A, NR2B, and NR2C/D) pharmacology, we found NMDARs at these inputs to be distinct. Furthermore, NMDARs activated by the intracortical pathway were more efficient at integrating EPSPs and bringing the neuron closer to the spike-firing threshold than the callosal pathway. These results suggest that pyramidal neurons encode information differentially depending on the origin of their neocortical inputs and that NMDAR-dependent synaptic plasticity may be pathway specific.
Tyrosine Phosphorylation of Rod Cyclic Nucleotide-Gated Channels Switches Off Ca2+/Calmodulin Inhibition
Authors: Krajewski Jeffrey L. , Luetje Charles W. , Kramer Richard H.
Published: April 2018

Cyclic nucleotide-gated (CNG) ion channels are crucial for phototransduction in rod photoreceptors. Light triggers a biochemical cascade that reduces the concentration of cGMP in rods, closing CNG channels, which leads to membrane potential hyperpolarization and a decrease in the concentration of intracellular Ca2+. During light adaptation, the sensitivity of CNG channels to cGMP is decreased by Ca2+, which in conjunction with calmodulin (CaM), binds directly to CNG channels. The cGMP sensitivity of rod CNG channels is also reduced by phosphorylation of specific tyrosine residues in the three CNGA1 subunits and one CNGB1 subunit that comprise the rod channel. Here we show that phosphorylation prevents Ca2+/CaM inhibition. Experiments on native channels in rod outer segments and expressed channels inXenopusoocytes show that Ca2+/CaM inhibition can be toggled off or on by promoting phosphorylation or dephosphorylation, respectively. Experiments in which the crucial tyrosine phosphorylation sites in CNGA1 and CNGB1 are replaced with phenylalanines show that residue Y498 in CNGA1 is the phosphorylation site responsible for regulating Ca2+/CaM inhibition. Ca2+/CaM inhibits the rod channel by binding to the N terminus of the CNGB1 subunit, causing it to uncouple from the C terminus of CNGA1. We propose that phosphorylation of CNGA1Y498, on the C terminus of CNGA1, triggers an equivalent uncoupling from the C terminus of CNGB1, thereby curtailing Ca2+/CaM inhibition. The control of CaM inhibition by CNG channel phosphorylation may be important for light adaptation and the regulation of phototransduction by IGF-1, a retinal paracrine factor that alters the tyrosine phosphorylation state of rod CNG channels.
TrkB Receptor Signaling Regulates Developmental Death Dynamics, But Not Final Number, of Retinal Ganglion Cells
Authors: Pollock Graeme S. , Robichon Regine , Boyd Kristina A. , Kerkel Kristi A. , Kramer Melissa , Lyles Johnalyn , Ambalavanar Ranjini , Khan Asema , Kaplan David R. , Williams Robert W. , Frost Douglas O.
Published: April 2018

We investigated the effects of endogenous neurotrophin signaling on the death-survival of immature retinal ganglion cells (RGCs)in vivo. Null mutation of brain-derived neurotrophic factor [(BDNF) alone or in combination with neurotrophin 4 (NT4)] increases the peak rate of developmental RGC death as compared with normal. Null mutation of NT4 alone is ineffective. Null mutation of the full-length trkB (trkBFL) receptor catalytic domain produces a dose-dependent increase in the peak RGC death rate that is negatively correlated with retinal levels of trkBFLprotein and phosphorylated (activated) trkBFL. Depletion of target-derived trkB ligands by injection of trkB-Fc fusion protein into the superior colliculus increases the peak rate of RGC death compared with trkA-Fc-treated and normal animals. Adult trkBFL+/-mice have a normal number of RGCs, despite an elevated peak death rate of immature RGCs. Thus, target-derived BDNF modulates the dynamics of developmental RGC death through trkBFLactivation, but BDNF/trkB-independent mechanisms determine the final number of RGCs.
Long-Term Enhancement of Neuronal Excitability and Temporal Fidelity Mediated by Metabotropic Glutamate Receptor Subtype 5
Authors: Sourdet Valérie , Russier Michaël , Daoudal Gaël , Ankri Norbert , Debanne Dominique
Published: April 2018

The cellular substrate for memory is generally attributed to long-lasting changes in synaptic strength. We report here that synaptic or pharmacological activation of the metabotropic glutamate receptor subtype 5 (mGluR5) induces long-term potentiation of intrinsic excitability (LTP-IE) in layer V pyramidal neurons. mGluR5-dependent LTP-IE was associated with a persistent reduction of the afterhyperpolarization (AHP) outward current (IAHP), resulting in the potentiation of EPSP-spike coupling. Apamin occluded induction of LTP-IE, indicating that downregulation of small conductance calcium-dependent potassium (SK) channels mediates this process. In addition to the improved reliability of the input-output function, LTP-IE led to increased temporal precision. The induced reduction ofIAHPaccelerated the rate of membrane depolarization preceding each action potential and subsequently decreased the jitter of the neuronal discharge. We conclude that mGluR5-dependent LTP-IE not only promotes the spread of excitation in the cortical network but also persistently enhances the temporal fidelity of the neuronal message.
Enhanced Rewarding Properties of Morphine, but not Cocaine, in βarrestin-2 Knock-Out Mice
Authors: Bohn Laura M. , Gainetdinov Raul R. , Sotnikova Tatyana D. , Medvedev Ivan O. , Lefkowitz Robert J. , Dykstra Linda A. , Caron Marc G.
Published: April 2018

The reinforcing and psychomotor effects of morphine involve opiate stimulation of the dopaminergic system via activation of μ-opioid receptors (μOR). Both μ-opioid and dopamine receptors are members of the G-protein-coupled receptor (GPCR) family of proteins. GPCRs are known to undergo desensitization involving phosphorylation of the receptor and the subsequent binding of βarrestins, which prevents further receptor-G-protein coupling. Mice lacking βarrestin-2 (βarr2) display enhanced sensitivity to morphine in tests of pain perception attributable to impaired desensitization of μOR. However, whether abrogating μOR desensitization affects the reinforcing and psychomotor properties of morphine has remained unexplored. In the present study, we examined this question by assessing the effects of morphine and cocaine on locomotor activity, behavioral sensitization, conditioned place preference, and striatal dopamine release in βarr2 knock-out (βarr2-KO) mice and their wild-type (WT) controls. Cocaine treatment resulted in very similar neurochemical and behavioral responses between the genotypes. However, in the βarr2-KO mice, morphine induced more pronounced increases in striatal extracellular dopamine than in WT mice. Moreover, the rewarding properties of morphine in the conditioned place preference test were greater in the βarr2-KO mice when compared with the WT mice. Thus, βarr2 appears to play a more important role in the dopaminergic effects mediated by morphine than those induced by cocaine.
Buprenorphine-Induced Antinociception Is Mediated by μ-Opioid Receptors and Compromised by Concomitant Activation of Opioid Receptor-Like Receptors
Authors: Lutfy Kabirullah , Eitan Shoshana , Bryant Camron D. , Yang Yu C. , Saliminejad Nazli , Walwyn Wendy , Kieffer Brigitte L. , Takeshima Hiroshi , Carroll F. Ivy , Maidment Nigel T. , Evans Christopher J.
Published: April 2018

Buprenorphine is a mixed opioid receptor agonist-antagonist used clinically for maintenance therapy in opiate addicts and pain management. Dose-response curves for buprenorphine-induced antinociception display ceiling effects or are bell shaped, which have been attributed to the partial agonist activity of buprenorphine at opioid receptors. Recently, buprenorphine has been shown to activate opioid receptor-like (ORL-1) receptors, also known as OP4 receptors. Here we demonstrate that buprenorphine, but not morphine, activates mitogen-activated protein kinase and Akt via ORL-1 receptors. Because the ORL-1 receptor agonist orphanin FQ/nociceptin blocks opioid-induced antinociception, we tested the hypothesis that buprenorphine-induced antinociception might be compromised by concomitant activation of ORL-1 receptors. In support of this hypothesis, the antinociceptive effect of buprenorphine, but not morphine, was markedly enhanced in mice lacking ORL-1 receptors using the tail-flick assay. Additional support for a modulatory role for ORL-1 receptors in buprenorphine-induced antinociception was that coadministration of J-113397, an ORL-1 receptor antagonist, enhanced the antinociceptive efficacy of buprenorphine in wild-type mice but not in mice lacking ORL-1 receptors. The ORL-1 antagonist also eliminated the bell-shaped dose-response curve for buprenorphine-induced antinociception in wild-type mice. Although buprenorphine has been shown to interact with multiple opioid receptors, mice lacking μ-opioid receptors failed to exhibit antinociception after buprenorphine administration. Our results indicate that the antinociceptive effect of buprenorphine in mice is μ-opioid receptor-mediated yet severely compromised by concomitant activation of ORL-1 receptors.
Dopamine and Octopamine Differentiate between Aversive and Appetitive Olfactory Memories inDrosophila
Authors: Schwaerzel Martin , Monastirioti Maria , Scholz Henrike , Friggi-Grelin Florence , Birman Serge , Heisenberg Martin
Published: April 2018

The catecholamines play a major role in the regulation of behavior. Here we investigate, in the flyDrosophila melanogaster, the role of dopamine and octopamine (the presumed arthropod homolog of norepinephrine) during the formation of appetitive and aversive olfactory memories. We find that for the formation of both types of memories, cAMP signaling is necessary and sufficient within the same subpopulation of mushroom-body intrinsic neurons. On the other hand, memory formation can be distinguished by the requirement for different catecholamines, dopamine for aversive and octopamine for appetitive conditioning. Our results suggest that in associative conditioning, different memories are formed of the same odor under different circumstances, and that they are linked to the respective motivational systems by their specific modulatory pathways.
Selective Reactions of Cutaneous and Muscle Afferent Neurons to Peripheral Nerve Transection in Rats
Authors: Hu Ping , McLachlan Elspeth M.
Published: April 2018

To determine whether peripheral nerve injury has similar effects on all functional types of afferent neuron, we retrogradely labeled populations of neurons projecting to skin and to muscle with FluoroGold and lesioned various peripheral nerves in the rat. Labeled neurons were counted after different periods and related to immunohistochemically identified ectopic terminals and satellite cells in lumbar dorsal root ganglia.

After 10 weeks, 30% of cutaneous afferent somata labeled from transected sural nerves had disappeared but, if all other branches of the sciatic nerve had also been cut, 60% of cutaneous neurons were lost. Small-diameter sural neurons preferentially disappeared. In contrast, the number of muscle afferent somata was not affected by transection of various nerves. p75 was downregulated in axotomized cutaneous neurons but in not axotomized muscle neurons.

Conversely, p75 was upregulated in satellite cells around cutaneous but not muscle neurons. Consistent with this, perineuronal rings containing tyrosine hydroxylase, calcitonin gene-related peptide, galanin, or synaptophysin were formed preferentially around cutaneous neurons. Selective lesions of predominantly cutaneous nerves triggered the formation of rings, but none were detected after selective lesions of muscle nerves.

We conclude that cutaneous neurons are both more vulnerable and more associated with ectopic nerve terminals than muscle neurons in dorsal root ganglia after transection and ligation of peripheral nerves.
Dynamic Expression ofRGS4in the Developing Nervous System and Regulation by the Neural Type-Specific Transcription Factor Phox2b
Authors: Grillet Nicolas , Dubreuil Véronique , Dufour Héloïse D. , Brunet Jean-François
Published: April 2018

Previous studies have shown that members of the family of regulators of G-protein signaling (RGS), including RGS4, have a discrete expression pattern in the adult brain (Gold et al., 1997). Here, we describe forRGS4a distinct, mostly transient phase of neuronal expression, during embryonic development: transcription ofRGS4occurs in a highly dynamic manner in a small set of peripheral and central neuronal precursors. This expression pattern overlaps extensively with that of the paired-like homeodomain protein Phox2b, a determinant of neuronal identity. In embryos deficient forPhox2b, RGS4expression is downregulated in the locus coeruleus, sympathetic ganglia, and cranial motor and sensory neurons. Moreover, Phox2b cooperates with the basic helix-loop-helix protein Mash1 to transiently switch onRGS4after ectopic expression in the chicken spinal cord. Intriguingly, we also identify a heterotrimeric G-protein α-subunit, gustducin, as coexpressed with RGS4 in developing facial motor neurons, also under the control of Phox2b. Altogether, these data identify components of the heterotrimeric G-protein signaling pathway as part of the type-specific program of neuronal differentiation.
Calcium/Calmodulin-Dependent Protein Kinase II Contributes to Activity-Dependent Filopodia Growth and Spine Formation
Authors: Jourdain Pascal , Fukunaga Kohji , Muller Dominique
Published: April 2018

Remodeling of synaptic networks through an activity-dependent formation or elimination of synaptic connections is believed to contribute to information processing and long-term memory. Recent work showed that enhanced synaptic activation, including induction of long-term potentiation and sensory stimulation, promote a rapid growth of dendritic filopodia and the formation of new spines or new types of synapses. Here, we investigated whether calcium/calmodulin-dependent protein kinase II (CaMKII), an enzyme implicated in the control of synaptic efficacy, also participated in these mechanisms. We show that the intracellular application of autophosphorylated CaMKII reproduced these morphological changes and triggered filopodia growth and spine formation. In addition, we find that activation of endogenous kinase through the inhibition of phosphatases or the application of calmodulin in the cell produced similar effects. Conversely, blockade of CaMKII activity prevented the synaptic enhancement, the growth of filopodia and formation of new spines triggered by LTP induction, and a short anoxia/hypoglycemia. Together, these results support the interpretation that CaMKII contributes to the control of activity-dependent structural plasticity.
Reduction of Detyrosinated Microtubules and Golgi Fragmentation Are Linked to Tau-Induced Degeneration in Astrocytes
Authors: Yoshiyama Yasumasa , Zhang Bin , Bruce Jennifer , Trojanowski John Q. , Lee Virginia M.-Y.
Published: April 2018

Several human neurodegenerative diseases are associated with abnormal accumulations of aggregated tau proteins and glial degeneration in astrocytes, but the mechanism whereby tau proteins cause astrocytic degeneration is unclear. Here, we analyzed the biological consequences of overexpressing the longest human tau isoform in primary cultures of rat astrocytes using adenoviral-mediated gene transfer. Significantly, we found specific decreases in stable detyrosinated [glutamate (Glu)] microtubules (MTs) with concomitant increases in tubulin biosynthesis and the accumulation of acetylated, tyrosinated, α- and β-tubulin. The consequences of this selective reduction in stable Glu-MTs included contemporaneous decreases in kinesin levels, collapse of the intermediate filament network, progressive disruption of kinesin-dependent trafficking of organelles, fragmentation of the Golgi apparatus that culminated in atrophy, and non-apoptotic death of astrocytes. These results suggest that reduced stable Glu-MTs is a primary consequence of tau accumulation that initiates mechanisms underlying astrocyte dysfunction and death in human neurodegenerative glial tauopathies.
Mechanism of Toxicity in Rotenone Models of Parkinson's Disease
Authors: Sherer Todd B. , Betarbet Ranjita , Testa Claudia M. , Seo Byoung Boo , Richardson Jason R. , Kim Jin Ho , Miller Gary W. , Yagi Takao , Matsuno-Yagi Akemi , Greenamyre J. Timothy
Published: April 2018

Exposure of rats to the pesticide and complex I inhibitor rotenone reproduces features of Parkinson's disease, including selective nigrostriatal dopaminergic degeneration and α-synuclein-positive cytoplasmic inclusions (Betarbet et al., 2000; Sherer et al., 2003). Here, we examined mechanisms of rotenone toxicity using three model systems. In SK-N-MC human neuroblastoma cells, rotenone (10 nmto 1 μm) caused dose-dependent ATP depletion, oxidative damage, and death. To determine the molecular site of action of rotenone, cells were transfected with the rotenone-insensitive single-subunit NADH dehydrogenase ofSaccharomyces cerevisiae(NDI1), which incorporates into the mammalian ETC and acts as a “replacement” for endogenous complex I. In response to rotenone, NDI1-transfected cells did not show mitochondrial impairment, oxidative damage, or death, demonstrating that these effects of rotenone were caused by specific interactions at complex I. Although rotenone caused modest ATP depletion, equivalent ATP loss induced by 2-deoxyglucose was without toxicity, arguing that bioenergetic defects were not responsible for cell death. In contrast, reducing oxidative damage with antioxidants, or by NDI1 transfection, blocked cell death. To determine the relevance of rotenone-induced oxidative damage to dopaminergic neuronal death, we used a chronic midbrain slice culture model. In this system, rotenone caused oxidative damage and dopaminergic neuronal loss, effects blocked by α-tocopherol. Finally, brains from rotenone-treated animals demonstrated oxidative damage, most notably in midbrain and olfactory bulb, dopaminergic regions affected by Parkinson's disease. These results, using three models of increasing complexity, demonstrate the involvement of oxidative damage in rotenone toxicity and support the evaluation of antioxidant therapies for Parkinson's disease.
Progressive Degradation and Subsequent Refinement of Acoustic Representations in the Adult Auditory Cortex
Authors: Bao Shaowen , Chang Edward F. , Davis Jonathan D. , Gobeske Kevin T. , Merzenich Michael M.
Published: April 2018

Correlated neuronal activity is believed to play an important role in refining and maintaining cortical circuitry during early development. Here we provide evidence that globally and locally correlated activity mediate different forms of adult plasticity. Pulses of broad-spectrum noise were used to activate time-locked responses across large areas of the rat auditory cortex, globally synchronizing cortical activity. Brief tone pips were used to activate relatively small groups of neurons, generating locally correlated activity. Pairing pulsed noises with nucleus basalis (NB) stimulation in awake rats for 4 weeks broadened spectral tuning, disrupted tonotopic maps, and reduced spontaneous discharge correlation in the primary auditory cortex (AI), as examined under anesthesia. Those effects caused AI neurons to appear qualitatively similar to neurons in nonprimary auditory fields of naive animals. Subsequent pairing of tone pips with NB stimulation for a period of 4 weeks completely reversed these effects induced by previous noise-NB pairing. These findings further demonstrate that the adult auditory cortex retains a substantial capacity for receptive field plasticity and tonotopic map reorganization and that locally correlated activity plays an important role in plasticity in the adult, as in the developing cortex.
Surface Expression of the Netrin Receptor UNC5H1 Is Regulated through a Protein Kinase C-Interacting Protein/Protein Kinase-Dependent Mechanism
Authors: Williams Megan E. , Wu Sareina C.-Y. , McKenna William L. , Hinck Lindsay
Published: April 2018

Netrin-1 is a bifunctional guidance cue that directs migrating neurons and axons based on specific receptors expressed on the cell surface. Attraction occurs through the receptor Deleted in Colorectal Cancer (DCC) and repulsion occurs through a receptor complex of DCC and UNC5H, the vertebrate homolog toCaenorhabditis elegansUNC-5, but how the specific surface expression of these receptors is achieved remains unknown. Here, we demonstrate that surface expression of UNC5H1 is regulated in neurons by protein interacting with C kinase-1 (PICK1) and protein kinase C (PKC), and show that one mechanism by which cells control their response to netrin-1 is by changing the surface availability of receptors. We identified PICK1 as a binding partner for UNC5H1 using the yeast two-hybrid system and found that the extreme three C-terminal amino acids of UNC5H1 interact with the PSD-95/Dlg/ZO-1 (PDZ) domain of PICK1. Coexpression of UNC5H1 and PICK1 in heterologous cells results in the recruitment of PICK1 to UNC5H1 clusters. Endogenous UNC5H1 and PICK1 coimmunoprecipitate from extracts of cultured hippocampal neurons and P4 cortices, and immunohistochemistry shows that UNC5H1, PICK1, and PKC are all present in growth cones. PKC activation induces the formation of UNC5H1/PICK1/PKC complexes and leads to the specific removal of UNC5H1, but not DCC, from the surface of neurons and growth cones via a PICK1/PKC-dependent mechanism. Lastly, we demonstrate that activating PKC, which decreases surface expression of UNC5H1, inhibits netrin-1-dependent collapse of hippocampal growth cones. Together, our results suggest that by regulating the surface expression of UNC5Hs, an axon can modulate its repellent response to netrin-1.
Comparative Distribution of Glutamate Transporters and Receptors in Relation to Afferent Innervation Density in the Mammalian Cochlea
Authors: Furness David N. , Lawton D. Maxwell
Published: April 2018

The local expression of proteins involved in handling glutamate may be regulated by the number and activity of synapses in regions of glutamatergic innervation. The systematically varying innervation of inner hair cells (IHCs) of the cochlea provides a model to test this suggestion. IHCs are glutamatergic and form a single row along the cochlear spiral. Along this row the number of afferent fibers terminating on IHCs increases toward the base, reaching a peak and thereafter declining. The afferents are segregated so that higher spontaneous rate fibers terminate on the pillar-cell side of the IHC and lower rate fibers terminate on the modiolar side. Using immunofluorescence and postembedding immunogold labeling, we investigated the distributions of the glutamate-aspartate transporter (GLAST or excitatory amino acid transporter 1), vesicular glutamate transporter (VGLUT1), and the AMPA receptor glutamate receptor 4 (GluR4) along the spiral. Immunofluorescent labeling for GLAST in IHC supporting cells increased in intensity to a peak in the region of 6-9 mm from the apex. Immunogold labeling for GLAST was greater overall in these cells in the 10 mm region than in the 1 mm region and also on the pillar-cell side of the IHC compared with the modiolar side. Immunogold labeling for GluR4 was confined to synaptic sites, represented by puncta in immunofluorescence. The relative numbers of puncta changed with a gradient similar to that of GLAST labeling. VGLUT1 labeling occurred in IHCs but showed no clear cochleotopic gradient. These data suggest that both the density of innervation and the activity levels of glutamatergic synapses may be involved in modulating regional expression of GLAST.
Selective Activation Induced Cleavage of the NR2B Subunit by Calpain
Authors: Simpkins Kelly L. , Guttmann Rodney P. , Dong Yina , Chen Zhaoming , Sokol Set , Neumar Robert W. , Lynch David R.
Published: April 2018

Although activation of calcium-activated neutral protease (calpain) by the NMDA receptor has been suggested to play critical roles in synaptic modulation and neurologic disease, the nature of its substrates has not been completely defined. In this study, we examined the ability of calpain to cleave the NMDA receptor in cultured hippocampal neurons. Activation of the NMDA receptor by agonist application led to rapid calpain-specific proteolysis of spectrin and decreased levels of NR2A/2B subunits. Cleavage of the NR2A/2B subunit created a 115 kDa product that retained the ability to bind125I-MK-801 and is predicted to be active. Increases in levels of this product appeared within 5 min of NMDA receptor activation and were stable for periods of >30 min. Subtype-specific antibodies demonstrated that the NR2B subunit was cleaved in these primary cultures, but the NR2A subunit was not. An inhibitor of calpain blocked both the decrease of intact NR2B and the increase of the low molecular weight form, whereas neither caspase nor cathepsin inhibitors had an effect on these events. Cell surface biotinylation experiments demonstrated that the 115 kDa fragment remained on the cell surface. This NR2B fragment was also found in the rat hippocampus after transient forebrain ischemia, showing that this process also occursin vivo. This suggests that calpain-mediated cleavage of the NR2B subunit occurs in neurons and gives rise to active NMDA receptor forms present on the cell surface after excitotoxic glutamatergic stimulation. Such forms could contribute to excitotoxicity and synaptic remodeling.
Reduced Expression of P2Y1Receptors in Connexin43-Null Mice Alters Calcium Signaling and Migration of Neural Progenitor Cells
Authors: Scemes Eliana , Duval Nathalie , Meda Paolo
Published: April 2018

Glial calcium signals play important roles during CNS development. Calcium transients induced by ATP, acting on purinergic receptors, stimulate DNA synthesis, increase astrocytic and neural stem cell proliferation, and are prominent during the differentiation of radial glia. We have shown previously that expression of P2Y receptors in astrocytes is altered when connexin43 (Cx43) is downregulated. To evaluate the consequences of Cx43 deletion on calcium signaling during neural progenitor development, studies were performed on neurospheres derived from embryonic striatum. After adhesion, cells migrating from wild-type (WT) and Cx43-null neurospheres displayed spontaneous calcium oscillations. Such activity was blunted by apyrase, 2′-deoxy-N6-methyladenosine 3′,5′-bisphosphate (MRS-2179), and suramin, suggesting that ATP released by neural cells acts on purinergic receptors to induce calcium oscillations. The amplitudes of Ca2+transients induced by P2Y but not P2X receptor agonists were larger in WT than in Cx43-null progenitors, suggesting that these two cell populations express different P2 receptors. Suramin, a nonselective P2 receptor antagonist, and MRS-2179, a P2Y1receptor-selective antagonist, reduced the proliferation rate and the migration of WT progenitor cells to levels similar to those of Cx43-null cells. Conversely, exogenous expression of P2Y1receptors in Cx43-null cells restored their migration pattern to levels seen in WT progenitors. However, treatment with P2 receptor antagonists did not alter the ratio of nestin to GFAP expression in WT neural progenitors. These data show that altered autocrine-paracrine communication attributable to reduced levels of P2Y1receptors in neural progenitor cells lacking Cx43 affects proliferation and migration but not cell differentiation during early CNS development.
Expectation Enhances the Regional Brain Metabolic and the Reinforcing Effects of Stimulants in Cocaine Abusers
Authors: Volkow Nora D. , Wang Gene-Jack , Ma Yemin , Fowler Joanna S. , Zhu Wei , Maynard Laurence , Telang Frank , Vaska Paul , Ding Yu-Shin , Wong Christopher , Swanson James M.
Published: April 2018

The reinforcing effects of drugs of abuse result from the complex interaction between pharmacological effects and conditioned responses. Here we evaluate how expectation affects the response to the stimulant drug methylphenidate in 25 cocaine abusers. The effects of methylphenidate (0.5 mg/kg, i.v.) on brain glucose metabolism (measured by [18F]deoxyglucose-positron emission tomography) and on its reinforcing effects (self-reports of drug effects) were evaluated in four conditions: (1) expecting placebo and receiving placebo; (2) expecting placebo and receiving methylphenidate; (3) expecting methylphenidate and receiving methylphenidate; (4) expecting methylphenidate and receiving placebo. Methylphenidate increased brain glucose metabolism, and the largest changes were in cerebellum, occipital cortex, and thalamus. The increases in metabolism were ∼50% larger when methylphenidate was expected than when it was not, and these differences were significant in cerebellum (vermis) and thalamus. In contrast, unexpected methylphenidate induced greater increases in left lateral orbitofrontal cortex than when it was expected. Methylphenidate-induced increases in self-reports of “high” were also ∼50% greater when subjects expected to receive it than when they did not and were significantly correlated with the metabolic increases in thalamus but not in cerebellum. These findings provide evidence that expectation amplifies the effects of methylphenidate in brain and its reinforcing effects. They also suggest that the thalamus, a region involved with conditioned responses, may mediate the enhancement of the reinforcing effects of methylphenidate by expectation and that the orbitofrontal cortex mediates the response to unexpected reinforcement. The enhanced cerebellar activation with expectation may reflect conditioned responses that are not linked to conscious responses.
“Não é competência do professor ser sexólogo”: o debate público sobre gênero e sexualidade no Plano Nacional de Educação
Authors: Brandão Elaine Reis , Lopes Rebecca Faray Ferreira
Published: April 2018

O trabalho discute as premissas que regem o debate público na sociedadebrasileira sobre a inclusão dos conteúdos relativos ao gênero e à sexualidade noPlano Nacional de Educação. Trata-se de pesquisa socioantropológica documental, com documentos extraídos de fontes públicas na internet, no período 2011-2017, compreendendo órgãos governamentais, organizações não governamentais, portais de notícias diversos. A perspectiva de construção social do gênero e da sexualidade é questionada por ser considerada disruptiva à família para certos segmentos religiosos e políticos, não devendo ser tratada na escola. Outra visão se apoia nas discriminações e violências sofridas por estudantes devido ao estigma e desigualdade de gênero persistente nos espaços escolares. Assim, tais conteúdos ajudariam no processo educativo de convivência com a diversidade sexual, de gênero, e racial. Nesse debate, a dimensão sociocultural e política do gênero e da sexualidade se afirmam. Aspectos intervenientes na aprovação das políticas públicas sinalizam dificuldades para se garantir o Estado laico, denotando o que Carrara designa como “nova geografia do mal e do perigo sexual” ao discutir as politicas sexuais e seus peculiares estilos de regulação moral.
Gênero, sexualidade e experimentação de si em plataformas digitais on-line
Authors: Leitão Débora Krischke , Gomes Laura Graziela
Published: April 2018

Esse trabalho parte de pesquisa realizada em um mundo virtual 3D e outras plataformas digitais, para refletir sobre novas formas de experimentação de si, presentes nas mídias digitais contemporâneas. Enfatizamos usos e apropriações criativas dessas plataformas em experimentações de gênero e sexualidade, propomos pensar nessas tecnologias como agenciadoras de novos processos de subjetivação.
Sound Pollution Effect on Motor Drivers and Auto-Mechanics Using the 7D Sensitivity Index Model
Authors: F.U. Nte, , U. Ogoke,
Published: April 2018

This study developed a 7D impact model for the purpose of examining peoples’ perception of noise intensity from selected occupational groups, using the Junior secondary school students as the base line model. It structured “20-29dBA as dictable” “30-49dBA Distinctive” “50-69dBA Disturebing” 70-79dBA deterring” “80-89dBA Destructive and “110-160dBA Devastating” Levels. A hypersonic disco set was used to generate these noise level at Ologbu hall N04053139.9 E0060 54037.71 and discovered that the taxi drivers, mechanics and pump attendants at the filling stations are the most vulnerable to noise impacts. Sixty volunteer participants were randomly selected 10 each to cover market women, taxi drivers, Road side Mechanics, Sciences and Engineering workshop. Staff, University and Secondary School Students. The results were tabulated and the analysis showed high correlation in the group response which validated the model using Pearson Correlation. The discrimination in the group response measure of hearing loss or threshold shift particularly at the detectable level. While the correlation at the destructive, devastating levels are indicative that all the groups appreciate the impact at higher level of noise, irrespective of the initial threshold shift which is the hearing loses. The study bench shift between the 0dBA to 110dBA is found to be 10dBA at + 5 for the taxi drivers, mechanics and pump attendants possible due to indiscriminate horning, electronic sources and traffic.
ANALISIS PENGAWASAN KAPAL PERIKANAN TERHADAP PENANGGULANGAN ILLEGAL FISHING DI PERAIRAN KABUPATEN KEPULAUAN SANGIHE, INDONESIA
Authors: Suharto Bayu Y. , Budiman Johnny , Karwur Denny BA
Published: April 2018

Kabupaten Kepulauan Sangihe termasuk wilayah yang berbatasan langsung dengan negara lain yaitu Philipina dan juga mempunyai karakteristik wilayah perairan yang memiliki keragaman sumberdaya hayati yang bernilai ekonomis tinggi. Permasalahan yang dihadapai saat ini adalah masih maraknya kegiatan illegal fishing yang terjadi baik dilakukan oleh kapal ikan asing ataupun kapal ikan Indonesia. Tujuan dari penelitian ini adalah menganalisis stakeholder prioritas dan faktor-faktor penting dalam pengawasan kegiatan illegal fishing. Metode analisis yang digunakan adalah Analisis AHP (Analisis Hirarki Proses) yaitu untuk menentukan stakeholder prioritas dan faktor-faktor prioritas dalam pengawasan kapal perikanan dan meningkatkan strategi penerapan kebijakan yang tepat dalam kegiatan pengawasanillegal fishing di wilayah perairan Kabupaten Kepulauan Sangihe. Hasil penelitian ini menunjukan bahwa pemerintah pusat menjadi stakholder prioritas dalam pengawasan kegiatan illegal fishing di perairan Kabupaten Kepulauan Sangihe, yang didukung oleh kegiatan penegakan hukum dan peran dari pemerintah daerah. Faktor-faktor penting dalam pengawasan kegiatan illegal fishing yaitu ketersediaanya sarana, prasarana pengawasan dan anggaran pengawasan serta ditunjang dengan sumber daya manusia pengawas yang terampil dan juga sosialisasi peraturan sehingga kegiatan pengawasan kapal perikanan dapat berjalan dengan optimal.Title: Analysis of Fishing Vessel Supervision on Illegal Fishing Control in the Waters of The Regency of Sangihe Islands, IndonesiaThe regency of Sangihe Islands belongs to an area directly bordering with the neighborhood country, the Philippines and also possesses a typical marine waters with diverse highly economic living resources. Recent problem is illegal fishing practices done by either Indonesian or foreign fishing vessels. Analyze stakeholder priorities and important factors in controlling the illegal fishing activities. The study used a Hierarchy Process Analysis to determine the priority stakeholders and the priority factors in fishery vessel supervision and develop the appropriate policy implementation strategy in illegal fishing surveillance activities in the territorial waters of Sangihe Islands Regency. Results indicated that the Central Government became the priority stakeholder in supervising the illegal fishing in the waters of Sangihe Islands regency, supported by law enforcement activities and the role of the local government. Important factors in the supervision of illegal fishing activities are availability of facilities, monitoring infrastructure and supervision budget and supported by skilled human resources supervisor and also socialization of regulation so that fishery supervision activity can run optimal.
“You’ve Done Very Well” (“Das haben Sie sehr schön gemacht”)
Authors: Schmohl Corinna
Published: April 2018

Although it is not unusual to be called ad hoc onto a ward where one is not on regular duty, there are special challenges for the pastoral caregiver. For example, one might not be familiar with the staff or with the medical focus of the unit. This study (on multiple visits over the course of a long day) demonstrates vividly that the reason a chaplain is called may not always match the real need of the patient and/or of the persons who are close to that patient. Questions that seem to have nothing to do with pastoral care may have a spiritual core or may imply suffering from feelings of futility, of spiritual pain and unresolved religious issues that often remain largely ignored in practice, despite the “total pain” concept in palliative care. The courage to address spiritual issues explicitly, for example, by offering a ritual in pastoral care, can be crucial inmaking positive changes possible.
Triguņa and chitta bhũmike in Yoga practitioners
Authors: S. Jayasheela . , K. Salagame Kiran Kumar
Published: April 2018

According to Indian thought, triguņa represents essential energies of the mind and individual's personality is
determined and dependent on triguņa viz., satva, rajas and tamas. The three guņa influence the physical and mental
activities of every individual. Vyasa in his commentary on Patanjali's Yoga Sutra distinguishes between five states
of mind viz., kshipta, mũdha, vikshipta, ekāgra and niruddha. Each of these states of mind involves certain cognitive
and personality characteristics, which are associated with satva, rajas and tamas. It is stated that yoga practices lead
to enhancement of satva and regulation and decline of rajas and tamas. To examine this 60 YP and 60 normal
controls (n=120) were studied using Vedic Personality Inventory and Chitta bhumike Inventory. The scores on the
two inventories were correlated. The obtained correlations in both the groups indicate that kshipta and mũdha states
of mind are negatively correlated with satva and positively correlated with tamas, as discussed in Yogic literature.
Only in yoga practitioner group kshipta and mũdha shows positive correlation with rajas. Scores of Vikshipta,
ekāgra and niruddha sub-scales do not show significant correlations with the three guņa. The t-tests show that the
two groups differed significantly on chitta bhumike but not on the three guņa.
Decision making power of college girls in relation to clothing
Authors: Gill Parul , Malik Poonam , Gill Pankaj
Published: April 2018

The present study was undertaken to explore the decision making patterns of college girls in relation to clothing and their satisfaction level with these decision making patterns. Thirty under graduate college girls from Panipat city were approached to record their responses regarding decision making in relation to clothing and satisfaction level through a well structured questionnaire. It was found that most of the girls (56.66%) themselves made the decisions about the type of garment (Indian, western or both) they wear and majority of girls (70%) were highly satisfied with
this decision making. Parents performed the role of buyers for their college going daughters' garments in most of the
cases (63.33%) and the 73.33% girls had high level of satisfaction with this. In most of the cases (60%) the decision
about the garment design was made by the girls themselves and they were highly satisfied with it.
Keywords: clothing, college, girls, decision making.
Hierarchy culture as a moderator on the relationship between work motivation and work commitment
Authors: Irfan Saira , Marzuki Najib Ahmad
Published: April 2018

For the understanding of economic and cultural advancement in a society, higher education is one of the key factors.Present study intended to examine the role of hierarchy culture as a moderator on the relationship between work
motivation and work commitment among university teachers. The study design was based on quantitative methods.
Sample comprised of 351 teachers from public universities of Punjab, Pakistan. Multivariate analysis and
descriptive statistics were performed using Smart PLS 3.0. Findings confirmed the moderating effects of hierarchy
culture. The findings have implications for policy makers to take advantage of work motivation because motivated
teachers preserve commitment despite the controlled and structured features of hierarchy culture. Study findings
also propose the development of supportive culture to enhance work commitment.
Keywords: hierarchy culture, work motivation, work commitment, university teachers, partial least square