bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Self-Administered Cocaine and Cocaine Cues on Extracellular Dopamine in Mesolimbic and Sensorimotor Striatum in Rhesus Monkeys
Authors: Bradberry Charles W. , Barrett-Larimore Rita L. , Jatlow Peter , Rubino Susan R.
Published: April 2018

Studies were conducted to determine the impact of self-administered cocaine on extracellular striatal dopamine in four rhesus monkeys. The extent to which external cue conditioning contributed to the effects of cocaine and whether there is activation of striatal dopaminergic neurotransmission during drug-seeking behavior was also examined. Microdialysis measurements were made at 2 min intervals in sensorimotor (dorsolateral) and mesolimbic (central and ventromedial) striatum. A fixed-ratio schedule of reinforcement was used, with cocaine availability signaled by a visual cue. Studies examined the effects of cocaine or cocaine cues against a drug-free baseline. Large (fivefold to eightfold) increases in extracellular dopamine after a self-administered infusion of 0.5 mg/kg cocaine were quite rapid and matched the time course of reported subjective effects in human laboratory studies. To determine if conditioning to external cues contributed to the cocaine-induced increases, saline was substituted for cocaine in the infusion, leaving all other visual and auditory stimuli unchanged. No increase in extracellular dopamine in either sensorimotor or mesolimbic striatal subdivisions was observed. Extracellular dopamine during extended periods of drug-seeking behavior triggered by a visual cue was determined in both central and ventromedial striatum. This procedure also did not result in any measurable changes in extracellular dopamine. These studies demonstrate rapid and pronounced pharmacological actions of self-administered cocaine. No apparent conditioned component of those actions was associated with external environmental cues, suggesting that cues that trigger drug-seeking behavior in nonhuman primates do not cause conditioned increases in mesolimbic striatal dopamine.
Dendritic Depolarization Efficiently Attenuates Low-Threshold Calcium Spikes in Thalamic Relay Cells
Authors: Zhan X. J. , Cox C. L. , Sherman S. Murray
Published: April 2018

Thalamic relay cells respond in two distinct modes, burst and tonic, that depend on a voltage-dependent, low-threshold, transient Ca2+current (IT), and these modes relay different forms of information to cortex.ITactivation evokes a low-threshold spike (LTS), producing a burst of action potentials. Modulatory inputs from cortex and brainstem are known to activate metabotropic receptors on relay cell dendrites at which the T channels underlyingITmay be concentrated. We thus investigated the influence of activating these receptors on the LTS, using current-clamp intracellular recording in anin vitroslice preparation of the cat's lateral geniculate nucleus. We found a strong correlation between LTS amplitude and the number of action potentials evoked in the burst. We then found that activation of either metabotropic glutamate or muscarinic receptors produced a hyperpolarizing shift in the sigmoid relationship between LTS amplitude and the initial holding potentialwithout affecting the maximum LTS amplitude or slope of the relationship. This hyperpolarizing shift in the voltage dependency of LTS amplitude is best explained by space-clamp limitations and significantly more depolarization of T channels near the dendritic location of activated receptors than at the soma. Thus, nonretinal modulatory inputs may have a stronger influence onITand number of action potentials generated in a burst than previously imagined from somatic recording, because the EPSP amplitudes generated by these inputs at the dendritic location of most T channels are greater than after their electrotonic decay recorded at the soma.
Do Glia Have Heart? Expression and Functional Role forEther-A-Go-GoCurrents in Hippocampal Astrocytes
Authors: Emmi Adriana , Wenzel H. Jurgen , Schwartzkroin Philip A. , Taglialatela Maurizio , Castaldo Pasqualina , Bianchi Laura , Nerbonne Jeanne , Robertson Gail A. , Janigro Damir
Published: April 2018

Potassium homeostasis plays an important role in the control of neuronal excitability, and diminished buffering of extracellular K results in neuronal Hyperexcitability and abnormal synchronization. Astrocytes are the cellular elements primarily involved in this process. Potassium uptake into astrocytes occurs, at least in part, through voltage-dependent channels, but the exact mechanisms involved are not fully understood. Although most glial recordings reveal expression of inward rectifier currents (KIR), it is not clear how spatial buffering consisting of accumulation and release of potassium may be mediated by exclusively inward potassium fluxes. We hypothesized that a combination of inward and outward rectifiers cooperate in the process of spatial buffering. Given the pharmacological properties of potassium homeostasis (sensitivity to Cs+), members of the ether-a-go-go (ERG) channel family widely expressed in the nervous system could underlie part of the process. We used electrophysiological recordings and pharmacological manipulations to demonstrate the expression of ERG-type currents in cultured andin situhippocampal astrocytes. Specific ERG blockers (dofetilide and E 4031) inhibited hyperpolarization- and depolarization-activated glial currents, and ERG blockade impaired clearance of extracellular potassium with little direct effect on hippocampal neuron excitability. Immunocytochemical analysis revealed ERG protein mostly confined to astrocytes; ERG immunoreactivity was absent in presynaptic and postsynaptic elements, but pronounced in glia surrounding the synaptic cleft. Oligodendroglia did not reveal ERG immunoreactivity. Intense immunoreactivity was also found in perivascular astrocytic end feet at the blood–brain barrier. cDNA amplification showed that cortical astrocytes selectively expressHERG1, but notHERG2–3 genes. This study provides insight into a possible physiological role of hippocampal ERG channels and links activation of ERG to control of potassium homeostasis.
Modulation of Long-Term Depression by Dopamine in the Mesolimbic System
Authors: Thomas Mark J. , Malenka Robert C. , Bonci Antonello
Published: April 2018

Long-lasting adaptations in the mesolimbic dopamine (DA) system in response to drugs of abuse likely mediate many of the behavioral changes that underlie addiction. Recent work suggests that long-term changes in synaptic strength at excitatory synapses in the two major components of this system, the nucleus accumbens (NAc) and ventral tegmental area, may be particularly important for the development of drug-induced sensitization, a process that may contribute to addiction, as well as for normal response-reinforcement learning. Using whole-cell patch-clamp recording techniques fromin vitroslice preparations, we have examined the existence and basic mechanisms of long-term depression (LTD) at excitatory synapses on both GABAergic medium spiny neurons in the NAc and dopaminergic neurons in the midbrain. We find that both sets of synapses express LTD but that their basic triggering mechanisms differ. Furthermore, DA blocks the induction of LTD in the midbrain via activation of D2-like receptors but has minimal effects on LTD in the NAc. The existence of LTD in mesolimbic structures and its modulation by DA represent mechanisms that may contribute to the modifications of neural circuitry that mediate reward-related learning as well as the development of addiction.
Brain Localization and Behavioral Impact of the G-Protein-Gated K+Channel Subunit GIRK4
Authors: Wickman Kevin , Karschin Christine , Karschin Andreas , Picciotto Marina R. , Clapham David E.
Published: April 2018

Neuronal G-protein-gated potassium (KG) channels are activated by several neurotransmitters and constitute an important mode of synaptic inhibition in the mammalian nervous system. KGchannels are composed of combinations of four subunits termed G protein-gated inwardly rectifying K+channels (GIRK). All four GIRK subunits are expressed in the brain, and there is a general consensus concerning the expression patterns of GIRK1, GIRK2, and GIRK3. The localization pattern of GIRK4, however, remains controversial. In this study, we exploit the negative background of mice lacking a functional GIRK4 gene to identify neuronal populations that contain GIRK4 mRNA. GIRK4 mRNA was detected in only a few regions of the mouse brain, including the deep cortical pyramidal neurons, the endopiriform nucleus and claustrum of the insular cortex, the globus pallidus, the ventromedial hypothalamic nucleus, parafascicular and paraventricular thalamic nuclei, and a few brainstem nuclei (e.g., the inferior olive and vestibular nuclei). Mice lacking GIRK4 were viable and appeared normal and did not display gross deficiencies in locomotor activity, visual tasks, and pain perception. Furthermore, GIRK4-deficient mice performed similarly to wild-type controls in the passive avoidance paradigm, a test of aversive learning. GIRK4 knock-out mice did, however, exhibit impaired performance in the Morris water maze, a test of spatial learning and memory.
Developmental Regulation of Neuronal KCaChannels by TGFβ1: Transcriptional and Posttranscriptional Effects Mediated by Erk MAP Kinase
Authors: Lhuillier Loic , Dryer Stuart E.
Published: April 2018

An avian ortholog of transforming growth factor β1 (TGFβ1) is the target-derived factor responsible for the developmental expression of large-conductance Ca2+-activated K+(KCa) channels in chick ciliary ganglion (CG) neurons developingin vivoandin vitro. Application of TGFβ1 evokes an acute stimulation of KCathat can be observed immediately after cessation of a 12 hr exposure to this factor, that persists in the presence of protein synthesis inhibitors, and that is therefore mediated by posttranslational events. Here we show that a single 3 hr exposure to TGFβ1 can also induce long-lasting stimulation of macroscopic KCathat persists for at least 3.5 d after the end of the treatment. In contrast to the acute stimulation, this sustained effect is dependent on the transcription and synthesis of new proteins at approximately the time of TGFβ1 treatment. However TGFβ1 does not cause increases in the levels ofslowpokeα subunit transcripts in CG neurons, suggesting that induction of some other protein or proteins is required for sustained enhancement of macroscopic KCa. In addition, application of TGFβ1 evoked an almost immediate but transient phosphorylation of the mitogen-activated protein kinase Erk in CG neurons. TGFβ1-evoked Erk activation was blocked by the specific MEK1 inhibitor 2- (2′-amino-3′-methoxyphenyl)-oxanaphthalen-4-one (PD98059). Moreover, application of PD98059 blocked both acute and sustained KCastimulation evoked by TGFβ1. These results indicate that TGFβ1 elicits a biphasic stimulation of KCavia activation of an MEK1–Erk pathway and raise the possibility that other neuronal effects of TGFβ superfamily members entail Erk activation.
Insulin-Like Growth Factor-1 Inhibits Mature Oligodendrocyte Apoptosis during Primary Demyelination
Authors: Mason J. L. , Ye P. , Suzuki K. , D'Ercole A. J. , Matsushima G. K.
Published: April 2018

Metabolic insult results in apoptosis and depletion of mature oligodendrocytes during demyelination. To examine the role of insulin-like growth factor-1 (IGF-1) during acute demyelination and remyelination in the adult CNS, we exposed transgenic mice that continuously express IGF-1 (IGF-1 tg) to cuprizone intoxication. Demyelination was observed within the corpus callosum in both wild-type andIGF-1 tgmice 3 weeks after exposure to cuprizone. Wild-type mice showed significant apoptotic mature oligodendrocytes and a dramatic loss of these cells within the lesion that resulted in near complete depletion and demyelination by week 5. In contrast, the demyelinated corpus callosum of theIGF-1 tgmice was near full recovery by week 5. This rapid recovery was apparently caused by survival of the mature oligodendrocyte population because apoptosis was negligible, and by week 4, the mature oligodendrocyte population was completely restored. Furthermore, despite demyelination in both wild-type andIGF-1 tgmice, oligodendrocyte progenitors accumulated only in the absence of mature oligodendrocytes and failed to accumulate if the mature oligodendrocytes remained as demonstrated in theIGF-1 tgmice. These results suggest that IGF-1 may be important in preventing the depletion of mature oligodendrocytesin vivoand thus facilitates an early recovery from demyelination.
The SNARE Vti1a-β Is Localized to Small Synaptic Vesicles and Participates in a Novel SNARE Complex
Authors: Antonin Wolfram , Riedel Dietmar , von Mollard Gabriele Fischer
Published: April 2018

Specific solubleN-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) proteins are required for different membrane transport steps. The SNARE Vti1a has been colocalized with Golgi markers and Vti1b with Golgi and thetrans-Golgi network or endosomal markers in fibroblast cell lines. Here we study the distribution of Vti1a and Vti1b in brain. Vti1b was found in synaptic vesicles but was not enriched in this organelle. A brain-specific splice variant of Vti1a was identified that had an insertion of seven amino acid residues next to the putative SNARE-interacting helix. This Vti1a-β was enriched in small synaptic vesicles and clathrin-coated vesicles isolated from nerve terminals. Vti1a-β also copurified with the synaptic vesicle R-SNARE synaptobrevin during immunoisolation of synaptic vesicles and endosomes. Therefore, both synaptobrevin and Vti1a-β are integral parts of synaptic vesicles throughout their life cycle. Vti1a-β was part of a SNARE complex in nerve terminals, which boundN-ethylmaleimide-sensitive factor and α-SNAP. This SNARE complex was different from the exocytic SNARE complex because Vti1a-β was not coimmunoprecipitated with syntaxin 1 or SNAP-25. These data suggest that Vti1a-β does not function in exocytosis but in a separate SNARE complex in a membrane fusion step during recycling or biogenesis of synaptic vesicles.
Genetic Inactivation of an Inwardly Rectifying Potassium Channel (Kir4.1 Subunit) in Mice: Phenotypic Impact in Retina
Authors: Kofuji Paulo , Ceelen Paul , Zahs Kathleen R. , Surbeck Leslie W. , Lester Henry A. , Newman Eric A.
Published: April 2018

The inwardly rectifying potassium channel Kir4.1 has been suggested to underlie the principal K+conductance of mammalian Müller cells and to participate in the generation of field potentials and regulation of extracellular K+in the retina. To further assess the role of Kir4.1 in the retina, we generated a mouse line with targeted disruption of theKir4.1gene (Kir4.1 −/−). Müller cells from Kir4.1 −/− mice were not labeled with an anti-Kir4.1 antibody, although they appeared morphologically normal when stained with an anti-glutamine synthetase antibody. In contrast, in Müller cells from wild-type littermate (Kir4.1 +/+) mice, Kir4.1 was present and localized to the proximal endfeet and perivascular processes.In situwhole-cell patch-clamp recordings showed a 10-fold increase in the input resistance and a large depolarization of Kir4.1 −/− Müller cells compared with Kir4.1 +/+ cells. The slow PIII response of the light-evoked electroretinogram (ERG), which is generated by K+fluxes through Müller cells, was totally absent in retinas from Kir4.1 −/− mice. The b-wave of the ERG, in contrast, was spared in the null mice. Overall, these results indicate that Kir4.1 is the principal K+channel subunit expressed in mouse Müller glial cells. The highly regulated localization and the functional properties of Kir4.1 in Müller cells suggest the involvement of this channel in the regulation of extracellular K+in the mouse retina.
Induction of Postnatal Schwann Cell Death by the Low-Affinity Neurotrophin ReceptorIn Vitroand after Axotomy
Authors: Syroid Daniel E. , Maycox Peter J. , Soilu-Hänninen Merja , Petratos Steven , Bucci Tamara , Burrola Patrick , Murray Simon , Cheema Surindar , Lee Kuo-Fen , Lemke Greg , Kilpatrick Trevor J.
Published: April 2018

Schwann cells express the low-affinity neurotrophin receptor (p75), but no role for either the neurotrophins or their cognate receptors in Schwann cell development has been established. We have found that Schwann cells isolated from postnatal day 1 (P1) or P2 mice that were p75-deficient exhibited potentiated survival compared to wild-type cells after growth factor and serum withdrawal. There was, however, no disparity in the survival of p75-deficient and wild-type Schwann cells isolated at embryonic day 15, suggesting that the death-inducing effects of p75 are developmentally regulated. A comparable degree of cell death was also observed in the sciatic nerves of both wild-type and p75-deficient mice at P1. However, 24 hr after axotomy, there was a 13-fold increase in the percentage of apoptotic nuclei in the distal nerve stumps of the transected sciatic nerves of neonatal wild-type but not p75-deficient mice. The expression of both the p75 and nerve growth factor (NGF) genes was upregulated after axotomy in neonatal wild-type nerves. Collectively, these results suggest that NGF-mediated activation of p75 is likely to be an important mediator of Schwann cell apoptosis in the context of peripheral nerve injury.
A Role for p27/Kip1 in the Control of Cerebellar Granule Cell Precursor Proliferation
Authors: Miyazawa Kazuhiro , Himi Toshiyuki , Garcia Veronica , Yamagishi Hisakazu , Sato Shigeaki , Ishizaki Yasuki
Published: April 2018

During development, control of proliferation of neuronal precursor cells plays a crucial role in determining the number of neurons. Proliferation is driven by mitogens, but how it is terminated remains a mystery. In this study, we examined the role of cyclin-dependent kinase inhibitors in the control of proliferation of cerebellar granule cell precursors (GCPs). Among the inhibitors we examined, only p27/Kip1 (p27) was expressed at significant levels in cells of the granule cell lineage in the developing and adult cerebellum. In developing cerebella, p27 was expressed in the external germinal layer (the deeper regions), the molecular layer, and the granule layer. In adult cerebella, p27 was expressed in the cells of the granule layer. We isolated and purified GCPs from cerebella of developing mice and examined their bromodeoxyuridine (BrdU) uptake and p27 expression at various times. We found that there was an inverse correlation between BrdU uptake and p27 expression. Even in the presence of saturating amounts of Sonic hedgehog, a potent mitogen, the cells eventually stopped dividing and differentiated, expressing p27 strongly. We also examined mice in which one or both copies of the p27 gene have been inactivated by targeted gene disruption and found that their cerebella were larger than those of wild-type mice. In cell cultures, GCPs prepared from p27-deficient mice showed enhanced proliferation compared with GCPs from wild-type mice. Taken together, these results suggest that there is an intracellular mechanism that stops GCP division and causes GCPs to differentiate and that p27 is part of this mechanism.
Differential Modulation of Proliferation in the Neocortical Ventricular and Subventricular Zones
Authors: Haydar Tarik F. , Wang Feng , Schwartz Michael L. , Rakic Pasko
Published: April 2018

Recent studies have implicated the classical neurotransmitters GABA and glutamate in the regulation of neural progenitor proliferation. We now show that GABA and glutamate have opposite effects on the two neural progenitor populations in the ventricular zones (VZs) and subventricular zones (SVZs) of the embryonic cerebrum. Application of either molecule to organotypic slice cultures dramatically increases proliferation in the VZ by shortening the cell cycle, whereas proliferation in the SVZ is decreased. These disparate effects, measured both by bromodeoxyuridine uptake and the expansion of retrovirally labeled progenitor clones, are mimicked by the application of specific GABA and glutamate agonists and are blocked by antagonists. Thus, the relative contributions of the VZ and SVZ to neocortical growth may be regulated by differential responsiveness to GABA and glutamate.
Netrin-1 Promotes Thalamic Axon Growth and Is Required for Proper Development of the Thalamocortical Projection
Authors: Braisted Janet E. , Catalano Susan M. , Stimac Robert , Kennedy Timothy E. , Tessier-Lavigne Marc , Shatz Carla J. , O'Leary Dennis D. M.
Published: April 2018

The thalamocortical axon (TCA) projection originates in dorsal thalamus, conveys sensory input to the neocortex, and has a critical role in cortical development. We show that the secreted axon guidance molecule netrin-1 actsin vitroas an attractant and growth promoter for dorsal thalamic axons and is required for the proper development of the TCA projectionin vivo. As TCAs approach the hypothalamus, they turn laterally into the ventral telencephalon and extend toward the cortex through a population ofnetrin-1-expressing cells.DCCandneogenin, receptors implicated in mediating the attractant effects of netrin-1, are expressed in dorsal thalamus, whereasunc5h2andunc5h3, netrin-1 receptors implicated in repulsion, are not.In vitro, dorsal thalamic axons show biased growth toward a source of netrin-1, which can be abolished by netrin-1-blocking antibodies. Netrin-1 also enhances overall axon outgrowth from explants of dorsal thalamus. The biased growth of dorsal thalamic axons toward the internal capsule zone of ventral telencephalic explants is attenuated, but not significantly, by netrin-1-blocking antibodies, suggesting that it releases another attractant activity for TCAs in addition to netrin-1. Analyses ofnetrin-1−/− mice reveal that the TCA projection through the ventral telencephalon is disorganized, their pathway is abnormally restricted, and fewer dorsal thalamic axons reach cortex. These findings demonstrate that netrin-1 promotes the growth of TCAs through the ventral telencephalon and cooperates with other guidance cues to control their pathfinding from dorsal thalamus to cortex.
Long-Lasting Inhibitory Synaptic Depression is Age- and Calcium-Dependent
Authors: Kotak Vibhakar C. , Sanes Dan H.
Published: April 2018

The developmental refinement of excitatory synapses is often influenced by neuronal activity, and underlying synaptic mechanisms have been suggested. In contrast, few studies have asked whether inhibitory synapses are reorganized during development and whether this is accompanied by use-dependent changes of inhibitory synaptic strength. The topographic inhibitory projection from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) undergoes synapse elimination during development (Sanes and Takács, 1993). To determine whether there is an associated period of synaptic plasticity, whole-cell recordings were obtained from developing LSO neurons of gerbils in a brain slice preparation. In current-clamp recordings, low-frequency stimulation of the MNTB led to a decline in IPSP amplitude by 43%. In voltage-clamp recordings, hyperpolarized LSO neurons also exhibited a long-lasting depression of MNTB-evoked inhibitory synaptic currents (34%) after low-frequency stimulation. When LSO neurons were depolarized, low-frequency stimulation of the MNTB produced a significantly larger inhibitory synaptic depression (59%). This synaptic plasticity declined dramatically by postnatal days 17–19. Similar to well studied forms of excitatory synaptic plasticity, inhibitory depression depended on postsynaptic calcium. We propose that such activity-dependent synaptic depression may support the developmental rearrangement of inhibitory terminals as they compete with neighboring excitatory and/or inhibitory inputs.
Selection of Currently Relevant Memories by the Human Posterior Medial Orbitofrontal Cortex
Authors: Schnider Armin , Treyer Valerie , Buck Alfred
Published: April 2018

We have demonstrated previously that patients producing spontaneous confabulations fail to suppress currently irrelevant memory traces, so that they act and think on the basis of a false, temporally displaced (past) reality. All spontaneous confabulators had anterior limbic damage, in particular of the orbitofrontal cortex and basal forebrain. These findings indicated that these structures are essential for distinguishing between mental representations of ongoing reality and currently irrelevant memories. In the present study, we used a similar experimental paradigm as in our clinical studies and H215O positron emission tomography to explore the selection of currently relevant memories by the healthy human brain. Subjects were repeatedly presented with the same set of pictures, arranged in different order each time, and were requested to indicate picture recurrences within the runs. Thus, performance in the first run depended on new learning, whereas subsequent runs required the distinction between picture repetitions within the current run (“now”) and previous picture presentations in earlier runs. Whereas initial learning activated medial temporal structures, subsequent runs provoked circumscribed posterior medial orbitofrontal activation. We suggest that this area is essential for sorting out mental associations that pertain to ongoing reality.
Prostaglandin E2Activates the Histaminergic System via the EP4Receptor to Induce Wakefulness in Rats
Authors: Huang Zhi-Li , Sato Yo , Mochizuki Takatoshi , Okada Tetsuya , Qu Wei-Min , Yamatodani Atsushi , Urade Yoshihiro , Hayaishi Osamu
Published: April 2018

Prostaglandin (PG)E2promotes the wakeful state when administered into the posterior hypothalamus, in which the histaminergic tuberomammillary nucleus (TMN) is located. To explore the neurotransmitter mechanisms responsible for PGE2-induced wakefulness in rats, we examined the effect of PGE2on the activity of the histaminergic system and the involvement of PGE2receptor subtypes in the response. PGE2perfusion in the TMN at doses of 100, 200, and 400 pmol/min for 2 hr significantly increased histamine release from the medial preoptic area and frontal cortex in a dose-dependent manner, as measured byin vivomicrodialysis. Among the agonists of the four distinct subtypes of PGE2receptors (EP1–4) tested, only the EP4receptor agonist (ONO-AE1-329) mimicked the excitatory effect of PGE2on histamine release from both the medial preoptic area and frontal cortex. Perfusion of either PGE2or the EP4agonist into the TMN at a dose of 200 pmol/min for 1 hr increased histidine decarboxylase activity, histidine decarboxylase mRNA level, and histamine content in the hypothalamus.In situhybridization revealed that EP4receptor mRNA was expressed in histidine decarboxylase-immunoreactive neurons of the TMN region. Furthermore, EP4agonist perfusion into the TMN induced wakefulness. These findings indicate that PGE2induces wakefulness through activation of the histaminergic system via EP4receptors.
Possible Involvement of P2Y2Metabotropic Receptors in ATP-Induced Transient Receptor Potential Vanilloid Receptor 1-Mediated Thermal Hypersensitivity
Authors: Moriyama Tomoko , Iida Tohko , Kobayashi Kimiko , Higashi Tomohiro , Fukuoka Tetsuo , Tsumura Hideki , Leon Catherine , Suzuki Noboru , Inoue Kazuhide , Gachet Christian , Noguchi Koichi , Tominaga Makoto
Published: April 2018

The capsaicin receptor transient receptor potential V1 (TRPV1; also known as vanilloid receptor 1) is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. It has been reported that extracellular ATP potentiates the TRPV1 currents evoked by capsaicin or protons and reduces the temperature threshold for its activation through metabotropic P2Y receptors in a PKC-dependent pathway, suggesting that TRPV1 activation could trigger the sensation of pain at normal body temperature in the presence of ATP. Here, we show that ATP-induced thermal hyperalgesia was abolished in mice lacking TRPV1, suggesting the functional interaction between ATP and TRPV1 at a behavioral level. However, thermal hyperalgesia was preserved in P2Y1receptor-deficient mice. Patch-clamp analyses using mouse dorsal root ganglion neurons indicated the involvement of P2Y2rather than P2Y1receptors. Coexpression of TRPV1 mRNA with P2Y2mRNA, but not P2Y1mRNA, was determined in the rat lumbar DRG usingin situhybridization histochemistry. These data indicate the importance of metabotropic P2Y2receptors in nociception through TRPV1.
Maturation of EPSCs and Intrinsic Membrane Properties Enhances Precision at a Cerebellar Synapse
Authors: Cathala Laurence , Brickley Stephen , Cull-Candy Stuart , Farrant Mark
Published: April 2018

The timing of action potentials is an important determinant of information coding in the brain. The shape of the EPSP has a key influence on the temporal precision of spike generation. Here we use dynamic clamp recording and passive neuronal models to study how developmental changes in synaptic conductance waveform and intrinsic membrane properties combine to affect the EPSP and action potential generation in cerebellar granule cells. We recorded EPSCs at newly formed and mature mossy fiber–granule cell synapses. Both quantal and evoked currents showed a marked speeding of the AMPA receptor-mediated component. We also found evidence for age- and activity-dependent changes in the involvement of NMDA receptors. Although AMPA and NMDA receptors contributed to quantal EPSCs at immature synapses, multiquantal release was required to activate NMDA receptors at mature synapses, suggesting a developmental redistribution of NMDA receptors. These changes in the synaptic conductance waveform result in a faster rising EPSP and reduced spike latency in mature granule cells. Mature granule cells also have a significantly decreased input resistance, contributing to a faster decaying EPSP and a reduced spike jitter. We suggest that these concurrent developmental changes, which increase the temporal precision of EPSP-spike coupling, will increase the fidelity with which sensory information is processed within the input layer of the cerebellar cortex.
Active Signal Conduction through the Sensory Dendrite of a Spider Mechanoreceptor Neuron
Authors: Gingl Ewald , French Andrew S.
Published: April 2018

Rapid responses to sensory stimulation are crucial for survival. This must be especially true for mechanical stimuli containing temporal information, such as vibration. Sensory transduction occurs at the tips of relatively long sensory dendrites in many mechanoreceptors of both vertebrates and invertebrates, but little is known about the electrical properties of these crucial links between transduction and action potential generation. The VS-3 slit-sense organ of the spiderCupiennius saleicontains bipolar mechanosensory neurons that allow voltage-clamp recording from the somata, whereas mechanotransduction occurs at the tips of 100- to 200-μm-long sensory dendrites. We studied the properties of VS-3 sensory dendrites using three approaches. Voltage-jump experiments measured the spread of voltage outward from the soma by observing total mechanically transduced charge recovered at the soma as a function of time after a voltage jump. Frequency–response measurements between pseudorandom mechanical stimulation and somatic membrane potential estimated the passive cable properties of the dendrite for voltage spread in the opposite direction. Both of these sets of data indicated that the dendritic cable would significantly attenuate and retard a passively propagated receptor potential. Finally, current-clamp observations of receptor potentials and action potentials indicated that action potentials normally start at the distal dendrites and propagate regeneratively to the soma, reducing the temporal delay of passive conduction.
Sequential Signaling through Notch1 and erbB Receptors Mediates Radial Glia Differentiation
Authors: Patten Brooke A. , Peyrin Jean Michel , Weinmaster Gerry , Corfas Gabriel
Published: April 2018

Radial glia cells both generate neurons and physically guide nascent neurons to their target destination in the cortex, and as such they are essential for CNS development. It has been proposed that in the developing cerebellum, neuronal contact induces radial glia formation, however, the mechanisms involved in this process are not well understood. Here we demonstrate that neuronal induction of radial glia formation is the result of sequential signaling through Notch1 and erbB receptors. First, Notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (BLBP) and erbB2 genes. Interestingly, two different signaling pathways mediate these effects of Notch1 on transcription, BLBP expression being dependent on Su(H), whereas erbB2 is regulated by a yet unidentified Notch1 pathway. The subsequent increase in erbB2 receptor expression makes the glia more responsive to neuronal NRG, which then induces the morphological transformation into radial glia. Thus, these results unveil some of the mechanisms underlying radial glia formation.
An Abrupt Shift in the Day/Night Cycle Causes Desynchrony in the Mammalian Circadian Center
Authors: Nagano Mamoru , Adachi Akihito , Nakahama Ken-ichi , Nakamura Toru , Tamada Masako , Meyer-Bernstein Elizabeth , Sehgal Amita , Shigeyoshi Yasufumi
Published: April 2018

The suprachiasmatic nucleus (SCN) is the neuroanatomical locus of the mammalian circadian pacemaker. Here we demonstrate that an abrupt shift in the light/dark (LD) cycle disrupts the synchronous oscillation of circadian components in the rat SCN. The phases of the RNA cycles of the period genesPer1andPer2and the cryptochrome geneCry1shifted rapidly in the ventrolateral, photoreceptive region of the SCN, but were relatively slow to shift in the dorsomedial region. During the period of desynchrony, the animals displayed increased nighttime rest, the timing of which was inversely correlated with the expression ofPer1mRNA in the dorsomedial SCN. Molecular resynchrony required ∼6 d after a 10 hr delay and 9∼13 d after a 6 hr advance of the LD cycle and was accompanied by the reemergence of normal rest–activity patterns. This dissociation and slow resynchronization of endogenous oscillators within the SCN after an LD cycle shift suggests a mechanism for the physiological symptoms that constitute jet lag.
GRK1-Dependent Phosphorylation of S and M Opsins and Their Binding to Cone Arrestin during Cone Phototransduction in the Mouse Retina
Authors: Zhu Xuemei , Brown Bruce , Li Aimin , Mears Alan J. , Swaroop Anand , Craft Cheryl M.
Published: April 2018

The shutoff mechanisms of the rod visual transduction cascade involve G-protein-coupled receptor (GPCR) kinase 1 (GRK1) phosphorylation of light-activated rhodopsin (R*) followed by rod arrestin binding. Deactivation of the cone phototransduction cascade in the mammalian retina is delineated poorly. In this study we sought to explore the potential mechanisms underlying the quenching of the phototransduction cascade in cone photoreceptors by using mouse models lacking rods and/or GRK1. Using the “pure-cone” retinas of the neural retina leucine zipper (Nrl) knock-out (KO,-/-) mice (Mears et al., 2001), we have demonstrated the light-dependent, multi-site phosphorylation of both S and M cone opsins byin situphosphorylation and isoelectric focusing. Immunoprecipitation with affinity-purified polyclonal antibodies against either mouse cone arrestin (mCAR) or mouse S and M cone opsins revealed specific binding of mCAR to light-activated, phosphorylated cone opsins. To elucidate the potential role of GRK1 in cone opsin phosphorylation, we created Nrl and Grk1 double knock-out (Nrl-/-Grk1-/-) mice by crossing the Nrl-/-mice with Grk1-/-mice (Chen et al., 1999). We found that, in the retina of these mice, the light-activated cone opsins were neither phosphorylated nor bound with mCAR. Our results demonstrate, for the first time in a mammalian species, that cone opsins are phosphorylated and that CAR binds to phosphorylated cone opsins after light activation.
Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving
Authors: Wang Junshi , Ishikawa Masago , Yang Yue , Otaka Mami , Kim James Y. , Gardner George R. , Stefanik Michael T. , Milovanovic Mike , Huang Yanhua H. , Hell Johannes W. , Wolf Marina E. , Schlüter Oliver M. , Dong Yan
Published: April 2018

In human drug users, cue-induced drug craving progressively intensifies after drug abstinence, promoting drug relapse. This time-dependent progression of drug craving is recapitulated in rodent models, in which rats exhibit progressive intensification of cue-induced drug seeking after withdrawal from drug self-administration, a phenomenon termed incubation of drug craving. Although recent results suggest that functional alterations of the nucleus accumbens (NAc) contribute to incubation of drug craving, it remains poorly understood how NAc function evolves after drug withdrawal to progressively intensify drug seeking. The functional output of NAc relies on how the membrane excitability of its principal medium spiny neurons (MSNs) translates excitatory synaptic inputs into action potential firing. Here, we report a synapse-membrane homeostatic crosstalk (SMHC) in male rats, through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the intrinsic membrane excitability of NAc MSNs, and vice versa. After short-term withdrawal from cocaine self-administration, despite no actual change in the AMPA receptor-mediated excitatory synaptic strength, GluN2B NMDA receptors, the SMHC sensors of synaptic strength, are upregulated. This may create false SMHC signals, leading to a decrease in the membrane excitability of NAc MSNs. The decreased membrane excitability subsequently induces another round of SMHC, leading to synaptic accumulation of calcium-permeable AMPA receptors and upregulation of excitatory synaptic strength after long-term withdrawal from cocaine. Disrupting SMHC-based dysregulation cascades after cocaine exposure prevents incubation of cocaine craving. Thus, cocaine triggers cascades of SMHC-based dysregulation in NAc MSNs, promoting incubated cocaine seeking after drug withdrawal.

SIGNIFICANCE STATEMENTHere, we report a bidirectional homeostatic plasticity between the excitatory synaptic input and membrane excitability of nucleus accumbens (NAc) medium spiny neurons (MSNs), through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the membrane excitability, and vice versa. Cocaine self-administration creates a false homeostatic signal that engages this synapse-membrane homeostatic crosstalk mechanism, and produces cascades of alterations in excitatory synapses and membrane properties of NAc MSNs after withdrawal from cocaine. Experimentally preventing this homeostatic dysregulation cascade prevents the progressive intensification of cocaine seeking after drug withdrawal. These results provide a novel mechanism through which drug-induced homeostatic dysregulation cascades progressively alter the functional output of NAc MSNs and promote drug relapse.
PENGARUH BALIKAN FORMATIF TERINTERGRASI STRATEGI PEMBELAJARAN DIAGRAM VEE DAN KEMAMPUAN AWAL TERHADAP PENGUASAAN KONSEP SISWA
Authors: Sofianto E. W. N. , Wartono W. , Kusairi S.
Published: April 2018

Penelitian ini bertujuan untuk mengetahui interaksi antara penilaian formatif dengan kemampuan awal terhadap penguasaan konsep siswa materi fluida statis, suhu, dan kalor. Metode penelitian menggunakan kuasi eksperimen faktorial 2 x2. Populasi penelitian ini adalah seluruh siswa kelas X MIA SMA Negeri 1 Singosari tahun ajaran 2014/2015 yang terdiri dari 5 kelas dengan jumlah 170 siswa yang akan mendapatkan materi fluida statis, suhu dan kalor. Sampel yang digunakan adalah kelas X MIA 1 dengan pembelajaran Diagram Vee-balikan formatif, sedangkan X MIA 3 menggunakan Diagram Vee-penugasan. Penguasaan konsep siswa diukur dengan tes penguasaan konsep pada materi fluida statis, suhu dan kalor. Hasil dari tes penguasaan konsep dianalisis dengan uji prasyarat analisis. Pada uji normalitas, kemampuan awal siswa dan penguasaan konsep siswa terdistribusi normal dengan nilai p (sig) > 0,05. Pada uji homogenitas, kemampuan awal siswa dan penguasaan konsep siswa data homogen dengan p (sig) > 0,05. Hasil uji hipotesis penelitian menggunakan uji Anova Two Ways, menunjukkan tidak ada interaksi antara kemampuan awal dan penilaian formatif terhadap penguasaan konsep.This study aimed to determine interaction among formative assessment, prior knowledge and the student mastery of the concept of static fluid, heat and temperature. This research used quasi experimental method using 2x2 factorial. The population was all students of grade X, science program of Senior High School Singosari, school year 2014/2015 which consists of five class with 170 students who will get material of static fluid, heat and temperature. The samples were grade X science 1 with Diagram Vee formative assessment and grade X science 3 with Diagram Vee assignment. Mastery of concepts were measured by using sumative test of static fluid, heat and temperature. Result of mastery of concepts were tested by using analysis precondition test. The normality test showed that prior knowledge and mastery of concepts of student was normally distributed with p (sig) > 0,05. The homogeneity test showed that prior knowledge and mastery of concepts of student were homogenous with p (sig) > 0,05. Result of hypothesis testing with Anova Two Ways showed no interaction among prior knowledge, formative assessment and mastery of concepts .
PENGUKURAN KUALITAS CITRA DIGITAL COMPUTED RADIOGRAPHY MENGGUNAKAN PROGRAM PENGOLAH CITRA
Authors: Ningtias D. R. , Suryono S. , Susilo S.
Published: April 2018

Penelitian yang telah dilakukan adalah pembuatan dan penghitungan kualitas citra digital menggunakan program Modulation Transfer Function (MTF) pada sistem Computed Radiography (CR) untuk kegiatan Quality Control (QC). MTF dapat digunakan untuk menganalisis resolusi spasial citra digital secara akurat. Pada penelitian ini menggunakan phantom yang terbuat dari tembaga berukuran 15x15 cm dengan ketebalan 1 mm. Phantom dieksposi dengan variasi tegangan 50 kV, 60 kV, 70 kV dan 81 kV dan masing-masing dilakukan variasi arus. Data yang diperoleh berupa file citra digital radiografi format DICOM yang kemudian dilakukan analisis kualitas citranya menggunakan PC diluar sistem CR dengan metode MTF. Metode ini sangat efisien dalam melakukan QC resolusi spasial secara kuantitatif sehingga dapat digunakan untuk menilai kualitas pesawat CR. Hasil pengukuran menunjukkan bahwa semakin tinggi tegangan yang digunakan, maka kualitas citra semakin baik dengan arus optimal pada rentang 4-8 mAs dengan rata-rata nilai resolusi spasial 7,26 lp/mm.The research was analyzing of digital image quality by using Modulation Transfer Function (MTF) on Computed Radiography (CR) system for Quality Control (QC). MTF can be used for analyzing digital image spatial resolution accurately. The research used phantom that made of 15x15 cm2 copper and 1 mm thickness. The phantom was expounded with voltage variations by 50 kV, 60 kV, 70 kV dan 81 kV and each of them have been taken by variations of the current. The the image quality of data obtained in the form of radiography digital image files with DICOM format were then analyzed using PC out of CR system with methode of MTF. This methode is really efficient for QC spatial resolution quantitatively and so it can be used for assesing the quality of CR. The measurement results showed that the higher the voltage, the better image quality with optimal current was on the range between 4-8 mAs with the average value of MTF 7,26 lp/mm.
THE PROBLEM SOLVING LEARNING MODEL BY USING VIDEO RECORDING ON EXPERIMENTS OF KINEMATICS AND DYNAMICS TO IMPROVE THE STUDENTS COGNITION AND METACOGNITION
Authors: Mariati P. S. , Betty M. T. , Sehat S.
Published: April 2018

This research aimed to improve studentss cognition and metacognition through kinematics and dynamics of particle experiment assissted by video recording and tracker software analysis. The research used problem solving learning model which developed using R & D method with 4-D steps, they are define, design, develop, and disseminate. The research involved 86 physics education students academic year 2013/2014 at one of the universities in Medan. The research method is quasi-experimental using randomized control group pretest-posttest design. The experimental class used problem solving learning model assisted by video recording and the control class used direct learning model. The cognition data were collected using multiple-choice test and meta-cognition data were collected using essay test. The studentss cognition and metacognition improvement characterized by the normalized gain score. The research result show that the use of video recording and tracker software analysis was improve the students cognition and metacognition in Kinematics and Dynamics topic in moderate category.
TSUNAMI-MAGNETIC SIGNALS AND MAGNETIC ANOMALY GENERATED BY TSUNAMI WAVE PROPAGATION AT OPEN SEAS
Authors: Prastowo T. , Cholifah L. , Ngkoimani L. O. , Safiuddin L. O.
Published: April 2018

This research examines the generation of tsunami-induced magnetic signals, where local magnetic anomaly were measured as variations in the vertical bz and horizontal bH components of the secondary field. The maximum amplitudes of bz and bH were analytically estimated and compared to magnetogram provided by INTERMAGNET and BCMT for the 2010 Chilean, the 2011 Tohoku, the 2010 Mentawai and the 2004 Aceh tsunamis. For the first two cases, frozen-flux theory was used to estimate bz and bH where the phase lag between bz and bH was ?/2, relevant to time interval of T/4 between the two signals. For the Mentawai case, oceanic diffusion was unignored and bz significantly deviated from that calculated using the theory. However, the data from Mentawai where bz ? 2 nT were in good agreement with bz generated by large tsunamis occurring in regions near the equator and with magnetogram from the Aceh event.
SCIENCE LITERACY INDICATORS IN OPTICAL INSTRUMENTS OF HIGHSCHOOL PHYSICS TEXTBOOKS CHAPTER
Authors: Rokhmah A. , Sunarno W. , Masykuri M.
Published: April 2018

The direction of current science is emphasized on the importance of science literacy skill as a preparation for students returning to community after finishing school. Science literacy skill is believed can help the individuals to solve the problem scientifically and accountable. Science textbooks are instructional tools that help students learning science. The purpose of this research is to analyse the textbooks of Physics for high school grade X about Optical Instruments topic based on science literacy indicator. The study conducted in four senior highschools. There were two textbooks used in those schools, Book A and Book B. The results showed that on average the emergence of science literacy indicator of science nomenclature was 17.5%, intellectual process skills was 45.5%, the rules of scientific evidence was 8.5%, postulate of science was 19%, and scientific disposition was 9.5%. Book A contained of more research activities than Book B, but Book B linked the second indicator more comprehensive. The advantages and disadvantages of each analyzed textbooks can be used as a further background study for developing the good quality teaching material of physics-based scientific literacy.