bluuebunny/crossref_metadata_2025 huggingface dataset:
Stabilization of Growing Retinal Axons by the Combined Signaling of Nitric Oxide and Brain-Derived Neurotrophic Factor
Authors: Ernst Alan F. , Gallo Gianluca , Letourneau Paul C. , McLoon Steven C.
Published: April 2018

The pattern of axonal projections early in the development of the nervous system lacks the precision present in the adult. During a developmental process of refinement, mistargeted projections are eliminated while correct projections are retained. Previous studies suggest that during development nitric oxide (NO) is involved in the elimination of mistargeted retinal axons, whereas brain-derived neurotrophic factor (BDNF) may stabilize retinal axon arbors. It is unclear whether these neuromodulators interact. This study showed that NO induced growth cone collapse and retraction of developing retinal axons. This effect was not attributable to NO-induced neurotoxicity. BDNF protected growth cones and axons from the effects of NO. This effect was specific to BDNF, because neither nerve growth factor (NGF) nor neurotrophin-3 (NT-3) prevented NO-induced growth cone collapse and axon retraction. Exposure to both BDNF and NO, but not either factor alone, stabilized growth cones and axons. Stabilized axons exhibited minimal retraction or extension. This response appears to be a new axon “state” and not simply a partial amelioration of the effect of NO, because lower doses of BDNF or NO allowed axon extension. Furthermore, BDNF/NO-induced growth cone stabilization correlated with the appearance of a cytochalasin D-resistant population of actin filaments. BDNF protection from NO likely was mediated locally at the level of the growth cone, because growth cones or individual filopodia in contact with BDNF-coated beads were protected from NO-induced collapse. These findings suggest a cellular mechanism by which some axonal connections are stabilized and some are eliminated during development.
Developmental Changes in the Transmitter Properties of Sympathetic Neurons That Innervate the Periosteum
Authors: Asmus Stephen E. , Parsons Sarah , Landis Story C.
Published: April 2018

During the development of sweat gland innervation, interactions with the target tissue induce a change from noradrenergic to cholinergic and peptidergic properties. To determine whether the change in neurotransmitter properties that occurs in the sweat gland innervation occurs more generally in sympathetic neurons, we identified a new target of cholinergic sympathetic neurons in rat, the periosteum, which is the connective tissue covering of bone, and characterized the development of periosteal innervation of the sternum. During development, sympathetic axons grow from thoracic sympathetic ganglia along rib periosteum to reach the sternum. All sympathetic axons displayed catecholaminergic properties when they reached the sternum, but these properties subsequently disappeared. Many axons lacked detectable immunoreactivities for vesicular acetylcholine transporter and vasoactive intestinal peptide when they reached the sternum and acquired them after arrival. To determine whether periosteum could direct changes in the neurotransmitter properties of sympathetic neurons that innervate it, we transplanted periosteum to the hairy skin, a noradrenergic sympathetic target. We found that the sympathetic innervation of the transplant underwent a noradrenergic to cholinergic and peptidergic change. These results suggest that periosteum, in addition to sweat glands, regulates the neurotransmitter properties of the sympathetic neurons that innervate it.
Thalamic-Evoked Synaptic Interactions in Barrel Cortex Revealed by Optical Imaging
Authors: Laaris Nora , Carlson Greg C. , Keller Asaf
Published: April 2018

We used optical imaging of voltage-sensitive dye signals to study the spatiotemporal spread of activity in the mouse barrel cortex, evoked by stimulation of thalamocortical afferents in anin vitroslice preparation. Stimulation of the thalamus, at low current intensity, results in activity largely restricted to a single barrel, and to the border between layers Vb and VI. Low concentrations of the GABAAreceptor antagonist bicuculline increase the amplitude of the optical signals, without affecting their spatiotemporal propagation. Higher concentrations of bicuculline result in paroxysmal activity, which propagates via intracolumnar and intercolumnar excitatory pathways. Enhancing the activity of NMDA receptors, by removing Mg2+from the extracellular solution, dramatically alters the spatiotemporal pattern of excitation: activity spreads to supragranular and infragranular layers and adjacent barrel columns. This enhanced propagation is suppressed by the NMDA receptor antagonist AP5. A similar enhancement of activity propagation can be produced by stimulating the thalamus with a short, high-frequency pulse train. Application of AP5 suppresses the frequency-dependent spread of activity. These findings indicate that the spatiotemporal spread of activity in the barrel cortex is altered by varying the temporal patterns of thalamic inputs, via an NMDA receptor-mediated mechanism, and suggest that a similar process occurs during repetitive whisking activity.
Chemical Stimulation of the Ventral Hippocampus Elevates Nucleus Accumbens Dopamine by Activating Dopaminergic Neurons of the Ventral Tegmental Area
Authors: Legault Mark , Rompré Pierre-Paul , Wise Roy A.
Published: April 2018

Dual-probe microdialysis (with HPLC and electrochemical detection) in freely moving rats and single-unit recording in anesthetized rats were used to study the extent to which impulse flow through the ventral tegmental area (VTA) contributes to elevations in nucleus accumbens (NAS) dopamine (DA) evoked by stimulation of the ventral subiculum (VS). During perfusion of artificial extracellular fluid into the VTA, injections of 0.74 μg of the excitatory amino acid NMDA into the VS elevated accumbens DA to >150% of basal values. During intra-VTA perfusion of either 1 μmtetrodotoxin (which blocks impulse flow) or 1 mmkynurenic acid (which blocks excitatory glutamate receptors), injections of NMDA into the VS failed to elevate accumbens DA. Thus, increased impulse flow through VTA DA neurons, mediated by excitatory glutamate inputs to this region, appears critical for VS stimulation to elevate NAS DA. Increased impulse flow through VTA DA neurons was confirmed using single-unit recording in anesthetized rats. Intra-VS NMDA injections increased the firing rates of 45% (14 of 31), decreased the firing rates of 13% (4 of 31), and had no effect on 42% (13 of 31) of VTA DA neurons. Increases in firing rates were evident within 15 min of NMDA injections, a time at which VS NMDA injections elevate accumbens DA in awake animals. The results of the present experiments identify the VTA as a critical site through which outputs from the VS modulate NAS dopaminergic neurotransmission.
Isolation of Current Components and Partial Reaction Cycles in the Glial Glutamate Transporter EAAT2
Authors: Otis Thomas S. , Kavanaugh Michael P.
Published: April 2018

The kinetic properties of the excitatory amino acid transporter EAAT2 were studied using rapid applications ofl-glutamate to outside-out patches excised from transfected human embryonic kidney 293 cells. In the presence of the highly permeant anion SCN−, pulses of glutamate rapidly activated transient anion channel currents mediated by the transporter. In the presence of the impermeant anion gluconate, glutamate pulses activated smaller currents predicted to result from stoichiometric flux of cotransported ions. Both anion and stoichiometric currents displayed similar kinetics, suggesting that anion channel gating and stoichiometric charge movements are linked to early transitions in the transport cycle. Transporter-mediated anion currents were recorded with ion and glutamate gradients favoring either unidirectional influx or exchange. Analysis of deactivation and recovery kinetics in these two conditions suggests that, after binding, translocation of substrate is more likely than unbinding under physiological conditions. The kinetic properties of EAAT2, the dominant glutamate transporter in brain astrocytes, distinguish it as an efficient sink for synaptically released glutamate.
Muscarinic Receptor Activation Promotes the Membrane Association of Tubulin for the Regulation of Gq-Mediated Phospholipase Cβ1Signaling
Authors: Popova Juliana S. , Rasenick Mark M.
Published: April 2018

The microtubule protein tubulin regulates adenylyl cyclase and phospholipase Cβ1(PLCβ1) signaling via transactivation of the G-protein subunits Gαs, Gαi1, and Gαq. Because most tubulin is not membrane associated, this study investigates whether tubulin translocates to the membrane in response to an agonist so that it might regulate G-protein signaling. This was studied in SK-N-SH neuroblastoma cells, which possess a muscarinic receptor-regulated PLCβ1-signaling pathway. Tubulin, at nanomolar concentrations, transactivated Gαq by the direct transfer of a GTP analog and potentiated carbachol-activated PLCβ1. A specific and time-dependent association of tubulin with plasma membranes was observed when SK-N-SH cells were treated with carbachol. The same phenomenon was observed with membranes from Sf9 cells, expressing a recombinant PLCβ1cascade. The time course of this event was concordant both with transactivation of Gαq by the direct transfer of [32P]P3(4-azidoanilido)-P1-5′-GTP from tubulin as well as with the activation of PLCβ1. In SK-N-SH cells, carbachol induced a rapid and transient translocation of tubulin to the plasma membrane, microtubule reorganization, and a change in cell shape as demonstrated by confocal immunofluorescence microscopy. These observations presented a spatial and temporal resolution of the sequence of events underlying receptor-evoked involvement of tubulin in G-protein-mediated signaling. It is suggested that G-protein-coupled receptors might modulate cytoskeletal dynamics, intracellular traffic, and cellular architecture.
Brain-Derived Neurotrophic Factor Causes cAMP Response Element-Binding Protein Phosphorylation in Absence of Calcium Increases in Slices and Cultured Neurons from Rat Visual Cortex
Authors: Pizzorusso Tommaso , Ratto Gian Michele , Putignano Elena , Maffei Lamberto
Published: April 2018

Neurotrophins play a crucial role in the developmental plasticity of the visual cortex, but very little is known about the cellular mechanisms involved in their action. In many models of synaptic plasticity, increases in cytosolic calcium concentration and activation of the transcription factor cAMP response element-binding protein (CREB) are crucial factors for the induction and maintenance of long-lasting changes of synaptic efficacy. Whether BDNF modulates intracellular calcium levels in visual cortical neurons and the significance of this action for BDNF signal transduction is still controversial. We investigated whether CREB phosphorylation and calcium changes are elicited by acute BDNF presentation in postnatal visual cortical slices and cultures. We found that BDNF did not cause any calcium increase, but it induced robust CREB phosphorylation in neurons from both preparations. We further analyzed signal transduction and its dependency on calcium changes in cultured neurons. CREB phosphorylation required trkB activation because treatment with the trk inhibitor k252a completely blocked CREB phosphorylation. In agreement with the imaging experiments, we verified that calcium changes were not necessary for CREB activation because preincubation with BAPTA-AM did not diminish the level of CREB phosphorylation induced by BDNF stimulation. CREB phosphorylation was accompanied by gene expression, because we observed the upregulation of c-fos expression, which was also not affected by preincubation with BAPTA-AM. Finally, BDNF caused phosphorylation of mitogen-activated protein kinase (MAPK), and because the treatment with the MAPK inhibitor U0126 completely abolished CREB activation and c-fos upregulation, it is likely that both processes depend mainly on the MAP kinase pathway. These results indicate that MAPK and CREB, but not intracellular calcium, are important mediators of neurotrophin actions in the visual cortex.
ATP-Mediated Glia Signaling
Authors: Cotrina Maria Luisa , Lin Jane H.-C. , López-Garcı́a Juan Carlos , Naus Christian C. G. , Nedergaard Maiken
Published: April 2018

Glia calcium signaling has recently been identified as a potent modulator of synaptic transmission. We show here that the spatial expansion of calcium waves is mediated by ATP and subsequent activation of purinergic receptors. Ectopic expression of gap junction proteins, connexins (Cxs), leads to an increase in both ATP release and the radius of calcium wave propagation. Cx expression was also associated with a phenotypic transformation, and cortical neurons extended longer neurites when co-cultured with Cx-expressing than with Cx-deficient cells. Purinergic receptor activation mediated both these effects, because treatment with receptor antagonists restored the glia phenotype and slowed neurite outgrowth. These results identify a key role of ATP in both short-term calcium signaling events and in long-term differentiation regulated by glia.
The Role of the Hyperpolarization-Activated Current in Modulating Rhythmic Activity in the Isolated Respiratory Network of Mice
Authors: Thoby-Brisson Muriel , Telgkamp Petra , Ramirez Jan-Marino
Published: April 2018

We examined the role of the hyperpolarization-activated current (Ih) in the generation of the respiratory rhythm using a spontaneously active brainstem slice of mice. This preparation contains the hypoglossus (XII) nucleus, which is activated in-phase with inspiration and the pre-Bötzinger complex (PBC), the presumed site for respiratory rhythm generation. Voltage-clamp recordings (n= 90) indicate that cesium (Cs) (5 mm) blocked 77.2% of theIhcurrent, and ZD 7288 (100 μm) blocked 85.8% of theIhcurrent. This blockade increased the respiratory frequency by 161% in Cs and by 150% in ZD 7288 and increased the amplitude of integrated population activity in the XII by 97% in Cs and by 162% in ZD 7288, but not in the PBC (Cs, by 19%; ZD 7288, by −4.56%). All inspiratory PBC neurons (n= 44) recorded in current clamp within the active network revealed a significantly decreased frequency of action potentials during the interburst interval and an earlier onset of inspiratory bursts afterIhcurrent blockade. However, hyperpolarizing current pulses evoked only in a small proportion of inspiratory neurons (0% of type I; 29% of type II neurons) a depolarizing sag. Most of the neurons expressing anIhcurrent (86%) were pacemaker neurons, which continued to generate rhythmic bursts after inactivating the respiratory network pharmacologically with CNQX alone or with CNQX, AP-5, strychnine, bicuculline, and carbenoxolone. Cs and ZD 7288 increased the frequency of pacemaker bursts and decreased the frequency of action potentials between pacemaker bursts. Our findings suggest that theIhcurrent plays an important role in modulating respiratory frequency, which is presumably mediated by pacemaker neurons.
Role for Reelin in the Development of Granule Cell Dispersion in Temporal Lobe Epilepsy
Authors: Haas Carola A. , Dudeck Oliver , Kirsch Matthias , Huszka Csaba , Kann Gunda , Pollak Stefan , Zentner Josef , Frotscher Michael
Published: April 2018

The reelin signaling pathway plays a crucial role during the development of laminated structures in the mammalian brain. Reelin, which is synthesized and secreted by Cajal–Retzius cells in the marginal zone of the neocortex and hippocampus, is proposed to act as a stop signal for migrating neurons. Here we show that a decreased expression of reelin mRNA by hippocampal Cajal–Retzius cells correlates with the extent of migration defects in the dentate gyrus of patients with temporal lobe epilepsy. These results suggest that reelin is required for normal neuronal lamination in humans, and that deficient reelin expression may be involved in migration defects associated with temporal lobe epilepsy.
Automatic Postural Responses Are Delayed by Pyridoxine-Induced Somatosensory Loss
Authors: Stapley Paul J. , Ting Lena H. , Hulliger Manuel , Macpherson Jane M.
Published: April 2018

Pyridoxine given in large doses is thought to destroy selectively the large-diameter peripheral sensory nerve fibers, leaving motor fibers intact. This study examined the effects of pyridoxine-induced somatosensory loss on automatic postural responses to sudden displacements of the support surface in the standing cat. Two cats were trained to stand on four force plates mounted on a movable platform. They were given pyridoxine (350 mg/kg, i.p.) on 2 successive days (0 and 1). Electromyographic (EMG) activity was recorded from selected hindlimb muscles during linear ramp-and-hold platform displacements in each of 12 directions at 15 cm/sec. In control trials onset latencies of evoked activity in hindlimb flexor and extensor muscles ranged from 40 to 65 msec after the onset of platform acceleration. After injection the EMG latencies increased over days, becoming two to three times longer than controls by day 7. Excursions of the body center of mass (CoM) in the direction opposite to that of platform translation were significantly greater at day 7 compared with controls, and the time at which the CoM subsequently reversed direction was delayed. Both animals were ataxic from day 2 onward. Histological analysis of cutaneous and muscle nerves in the hindlimb revealed a significant loss of fibers in the group I range. Our results suggest that large afferent fibers are critical for the timing of automatic postural responses to ensure coordinated control of the body CoM and balance after unexpected disturbances of the support surface.
Synaptic Calcium-Channel Function inDrosophila: Analysis and Transformation Rescue of Temperature-Sensitive Paralytic and Lethal Mutations ofCacophony
Authors: Kawasaki Fumiko , Collins Stephen C. , Ordway Richard W.
Published: April 2018

Voltage-gated calcium channels play a key role in chemical synaptic transmission by providing the calcium trigger for regulated neurotransmitter release. Genes encoding the primary structural subunit, α1, as well as accessory subunits of presynaptic calcium channels have now been identified in a variety of organisms. Thecacophony (cac)gene inDrosophila, also known asnightblind A, encodes a voltage-gated calcium-channel α1 subunit homologous to vertebrate α1 subunits implicated in neurotransmitter release. A recent genetic screen in our laboratory isolatedcacTS2, a conditionalcacmutant exhibiting rapid paralysis at elevated temperatures. This mutant has allowed synaptic electrophysiology after acute perturbation of a specific calcium-channel gene product, demonstrating thatcacencodes a primary calcium channel functioning in neurotransmitter release. Here we report the molecular lesion incacTS2, a missense mutation within a calcium-dependent regulatory domain of the α1 subunit, as well as phenotypic rescue of temperature-sensitive and lethalcacmutations by transgenic expression of a wild-typecaccDNA. Notably, rescue of rapid, calcium-triggered neurotransmitter release was achieved by neural expression of a single cDNA containing a subset of alternative exons and lacking any conserved synaptic-protein interaction sequence. Possible implications of these findings are discussed in the context of structure–function studies of synaptic calcium channels, as well as alternative splicing and mRNA editing of thecactranscript.
A Dual Role for the SDF-1/CXCR4 Chemokine Receptor System in Adult Brain: Isoform-Selective Regulation of SDF-1 Expression Modulates CXCR4-Dependent Neuronal Plasticity and Cerebral Leukocyte Recruitment after Focal Ischemia
Authors: Stumm Ralf K. , Rummel Jutta , Junker Vera , Culmsee Carsten , Pfeiffer Manuela , Krieglstein Josef , Höllt Volker , Schulz Stefan
Published: April 2018

The chemoattractant stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) are key modulators of immune function. In the developing brain, SDF-1 is crucial for neuronal guidance; however, cerebral functions of SDF-1/CXCR4 in adulthood are unclear. Here, we examine the cellular expression of SDF-1 isoforms and CXCR4 in the brain of mice receiving systemic lipopolysaccharide (LPS) or permanent focal cerebral ischemia. CXCR4 mRNA was constitutively expressed in cortical and hippocampal neurons and ependymal cells. Hippocampal neurons targeted the CXCR4 receptor to their somatodendritic and axonal compartments. In cortex and hippocampus, CXCR4-expressing neurons exhibited an overlapping distribution with neurons expressing SDF-1 transcripts. Although neurons synthesized SDF-1α mRNA, the SDF-1β isoform was selectively expressed by endothelial cells of cerebral microvessels. LPS stimulation dramatically decreased endothelial SDF-1β mRNA expression throughout the forebrain but did not affect neuronal SDF-1α. After focal cerebral ischemia, SDF-1β expression was selectively increased in endothelial cells of penumbral blood vessels and decreased in endothelial cells of nonlesioned brain areas. In the penumbra, SDF-1β upregulation was associated with a concomitant infiltration of CXCR4-expressing peripheral blood cells, including macrophages. Neuronal SDF-1α was transiently downregulated and neuronal CXCR4 was transiently upregulated in the nonlesioned cerebral cortex in response to ischemia. Although endothelial SDF-1β may control cerebral infiltration of CXCR4-carrying leukocytes during cerebral ischemia, the neuronal SDF-1α/CXCR4 system may contribute to ischemia-induced neuronal plasticity. Thus, the isoform-specific regulation of SDF-1 expression modulates neurotransmission and cerebral infiltration via distinct CXCR4-dependent pathways.
Inflammation-Dependent Cerebral Deposition of Serum Amyloid A Protein in a Mouse Model of Amyloidosis
Authors: Guo Jun-tao , Yu Jin , Grass David , de Beer Frederick C. , Kindy Mark S.
Published: April 2018

The major pathological hallmark of amyloid diseases is the presence of extracellular amyloid deposits. Serum amyloid A (SAA) is an apolipoprotein primarily produced in the liver. Serum protein levels can increase one thousandfold after inflammation. SAA is the precursor to the amyloid A protein found in deposits of systemic amyloid A amyloid (AA or reactive amyloid) in both mouse and human. To study the factors necessary for cerebral amyloid formation, we have created a transgenic mouse that expresses the amyloidogenic mouse Saa1 protein in the brain. Using the synapsin promoter to drive expression of theSaa1gene, the brains of transgenic mice expressed both RNA and protein. Under noninflammatory conditions, transgenic mice do not develop AA amyloid deposits in the brain; however, induction of a systemic acute-phase response in transgenic mice enhanced amyloid deposition. This deposition was preceded by an increase in cytokine levels in the brain, suggesting that systemic inflammation may be a contributing factor to the development of cerebral amyloid. The nonsteroidal anti-inflammatory agent indomethacin reduced inflammation and protected against the deposition of AA amyloid in the brain. These studies indicate that inflammation plays an important role in the process of amyloid deposition, and inhibition of inflammatory cascades may attenuate amyloidogenic processes, such as Alzheimer's disease.
Interleukin-18 Involvement in Hypoxic–Ischemic Brain Injury
Authors: Hedtjärn Maj , Leverin Anna-Lena , Eriksson Kristina , Blomgren Klas , Mallard Carina , Hagberg Henrik
Published: April 2018

Inflammation is a critical factor for development of hypoxic–ischemic (HI) brain injury. Interleukin-18 (IL-18) is a proinflammatory cytokine expressed in microglia and processed by caspase-1. Our aim was to characterize the expression of IL-18 and its receptor in relation to caspase-1 and IL-1β after HI and to evaluate to what extent IL-18 contributes to HI brain injury. Seven-day-old rats were subjected to HI, and brain tissue was sampled at different time points (3 hr to 14 d) after insult. The mRNA for IL-18 and caspase-1 were analyzed with reverse transcriptase PCR, protein was analyzed by Western blot (IL-18, caspase-1) or ELISA (IL-1β), and the regional distribution was assessed by immunohistochemistry. HI was also induced in C57BL/6 mice, and brain injury in IL-18-deficient animals was compared with that in wild-type animals. The expression of mRNA/protein for caspase-1 and IL-18 in brain homogenates increased progressively at 12 hr to 14 d after HI, whereas IL-1β peaked at 8 hr. A widespread expression of caspase-1 and IL-18 protein in microglia was found in the HI hemisphere. The IL-18 receptor was expressed on neurons of the cerebral cortex and thalamus. IL-1β was primarily found in microglia in the habenular nucleus of the thalamus. The infarct volume was reduced by 21% (p= 0.01), and the neuropathology score was significantly decreased in the cerebral cortex (−35%), hippocampus (−22%), striatum (−18%), and thalamus (−17%) in mice with IL-18 deficiency compared with wild-type mice. In conclusion, we found that IL-18 expression in microglia was markedly increased after HI and that IL-18 appears to be important for the development of HI brain injury.
Activation of Presynaptic P2X7-Like Receptors Depresses Mossy Fiber–CA3 Synaptic Transmission through p38 Mitogen-Activated Protein Kinase
Authors: Armstrong John N. , Brust Tyson B. , Lewis Randall G. , MacVicar Brian A.
Published: April 2018

P2X7receptor subunits form homomeric ATP-gated, calcium-permeable cation channels. In this study, we used Western blots and immunocytochemistry to demonstrate that P2X7receptors are abundant on presynaptic terminals of mossy fiber synapses in the rat hippocampus. P2X7-immunoreactive protein was detected using a specific P2X7antibody in Western blots of protein isolated from whole hippocampus and from a subcellular fraction containing mossy fiber synaptosomes. P2X7immunoreactivity was colocalized with syntaxin 1A/B-immunoreactivity in mossy fiber terminals in the dentate hilus and stratum lucidum of CA3. Extracellular and whole-cell voltage-clamp recordings in CA3 revealed that bath application of the potent P2X7agonist 2′,3′-O-(4-benzoylbenzoyl)-ATP (Bz-ATP) caused a long-lasting inhibition of neurotransmission at mossy fiber–CA3 synapses. Consistent with a presynaptic action at mossy fiber synapses, Bz-ATP had no significant effect on neurotransmission at associational–commissural synapses in CA3 but increased paired-pulse facilitation during depression of mossy fiber evoked currents. In addition, Bz-ATP had no postsynaptic effect on holding current or conductance of CA3 neurons. Bz-ATP-induced mossy fiber synaptic depression was blocked by the P2X7antagonist oxidized ATP but not by the P2X1–3,5,6antagonist pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid or the P2Y antagonist reactive blue 2. Finally, an antagonist of p38 MAP kinase activation [4-(4-fluorophenyl)2-(4-methylsulfinylphenyl)5-(4-pyridyl)imidazole] but not extracellular signal-regulated kinase 1/2 MAP kinase (2′-amino-3′-methoxyflavone) blocked the synaptic depression mediated by Bz-ATP, suggesting that this presynaptic inhibition was mediated by activation of p38 MAP kinase. The results of the present study demonstrate that activation of presynaptic P2X7receptors depresses mossy fiber–CA3 synaptic transmission through activation of p38 MAP kinase.
Concurrent Autoreceptor-Mediated Control of Dopamine Release and Uptake during Neurotransmission: AnIn VivoVoltammetric Study
Authors: Wu Qun , Reith Maarten E. A. , Walker Q. David , Kuhn Cynthia M. , Carroll F. Ivy , Garris Paul A.
Published: April 2018

Receptor-mediated feedback control plays an important role in dopamine (DA) neurotransmission. Recent evidence suggests that release and uptake, key mechanisms determining brain extracellular levels of the neurotransmitter, are governed by presynaptic autoreceptors. The goal of this study was to investigate whether autoreceptors regulate both mechanisms concurrently. Extracellular DA in the caudate–putamen and nucleus accumbens, evoked by electrical stimulation of the medial forebrain bundle, was monitored in the anesthetized rat by real-time voltammetry. Effects of the D2antagonist haloperidol (0.5 mg/kg, i.p.) on evoked DA levels were measured to evaluate autoreceptor control mechanisms. Two strategies were used to resolve individual contributions of release and uptake to the robust increases in DA signals observed after acute haloperidol challenge in naive animals: pretreatment with 3β-(p-chlorophenyl)tropan-2β-carboxylic acidp-isothiocyanatophenylmethyl ester hydrochloride (RTI-76; 100 nmol, i.c.v.), an irreversible inhibitor of the DA transporter, and kinetic analysis of extracellular DA dynamics. RTI-76 effectively removed the uptake component from recorded signals. In RTI-76-pretreated rats, haloperidol induced only modest increases in DA elicited by low frequencies and had little or no effect at high frequencies. These results suggest that D2antagonism alters uptake at all frequencies but only release at low frequencies. Kinetic analysis similarly demonstrated that haloperidol decreasedVmaxfor DA uptake and increased DA release at low (10–30 Hz) but not high (40–60 Hz) stimulus frequencies. We conclude that presynaptic DA autoreceptors concurrently downregulate release and upregulate uptake, and that the mechanisms are also independently controlled during neurotransmission.
Interactions between Heterotypic Stressors and Corticosterone Reveal Integrative Mechanisms for Controlling Corticotropin-Releasing Hormone Gene Expression in the Rat Paraventricular Nucleus
Authors: Watts Alan G. , Sanchez-Watts Graciela
Published: April 2018

Although the convergence of neural and humoral afferent information onto paraventricular neuroendocrine corticotropin-releasing hormone (CRH) neurons is a major determinant for adaptive stress responses, the underlying integrative mechanisms are poorly understood. To dissect the relative contributions made by neural afferents and corticosterone to these processes, we determined how the concurrent application of two heterotypic physiological stressors, chronic dehydration (produced by drinking hypertonic saline) and sustained hypovolemia (produced by subcutaneous injections of polyethylene glycol), is interpreted by the synthetic and secretory activity of CRH neurons usingin situhybridization and plasma ACTH measurements. These two stressors are encoded by relatively simple, distinct, and well defined sets of neural afferents to CRH neurons. Both increase plasma corticosterone, but they have opposing actions onCRHgene expression when applied separately. In the first experiment, we showed that chronic dehydration suppressesCRHgene transcription after hypovolemia, but not the preproenkephalin and c-fosmRNA responses or ACTH secretion. In the second, we showed that negative feedback actions of corticosterone do not suppressCRHgene activation after hypovolemia, but instead determine the prestress lower limit of a range within which the CRH gene then responds. Collectively, these data show that at least two processes are integrated to control how theCRHgene responds to multiple stimuli. First, the presence of corticosterone, which although permissive for appropriately activating the CRH gene during hypovolemia, does not mediate the suppressed gene response. Second, neural afferent-driven processes that encode dehydration play a central role in suppressing CRH activation.
Involvement of the Olfactory Tubercle in Cocaine Reward: Intracranial Self-Administration Studies
Authors: Ikemoto Satoshi
Published: April 2018

Cocaine has multiple actions and multiple sites of action in the brain. Evidence from pharmacological studies indicates that it is the ability of cocaine to block dopamine uptake and elevate extracellular dopamine concentrations, and thus increase dopaminergic receptor activation, that makes cocaine rewarding. Lesion studies have implicated the nucleus accumbens (the dorsal portion of the “ventral striatum”) as the probable site of the rewarding action of the drug. However, the drug is only marginally self-administered into this site. We now report that cocaine (60 or 200 mmin 75 nl/infusion) is readily self-administered into the olfactory tubercle, the most ventral portion of the ventral striatum. Cocaine (200 mm) was self-administered marginally into the accumbens shell but not into the core, dorsal striatum, or ventral pallidum. In addition, cocaine injections (200 mmin 300 nl) into the tubercle but not the shell or ventral pallidum induced conditioned place preference. Rewarding effects of cocaine in the tubercle were blocked by coadministration of dopamine D1or D2antagonists (1 mmSCH 23390 or 3 mmraclopride) and were not mimicked by injections of the local anesthetic procaine (800 mm). In conclusion, the tubercle plays a critical role in mediating rewarding action of cocaine.
Two Distinct Subpopulations of Nestin-Positive Cells in Adult Mouse Dentate Gyrus
Authors: Fukuda Satoshi , Kato Fusao , Tozuka Yusuke , Yamaguchi Masahiro , Miyamoto Yusei , Hisatsune Tatsuhiro
Published: April 2018

Neurogenesis in the dentate gyrus of the adult mammalian hippocampus has been proven in a series of studies, but the differentiation process toward newborn neurons is still unclear. In addition to the immunohistochemical study, electrophysiological membrane recordings of precursor cells could provide an alternative view to address this differentiation process. In this study, we performed green fluorescent protein (GFP)-guided selective recordings of nestin-positive progenitor cells in adult dentate gyrus by means of nestin-promoter GFP transgenic mice, because nestin is a typical marker for precursor cells in the adult dentate gyrus. The patch-clamp recordings clearly demonstrated the presence of two distinct subpopulations (type I and type II) of nestin-positive cells. Type I cells had a lower input resistance value of 77.1 MΩ (geometric mean), and their radial processes were stained with anti-glial fibrillary acidic protein antibody. On the other hand, type II nestin-positive cells had a higher input resistance value of 2110 MΩ and expressed voltage-dependent sodium current. In most cases, type II cells were stained with anti-polysialylated neural cell adhesion molecule. Taken together with a bromodeoxyuridine pulse-chase analysis, our results may reflect a rapid and dynamic cell conversion of nestin-positive progenitor, from type I to type II, at an early stage of adult neurogenesis in the dentate gyrus.
Aberrant Formation of Glutamate Receptor Complexes in Hippocampal Neurons of Mice Lacking the GluR2 AMPA Receptor Subunit
Authors: Sans Nathalie , Vissel Bryce , Petralia Ronald S. , Wang Ya-Xian , Chang Kai , Royle Gordon A. , Wang Chang-Yu , O'Gorman Steve , Heinemann Stephen F. , Wenthold Robert J.
Published: April 2018

The number and type of receptors present at the postsynaptic membrane determine the response to the neurotransmitter released from the presynaptic terminal. Because most neurons receive multiple and distinct synaptic inputs and contain several different subtypes of receptors stimulated by the same neurotransmitter, the assembly and trafficking of receptors in neurons is a complex process involving many levels of regulation. To investigate the mechanism that neurons use to regulate the assembly of receptor subunits, we studied a GluR2 knock-out mouse. GluR2 is a critical subunit that controls calcium permeability of AMPA receptors and is present in most native AMPA receptors. Our data indicate that in the absence of GluR2, aberrant receptor complexes composed of GluR1 and GluR3 are formed in the hippocampus, and that there is an increased number of homomeric GluR1 and GluR3 receptors. We also show that these homomeric and heteromeric receptors are less efficiently expressed at the synapse. Our results show that GluR2 plays a critical role in controlling the assembly of AMPA receptors, and that the assembly of subunits may reflect the affinity of one subunit for another or the stability of intermediates in the assembly process. Therefore, GluR1 may have a greater preference for GluR2 than it does for GluR3.
Hyperdopaminergic Mutant Mice Have Higher “Wanting” But Not “Liking” for Sweet Rewards
Authors: Peciña Susana , Cagniard Barbara , Berridge Kent C. , Aldridge J. Wayne , Zhuang Xiaoxi
Published: April 2018

What is the role of dopamine in natural rewards? A genetic mutant approach was taken to examine the consequences of elevated synaptic dopamine on (1) spontaneous food and water intake, (2) incentive motivation and learning to obtain a palatable sweet reward in a runway task, and (3) affective “liking” reactions elicited by the taste of sucrose. A dopamine transporter (DAT) knockdown mutation that preserves only 10% of normal DAT, and therefore causes mutant mice to have 70% elevated levels of synaptic dopamine, was used to identify dopamine effects on food intake and reward. We found that hyperdopaminergic DAT knockdown mutant mice have higher food and water intake. In a runway task, they demonstrated enhanced acquisition and greater incentive performance for a sweet reward. Hyperdopaminergic mutant mice leave the start box more quickly than wild-type mice, require fewer trials to learn, pause less often in the runway, resist distractions better, and proceed more directly to the goal. Those observations suggest that hyperdopaminergic mutant mice attribute greater incentive salience (“wanting”) to a sweet reward in the runway test. But sucrose taste fails to elicit higher orofacial “liking” reactions from mutant mice in an affective taste reactivity test. These results indicate that chronically elevated extracellular dopamine facilitates “wanting” and learning of an incentive motivation task for a sweet reward, but elevated dopamine does not increase “liking” reactions to the hedonic impact of sweet tastes.
Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington's Disease Mice
Authors: Ferrante Robert J. , Kubilus James K. , Lee Junghee , Ryu Hoon , Beesen Ayshe , Zucker Birgit , Smith Karen , Kowall Neil W. , Ratan Rajiv R. , Luthi-Carter Ruth , Hersch Steven M.
Published: April 2018

The precise cause of neuronal death in Huntington's disease (HD) is unknown. Although no single specific protein-protein interaction of mutant huntingtin has emerged as the pathologic trigger, transcriptional dysfunction may contribute to the neurodegeneration observed in HD. Pharmacological treatment using the histone deacetylase inhibitor sodium butyrate to modulate transcription significantly extended survival in a dose-dependent manner, improved body weight and motor performance, and delayed the neuropathological sequelae in the R6/2 transgenic mouse model of HD. Sodium butyrate also increased histone and Specificity protein-1 acetylation and protected against 3-nitropropionic acid neurotoxicity. Microarray analysis showed increased expression of α- and β-globins and MAP kinase phosphatase-1 in sodium butyrate-treated R6/2 mice, indicative of improved oxidative phosphorylation and transcriptional regulation. These findings strengthen the hypothesis that transcriptional dysfunction plays a role in the pathogenesis of HD and suggest that therapies aimed at modulating transcription may target early pathological events and provide clinical benefits to HD patients.
The Synaptic Properties of Cells Define the Hallmarks of Interval Timing in a Recurrent Neural Network
Authors: Pérez Oswaldo , Merchant Hugo
Published: April 2018

Extensive research has described two key features of interval timing. The bias property is associated with accuracy and implies that time is overestimated for short intervals and underestimated for long intervals. The scalar property is linked to precision and states that the variability of interval estimates increases as a function of interval duration. The neural mechanisms behind these properties are not well understood. Here we implemented a recurrent neural network that mimics a cortical ensemble and includes cells that show paired-pulse facilitation and slow inhibitory synaptic currents. The network produces interval selective responses and reproduces both bias and scalar properties when a Bayesian decoder reads its activity. Notably, the interval-selectivity, timing accuracy, and precision of the network showed complex changes as a function of the decay time constants of the modeled synaptic properties and the level of background activity of the cells. These findings suggest that physiological values of the time constants for paired-pulse facilitation and GABAb, as well as the internal state of the network, determine the bias and scalar properties of interval timing.

SIGNIFICANCE STATEMENTTiming is a fundamental element of complex behavior, including music and language. Temporal processing in a wide variety of contexts shows two primary features: time estimates exhibit a shift toward the mean (the bias property) and are more variable for longer intervals (the scalar property). We implemented a recurrent neural network that includes long-lasting synaptic currents, which cannot only produce interval-selective responses but also follow the bias and scalar properties. Interestingly, only physiological values of the time constants for paired-pulse facilitation and GABAb, as well as intermediate background activity within the network can reproduce the two key features of interval timing.
Popping-a-Squat and Other Bits of Ephemera
Authors: Dykins Callahan Sara
Published: April 2018

This project posits the practice of scrapbooking as an arts-based, performative autoethnographic method of inquiry that allows me to interrogate my experiences teaching a tourism course grounded in critical performative pedagogy. Teaching American Expedition was sublime and, in its sublimity, it resists linear, dispassionate analysis. Choosing an arts-based method of inquiry, such as scrapbooking, opens up possibilities of thinking and understanding beyond the limitations of language, of honoring bodied experiences that are not easily or necessarily speakable, and of exploring how care is enacted in and through the practice of my pedagogy.
Epigenetic regulation in the tumorigenesis of MEN1-associated endocrine cell types
Authors: Iyer Sucharitha , Agarwal Sunita K
Published: April 2018

Epigenetic regulation is emerging as a key feature in the molecular characteristics of various human diseases. Epigenetic aberrations can occur from mutations in genes associated with epigenetic regulation, improper deposition, removal or reading of histone modifications, DNA methylation/demethylation and impaired non-coding RNA interactions in chromatin. Menin, the protein product of the gene causative for the multiple endocrine neoplasia type 1 (MEN1) syndrome, interacts with chromatin-associated protein complexes and also regulates some non-coding RNAs, thus participating in epigenetic control mechanisms. Germline inactivating mutations in theMEN1gene that encodes menin predispose patients to develop endocrine tumors of the parathyroids, anterior pituitary and the duodenopancreatic neuroendocrine tissues. Therefore, functional loss of menin in the various MEN1-associated endocrine cell types can result in epigenetic changes that promote tumorigenesis. Because epigenetic changes are reversible, they can be targeted to develop therapeutics for restoring the tumor epigenome to the normal state. Irrespective of whether epigenetic alterations are the cause or consequence of the tumorigenesis process, targeting the endocrine tumor-associated epigenome offers opportunities for exploring therapeutic options. This review presents epigenetic control mechanisms relevant to the interactions and targets of menin, and the contribution of epigenetics in the tumorigenesis of endocrine cell types from menin loss.
Modulation of Gq-Rho Signaling by the ERK MAPK Pathway Controls Locomotion in Caenorhabditis elegans
Authors: Coleman Brantley , Topalidou Irini , Ailion Michael
Published: April 2018

The heterotrimeric G protein Gq regulates neuronal activity through distinct downstream effector pathways. In addition to the canonical Gq effector phospholipase Cβ, the small GTPase Rho was recently identified as a conserved effector of Gq. To identify additional molecules important for Gq signaling in neurons, we performed a forward genetic screen in the nematode Caenorhabditis elegans for suppressors of the hyperactivity and exaggerated waveform of an activated Gq mutant. We isolated two mutations affecting the MAP kinase scaffold protein KSR-1 and found that KSR-1 modulates locomotion downstream of, or in parallel to, the Gq-Rho pathway. Through epistasis experiments, we found that the core ERK MAPK cascade is required for Gq-Rho regulation of locomotion, but that the canonical ERK activator LET-60/Ras may not be required. Through neuron-specific rescue experiments, we found that the ERK pathway functions in head acetylcholine neurons to control Gq-dependent locomotion. Additionally, expression of activated LIN-45/Raf in head acetylcholine neurons is sufficient to cause an exaggerated waveform phenotype and hypersensitivity to the acetylcholinesterase inhibitor aldicarb, similar to an activated Gq mutant. Taken together, our results suggest that the ERK MAPK pathway modulates the output of Gq-Rho signaling to control locomotion behavior in C. elegans.
Impact of lifestyle intervention on dry eye disease in office workers: a randomized controlled trial
Authors: Kawashima Motoko , Sano Kokoro , Takechi Sayuri , Tsubota Kazuo
Published: April 2018

Objectives

To evaluate the effects of a 2month lifestyle intervention for dry eye disease in office workers.

Methods

Prospective interventional study (randomized controlled study) . Forty-one middle-aged Japanese office workers (men, 22; women, 19; 39.2±8.0 years) with definite and probable dry eye disease were enrolled and randomized to an intervention group (n = 22) and a control group (n = 19). The intervention aimed at modifying diet, increasing physical activity, and encouraging positive thinking. The primary outcome was change in dry eye disease diagnoses. Secondary outcome was change in disease parameters, including dry eye symptoms, as assessed using the Dry Eye-Related Quality of Life Score, corneal and conjunctival staining scores, tear break-up time, and Schirmer test results.

Results

A total of 36 participants (intervention group, 17; control group, 19) completed the study. The number of definite dry eye disease diagnoses decreased from four to none (p = .05), and the dry eye symptom score showed a significant decrease in the intervention group (p = .03). In contrast, the corneal and conjunctival staining scores, tear break-up time, and Schirmer test results did not differ significantly between groups.

Conclusions

The 2-month lifestyle intervention employed in this study improved dry eye disease status among office workers, with a considerable decrease in subjective symptoms. Lifestyle intervention may be a promising management option for dry eye disease, although further investigation of long-term effects are required.