bluuebunny/crossref_metadata_2025 huggingface dataset:
Globus Pallidus Discharge Is Coincident with Striatal Activity during Global Slow Wave Activity in the Rat
Authors: Goldberg Joshua A. , Kats Svetlana S. , Jaeger Dieter
Published: April 2018

The emergence of bursting and oscillations in the basal ganglia under normal and pathological conditions has attracted considerable interest, but the neural substrate of these patterns is poorly understood. Here we use multisite recordings in anesthetized rats to examine the relationship of globus pallidus (GP) spiking and striatal activity in relation to cortical slow-wave activity. We found that GP neurons displayed increased spike rates or bursts coincident with cortical activation and striatal up states. Furthermore, the onset of GP bursts typically coincides with transitions to striatal up states that precede striatal spiking. These data indicate that GP activity is driven by excitatory corticosubthalamic input during periods of synchronized bursting activity.
Peptidergic Activation of Locomotor Pattern Generators in the Neonatal Spinal Cord
Authors: Pearson Selina A. , Mouihate Abdeslam , Pittman Quentin J. , Whelan Patrick J.
Published: April 2018

The development of motor networks in the spinal cord is partly activity-dependent. We have observed receptor-mediated excitatory effects of two peptides, arginine vasopressin (AVP) and oxytocin (OXT), on motor network activity in the neonate. With the use of an en blocin vitropreparation of mouse spinal cord (2-3 d old), which either was isolated completely or had muscles of the hindlimb left intact, we show that the bath application of AVP or OXT can evoke an increase in population bursting of motoneurons recorded from the lumbar ventral roots. By using antagonists for AVP and OXT, we found that these peptides were binding primarily to V1aand OXT receptors, respectively. Western blot analysis revealed a 48 kDa V1aand a 55 kDa OXT receptor immunoreactive band that was expressed in tissue obtained from L1-L6 sections of spinal cord. AVP, but not OXT, could, on occasion, evoke sustained periods of locomotor-like activity. In addition, when we applied AVP or OXT in combination with a 5-HT2agonist, bouts of locomotor-like activity could be observed in a majority of preparations. Collectively, these data point to a novel role for AVP and OXT in the activation of spinal motor networks.
Two Modes of Vesicle Recycling in the Rat Calyx of Held
Authors: de Lange R. P. J. , de Roos A. D. G. , Borst J. G. G.
Published: April 2018

Vesicle recycling was studied in the rat calyx of Held, a giant brainstem terminal involved in sound localization. Stimulation of brain slices containing the calyx-type synapse with a high extracellular potassium ion concentration in the presence of horseradish peroxidase resulted within several minutes in a reduction of the number of neurotransmitter vesicles and in the appearance of labeled endosome-like structures. After returning to normal solution, the endosome-like structures disappeared over a period of several minutes, whereas simultaneously the number of labeled vesicles increased. A comparison with afferent stimulation suggested that the endosome-like structures normally do not participate in the vesicle cycle. Afferent stimulation at 5 Hz resulted in sustained synaptic transmission, without vesicle depletion but with an estimated endocytotic activity of <0.2 synaptic vesicles per active zone per second. At 20 Hz, the presynaptic action potentials generally failed during prolonged stimulation. In identified synapses, the number of vesicles labeled by photoconversion after stimulation at 5 Hz in the presence of the styryl dye RH414 was much lower than the number of vesicles that were released, as determined by measuring EPSCs. No more than ∼5% of the vesicles were labeled after 20 min stimulation at 5 Hz, whereas this stimulation protocol was sufficient to largely destain a terminal after previous loading.

The results support a scheme for recycling in which two different modes coexist. At physiological demands, a pool of ∼5% of all vesicles provides sufficient vesicles for release. During intense stimulation, such as occurs in the presence of high extracellular K+, the synapse resorts to bulk endocytosis, a very slow mode of recycling.
The DEP Domain Determines Subcellular Targeting of the GTPase Activating Protein RGS9In Vivo
Authors: Martemyanov Kirill A. , Lishko Polina V. , Calero Nidia , Keresztes Gabor , Sokolov Maxim , Strissel Katherine J. , Leskov Ilya B. , Hopp Johnathan A. , Kolesnikov Alexander V. , Chen Ching-Kang , Lem Janis , Heller Stefan , Burns Marie E. , Arshavsky Vadim Y.
Published: April 2018

DEP (for Disheveled, EGL-10, Pleckstrin) homology domains are present in numerous signaling proteins, including many in the nervous system, but their function remains mostly elusive. We report that the DEP domain of a photoreceptor-specific signaling protein, RGS9 (for regulator of G-protein signaling 9), plays an essential role in RGS9 delivery to the intracellular compartment of its functioning, the rod outer segment. We generated a transgenic mouse in which RGS9 was replaced by its mutant lacking the DEP domain. We then used a combination of the quantitative technique of serial tangential sectioning-Western blotting with electrophysiological recordings to demonstrate that mutant RGS9 is expressed in rods in the normal amount but is completely excluded from the outer segments. The delivery of RGS9 to rod outer segments is likely to be mediated by the DEP domain interaction with a transmembrane protein, R9AP (for RGS9 anchoring protein), known to anchor RGS9 on the surface of photoreceptor membranes and to potentiate RGS9 catalytic activity. We show that both of these functions are also abolished as the result of the DEP domain deletion. These findings indicate that a novel function of the DEP domain is to target a signaling protein to a specific compartment of a highly polarized neuron. Interestingly, sequence analysis of R9AP reveals the presence of a conserved R-SNARE (for solubleN-ethylmaleimide-sensitive factor attachment protein receptor) motif and a predicted overall structural homology with SNARE proteins involved in vesicular trafficking and fusion. This presents the possibility that DEP domains might serve to target various DEP-containing proteins to the sites of their intracellular action via interactions with the members of extended SNARE protein family.
Surround Antagonism in Macaque Cone Photoreceptors
Authors: Verweij Jan , Hornstein Eric P. , Schnapf Julie L.
Published: April 2018

Center-surround antagonism is a hallmark feature of the receptive fields of sensory neurons. In retinas of lower vertebrates, surround antagonism derives in part from inhibition of cone photoreceptors by horizontal cells. Using whole-cell patch recording methods, we found that light-evoked responses of cones in macaque monkey were antagonized when surrounding cones were illuminated. The spatial and spectral properties of this antagonism indicate that it results from inhibition by horizontal cells. It has been suggested that horizontal cell inhibition is mediated by the neurotransmitter GABA. The inhibition observed here, however, was inconsistent with a GABA-gated chloride conductance mechanism. Instead, surround illumination evoked an increase in calcium conductance and calcium-activated chloride conductance in cones. We expect that these conductances modulate neurotransmitter release at the cone synapse and increase visual sensitivity to spatial contrast.
A Calcium-Induced Calcium Influx Factor, Nitric Oxide, Modulates the Refilling of Calcium Stores in Astrocytes
Authors: Li Nianzhen , Sul Jai-Yoon , Haydon Philip G.
Published: April 2018

The roles of nitric oxide are primarily undefined in astrocytes, cells that are active partners in synaptic transmission. Because nitric oxide synthases are present in astrocytes, we imaged the formation of nitric oxide in cultured murine cortical astrocytes using DAF-FM (4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate). We demonstrated that physiological concentrations of ATP induced a Ca2+-dependent production of nitric oxide. We then investigated the roles of nitric oxide in astrocytic Ca2+signaling by exogenous application of a nitric oxide donor and found that nitric oxide induced an influx of external Ca2+. Because these observations raise the possibility that nitric oxide-dependent Ca2+influx could lead to the refilling of internal stores with Ca2+, we directly monitored the Ca2+levels of the cytosol and of internal stores while manipulating nitric oxide. Cultures were coloaded with mag-fluo-4 and X-rhod-1 to differentially load the internal stores and cytosol, respectively. ATP induced a cytosolic increase in Ca2+that results from the IP3-dependent release of Ca2+from internal stores, detected as a simultaneous reduction in mag-fluo-4 and an increase in X-rhod-1 fluorescence. To monitor store refilling, we measured the recovery of mag-fluo-4 fluorescence after removal of ATP. When nitric oxide signaling was blocked by the nitric oxide scavenger 2-phenyl-4,4,5,5-ketramethyl-imidazoline-1-oxyl-3-oxide or by the nitric oxide synthase inhibitorNG-monomethyl-l-arginine, fluorescence recovery was significantly reduced. These data suggest that transmitters that induce Ca2+signaling in astrocytes lead to the Ca2+-dependent synthesis of nitric oxide. This in turn stimulates a Ca2+influx pathway that is, in part, responsible for the refilling of internal Ca2+stores.
Role of Tetrodotoxin-Resistant Na+Current Slow Inactivation in Adaptation of Action Potential Firing in Small-Diameter Dorsal Root Ganglion Neurons
Authors: Blair Nathaniel T. , Bean Bruce P.
Published: April 2018

When acutely dissociated small-diameter dorsal root ganglion (DRG) neurons were stimulated with repeated current injections or prolonged application of capsaicin, their action potential firing quickly adapted. Because TTX-resistant (TTX-R) sodium current in these presumptive nociceptors generates a large fraction of depolarizing current during the action potential, we examined the possible role of inactivation of TTX-R sodium channels in producing adaptation. Under voltage clamp, TTX-R current elicited by short depolarizations showed strong use dependence at frequencies as low as 1 Hz, although recovery from fast inactivation was complete in ∼10-30 msec. This use-dependent reduction was the result of the entry of TTX-R sodium channels into slow inactivated states. Slow inactivation was more effectively produced by steady depolarization than by cycling channels through open states. Slow inactivation was steeply voltage dependent, with a Boltzmann slope factor of 5 mV, a midpoint near -45 mV (5 sec conditioning pulses), and completeness of ∼93% positive to -20 mV. The time constant for entry (∼200 msec) was independent of voltage from -20 mV to +60 mV, whereas recovery kinetics were moderately voltage dependent (time constant, ∼1.5 sec at -60 mV and ∼0.5 sec at -100 mV). Using a prerecorded current-clamp response to capsaicin as a voltage-clamp command waveform, we found that adaptation of firing occurred with a time course similar to that of development of slow inactivation. Thus, slow inactivation of the TTX-R sodium current limits the duration of small DRG cell firing in response to maintained stimuli and may contribute to cross desensitization between chemical and electrical stimuli.
Paradoxical Actions of Hydrogen Peroxide on Long-Term Potentiation in Transgenic Superoxide Dismutase-1 Mice
Authors: Kamsler Ariel , Segal Menahem
Published: April 2018

Hydrogen peroxide (H2O2), a reactive oxygen species, is assumed to have a detrimental effect on neuronal plasticity. Indeed, H2O2suppresses long-term potentiation (LTP) in hippocampal slices of normal rats and wild-type (wt) mice. Transgenic mice overexpressing superoxide dismutase (SOD) 1 (tg-SOD), which maintain high ambient H2O2, have also been shown to be impaired in their ability to express hippocampal LTP. Paradoxically, H2O2,at a concentration (50 μm) that blocks LTP in wt mice, actually enhanced LTP in slices of 2-month-old tg-SOD mice. H2O2-dependent LTP in tg-SOD was blocked by the protein phosphatase calcineurin inhibitor FK506, but not by rapamycin, an FK-binding protein 12 (FKBP12) inhibitor or by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7), a serine-kinase inhibitor. Interestingly, wt and tg-SOD mice expressed similar levels of the antioxidant enzyme catalase and similar activity of glutathione peroxidase. An opposite situation was found in 2-year-old mice. Aged wt mice were impaired in LTP in a manner that could be reversed by the addition of H2O2. Surprisingly, aged tg-SOD mice exhibited larger LTP than that found in wt mice, but this was now reduced by 50 μmH2O2. Both young tg-SOD and aged control mice displayed altered protein phosphatase activity, compared with that of young controls; moreover, FK506 inhibited LTP in old tg-SOD as well as in old wt mice treated with H2O2. These data promoted a dual role for H2O2in the regulation of LTP, and proposed that it is mediated by the protein phosphatase calcineurin.
Decreased Anxiety, Altered Place Learning, and Increased CA1 Basal Excitatory Synaptic Transmission in Mice with Conditional Ablation of the Neural Cell Adhesion Molecule L1
Authors: Law Janice W. S. , Lee Alan Y. W. , Sun Mu , Nikonenko Alexander G. , Chung Sookja K. , Dityatev Alexander , Schachner Melitta , Morellini Fabio
Published: April 2018

L1, a neural cell adhesion molecule of the immunoglobulin superfamily, is involved in neuronal migration and differentiation and axon outgrowth and guidance. Mutations in the human and mouse L1 gene result in similarly severe neurological abnormalities. To dissociate the functional roles of L1 in the adult brain from developmental abnormalities, we have generated a mutant in which the L1 gene is inactivated by cre-recombinase under the control of the calcium/calmodulin-dependent kinase II promoter. This mutant (L1fy+) did not show the overt morphological and behavioral abnormalities observed previously in constitutive L1-deficient (L1-/-) mice; however, there was an increase in basal excitatory synaptic transmission that was not apparent inL1-/- mice. Similar toL1-/- mice, no defects in short- and long-term potentiation in the CA1 region of the hippocampus were observed. Interestingly,L1fy+ mice showed decreased anxiety in the open field and elevated plus-maze, contrary toL1-/- mice, and altered place learning in the water maze, similar toL1-/- mice. Thus, mice conditionally deficient in L1 expression in the adult brain share some abnormalities, but also display different ones, as compared withL1-/- mice, highlighting the role of L1 in the regulation of synaptic transmission and behavior in adulthood.
Chromosome Segregation Defects Contribute to Aneuploidy in Normal Neural Progenitor Cells
Authors: Yang Amy H. , Kaushal Dhruv , Rehen Stevens K. , Kriedt Kristin , Kingsbury Marcy A. , McConnell Michael J. , Chun Jerold
Published: April 2018

Recent studies based predominantly on nucleotide hybridization techniques have identified aneuploid neurons and glia in the normal brain. To substantiate these findings and address how neural aneuploidy arises, we examined individual neural progenitor cells (NPCs) undergoing mitosis. Here we report the identification of chromosomal segregation defects in normal NPCs of the mouse cerebral cortex. Immunofluorescence in fixed tissue sections revealed the presence of supernumerary centrosomes and lagging chromosomes among mitotic NPCs. The extent of aneuploidy followed the prevalence of supernumerary centrosomes within distinct cell populations. Real-time imaging of live NPCs revealed lagging chromosomes and multipolar divisions. NPCs undergoing nondisjunction were also observed, along with interphase cells that harbored micronuclei or multiple nuclei, consistent with unbalanced nuclear division. These data independently confirm the presence of aneuploid NPCs and demonstrate the occurrence of mitotic segregation defects in normal cells that can mechanistically account for aneuploidy in the CNS.
Resonant Synchronization in Heterogeneous Networks of Inhibitory Neurons
Authors: Maex Reinoud , De Schutter Erik
Published: April 2018

Brain rhythms arise through the synchronization of neurons and their entrainment in a regular firing pattern. In this process, networks of reciprocally connected inhibitory neurons are often involved, but what mechanism determines the oscillation frequency is not completely understood. Analytical studies predict that the emerging frequency band is primarily constrained by the decay rate of the unitary IPSC. We observed a new phenomenon of resonant synchronization in computer-simulated networks of inhibitory neurons in which the synaptic current has a delayed onset, reflecting finite spike propagation and synaptic transmission times. At the resonant level of network excitation, all neurons fire synchronously and rhythmically with a period approximately four times the mean delay of the onset of the inhibitory synaptic current. The amplitude and decay time constant of the synaptic current have relatively minor effects on the emerging frequency band. By varying the axonal delay of the inhibitory connections, networks with a realistic synaptic kinetics can be tuned to frequencies from 40 to >200 Hz. This resonance phenomenon arises in heterogeneous networks with, on average, as few as five connections per neuron. We conclude that the delay of the synaptic current is the primary parameter controlling the oscillation frequency of inhibitory networks and propose that delay-induced synchronization is a mechanism for fast brain rhythms that depend on intact inhibitory synaptic transmission.
Heterogeneity of Ca2+-Permeable AMPA/Kainate Channel Expression in Hippocampal Pyramidal Neurons: Fluorescence Imaging and Immunocytochemical Assessment
Authors: Ogoshi Fumio , Weiss John H.
Published: April 2018

The presence of Ca2+-permeable AMPA/kainate (Ca-A/K) channels on hippocampal pyramidal neurons (HPNs) has been controversial, although they are present on many forebrain GABAergic neurons. We combined high-resolution fluorescence Ca2+imaging with surface AMPA receptor (AMPAR) subunit immunocytochemistry to examine the expression of functional Ca-A/K channels in dissociated hippocampal neurons at the subcellular level. In GABAergic neurons [identified by glutamate decarboxylase (GAD) immunocytochemistry], focal application of AMPA induced large dendrosomatic intracellular [Ca2+] ([Ca2+]i) rises, consistent with their known strong Ca-A/K channel expression. Surface immunostaining for the AMPAR subunits GluR1 and GluR2 revealed abundant dendritic GluR1 puncta containing little or no GluR2, which, when present, was limited to diffuse staining in the soma and proximal dendrites. In contrast, the majority of HPNs (putatively identified by morphological criteria and lack of GAD labeling) showed little or no AMPA-induced [Ca2+]irise. Correspondingly, most HPNs showed strong dendritic labeling for both GluR1 and GluR2 that colocalized extensively. A subpopulation of HPNs, however, displayed noticeable [Ca2+]irises that began and often reached their highest levels in discrete dendritic regions. In these HPNs, levels of GluR1 relative to GluR2 were higher, and GluR1 was often present without overlying GluR2. The present studies, which are the first to directly examine the relationship between the local complement of cell surface AMPAR and the presence of dendritic Ca-A/K channels, clearly indicate that considerable cell surface GluR2 does not preclude the presence of Ca-A/K channels and further show that HPNs display considerable heterogeneity in terms of apparent Ca-A/K channel expression.
Divergent Functions of Neuronal Rab11b in Ca2+-Regulated versus Constitutive Exocytosis
Authors: Khvotchev Mikhail V. , Ren Mindong , Takamori Shigeo , Jahn Reinhard , Südhof Thomas C.
Published: April 2018

Using PC12 cells that express transfected human growth hormone (hGH) as a secreted reporter protein, we have searched for Rab proteins that function in exocytosis. Among the Rab proteins tested, we found that besides the previously described Rab3 proteins, only members of the Rab11 family (Rab11a, 11b, and 25) impaired Ca2+-induced exocytosis. Rab11b, which is enriched in brain, had the strongest effect. Consistent with a role in exocytosis, Rab11 and Rab3 proteins were colocalized with other vesicle proteins on secretory vesicles in PC12 cells and on mature synaptic vesicles in brain. Rab11b mutants that fix Rab11b in the GTP- or GDP-bound state both effectively inhibited Ca2+-induced exocytosis but seemed to act by distinct mechanisms: whereas GDP-bound Rab11b greatly stimulated constitutive secretion of hGH and depleted hGH stores in secretory vesicles, GTP-bound Rab11b only had a moderate effect on constitutive secretion and no effect on vesicular hGH stores. These results suggest that, consistent with a GTP-dependent regulation of Rab function, GDP-bound Rab11b indirectly inhibits Ca2+-triggered exocytosis by causing the loss of hGH from the PC12 cells, whereas GTP-bound Rab11b directly impairs Ca2+-triggered exocytosis. In contrast to neuroendocrine PC12 cells in which GTP- and GDP-bound Rab11b inhibited Ca2+-induced, but not constitutive, exocytosis, in non-neuronal cells GTP- and GDP-bound Rab11b inhibited constitutive exocytosis and caused an accumulation of cellular hGH. Viewed together, our data suggest that, in addition to other functions, Rab11 has a specific role in neuronal and neuroendocrine but not in non-neuronal cells as a GTP-dependent switch between regulated and constitutive secretory pathways.
Activation of erbB-1 Signaling in Tanycytes of the Median Eminence Stimulates Transforming Growth Factor β1Release via Prostaglandin E2Production and Induces Cell Plasticity
Authors: Prevot Vincent , Cornea Anda , Mungenast Alison , Smiley Gregory , Ojeda Sergio R.
Published: April 2018

The activation of transforming growth factor α (TGFα)-erbB-1 and neuregulin-erbB-4 signaling pathways in hypothalamic astrocytes has been shown to play a key role in the process by which the neuroendocrine brain controls luteinizing hormone-releasing hormone (LHRH) secretion. Earlier studies suggested that tanycytes, an ependymoglial cell type of the median eminence, regulate LHRH release during the estrous cycle by undergoing plastic changes that alternatively allow or prevent direct access of the LHRH nerve terminals to the portal vasculature. Neither the molecules responsible for these plastic changes nor the underlying controlling mechanisms have been identified. Here we show that cultured tanycytes express erbB-1 and erbB-2, two of the four members of the erbB receptor family, and respond to TGFα with receptor phosphorylation, release of prostaglandin E2(PGE2), and a PGE2-dependent increase in the release of TGFβ1, a growth factor previously implicated in the glial control of LHRH secretion. Blockade of either erbB-1 receptor signal transduction or prostaglandin synthesis prevented the stimulatory effect of TGFα on both PGE2and TGFβ1release. Time-lapse studies revealed that TGFα and TGFβ1have dramatically opposite effects on tanycyte plasticity. Whereas TGFα promotes tanycytic outgrowth, TGFβ1elicits retraction of tanycytic processes. Blockade of metalloproteinase activity abolished the effect of TGFβ1, suggesting that TGFβ1induces tanycytic retraction by facilitating dissolution of the extracellular matrix. Prolonged (>12 hr) exposure of tanycytes to TGFα resulted in focal tanycytic retraction, an effect that was abolished by immunoneutralization of TGFβ1action, indicating that the retraction was attributable to TGFα-induced TGFβ1formation. Thesein vitroresults identify tanycytes as targets of TGFα action and demonstrate that activation of erbB-1-mediated signaling in these cells results in plastic changes that, involving PGE2and TGFβ1as downstream effectors, mimic the morphological plasticity displayed by tanycytes during the hours encompassing the preovulatory surge of LHRH.
Decreased Cyclin-Dependent Kinase 5 (cdk5) Activity Is Accompanied by Redistribution of cdk5 and Cytoskeletal Proteins and Increased Cytoskeletal Protein Phosphorylation in p35 Null Mice
Authors: Hallows Janice L. , Chen Ken , DePinho Ronald A. , Vincent Inez
Published: April 2018

Cdk5/p35 has been implicated in cytoskeletal protein phosphorylation in normal brain and in many human neurodegenerative disorders. Yet, mouse models of cdk5/p35 hyperactivity have not yielded corresponding changes in cytoskeletal protein phosphorylation. To elucidate the relationship between p35, cdk5, and the neuronal cytoskeleton, we deleted thep35gene in mice having a pure C57BL/6 background. We found that p35 deficiency leads to a 38% reduction of cdk5 activity in adult brain. In addition, loss of p35 causes an anterograde redistribution of cdk5 toward peripheral neuronal processes. The unusual presence of nonphosphorylated neurofilament (NF) in aberrant axon fascicles and the relocation of tau and MAP2B from cell bodies and proximal neuronal processes to more distal sites of the neuropil inp35-/- mouse brain implicate p35 in neuronal trafficking, particularly in dynein-driven retrograde transport. In many axons of normal brain, cdk5 fails to colocalize with phosphorylated cytoskeletal protein epitopes. This observation, together with an unexpected increase of NF, tau, and MAP2B phosphoepitopes accompanying the decreased cdk5 activity inp35-/- mice, supports the idea that cdk5 does not phosphorylate cytoskeletal proteins directly. Rather, in structures where cdk5 does colocalize with phosphorylated cytoskeletal protein epitopes, it may function as a negative regulator of other proline-directed kinases that directly phosphorylate the proteins. Evidence for increased glycogen synthase kinase 3β (GSK3β) activity inp35-/- mice suggests that GSK3β may be one such kinase regulated by cdk5. Our studies illustrate that p35 regulates the subcellular distribution of cdk5 and cytoskeletal proteins in neurons and that cdk5 has a hierarchical role in regulating the phosphorylation and function of cytoskeletal proteins.
Impact of Photon Noise on the Reliability of a Motion-Sensitive Neuron in the Fly's Visual System
Authors: Grewe Jan , Kretzberg Jutta , Warzecha Anne-Kathrin , Egelhaaf Martin
Published: April 2018

Variable behavioral responses to identical visual stimuli can, in part, be traced back to variable neuronal signals that provide unreliable information about the outside world. This unreliability in encoding of visual information is caused by several noise sources such as photon noise, synaptic noise, or the stochastic nature of ion channels. Neurons of the fly's visual motion pathway have been claimed to represent perfect encoders, with photon noise as the main noise source limiting their performance. Other studies on the fly's visual system suggest, however, that internal noise emerging within the nervous system also affects the reliability of motion vision. To resolve these contradictory interpretations, we performed an electrophysiological investigation, inspired by the “equivalent noise” paradigm applied in psychophysics, on the fly's motion-sensitive H1 neuron. Noise-like brightness fluctuations of different strength were superimposed on the motion stimuli. Because the noise level found to affect the temporal properties of the spike responses is much larger than the estimate of photon noise under the experimental conditions, our results indicate that motion vision is more likely to be limited by internal sources of variability than by photon noise.
Developmental Assembly of Transduction Apparatus in Chick Basilar Papilla
Authors: Si Fan , Brodie Hilary , Gillespie Peter G. , Vazquez Ana E. , Yamoah Ebenezer N.
Published: April 2018

Hair cells, the sensory receptors of auditory and vestibular systems, use a transducer apparatus that renders them remarkably sensitive to mechanical displacement as minute as 1 nm. To study the embryonic development of the transducer apparatus in hair cells of the chick auditory papilla, we examined hair cells that have been labeled withN-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridiniumdibromide, which has been shown to permeate the transducer channels. In addition, mechanotransduction currents were recorded directly using whole-cell patch-clamp techniques. The structure of the hair bundle was examined using scanning electron microscopy, and immunofluorescence labeling for myosin 1c, myosin 7a, and plasma membrane Ca2+ATPase 2 was studied to determine the developmental expression of these proteins in embryonic chick papillas. We demonstrate that the transducer apparatus is assembled jointly at embryonic day 11 (E11) of the developing chick basilar papilla. The resting open probability of the transducer channels was high at E12 (∼0.5) and remained substantially elevated at E14-16; it then declined to the mature value of ∼0.15 at E21. The displacement sensitivity of the transduction apparatus, the gating force, increased from E12 to E21. Although the expression of different components of the transducer apparatus and the transduction current peaked at ∼E14-16, marked refinement occurred beyond E16. For example, myosin 1c appeared diffusely localized in hair bundles from E12 to E16, but subsequently consolidated into punctate pattern. The fine temporal and precise spatial assembly of the transducer apparatus likely contributes toward the exquisite sensitivity of the transduction ensemble.
Reward without Dopamine
Authors: Cannon Claire Matson , Palmiter Richard D.
Published: April 2018

Dopamine (DA) is believed to play a fundamental role in reward processes. Virtually all drugs of abuse activate dopaminergic systems, as do “natural” rewards such as sexual interaction and food. Sweet-tasting solutions, for example, are a well characterized natural reward. In the present experiments, we used mice that cannot make DA (DD mice) to test the hypothesis that DA is necessary for reward. Sucrose preference, assessed with a computerized “lickometer,” was used to determine whether DD mice respond preferentially for rewarding stimuli. DD mice preferentially chose sucrose over water, and also preferred the noncaloric sweetener saccharin. Furthermore, the rate of licking, bout size, and length were greater in DD mice drinking sweets than in controls. These data refute the necessity of DA for the reward processes manifested by sucrose preference. However, DD mice initiated licking less frequently than control mice and had fewer total licks. We suggest that DD mice have a deficit of goal-directed behavior that is not specific to reward processes. Lastly, juvenile DD mice demonstrate robust sucrose preference before experience with food in the presence of DA. Thus, DA is not required for mice to learn to consume sweet solutions preferentially. We conclude that DA is not required to find the sweet tastes of sucrose or saccharin rewarding.
Amyloid-β Antibody Treatment Leads to Rapid Normalization of Plaque-Induced Neuritic Alterations
Authors: Lombardo Julianne A. , Stern Edward A. , McLellan Megan E. , Kajdasz Stephen T. , Hickey Gregory A. , Bacskai Brian J. , Hyman Bradley T.
Published: April 2018

The accumulation of amyloid-β into insoluble plaques is a characteristic feature of Alzheimer's disease. Neuronal morphology is distorted by plaques: rather than being essentially straight, they are substantially more curved than those in control tissue, their trajectories become altered, and they are frequently distended or swollen, presumably affecting synaptic transmission. Clearance of plaques by administration of antibodies to amyloid-β is a promising therapeutic approach to the treatment of Alzheimer's disease, leading to stabilization of dementia by an unknown cellular mechanism. The effect of plaque clearance on plaque-induced neuronal alterations has not been studied previously. Here we show that both plaques and neuritic lesions are reversible in a strikingly short period of time after administration of a single dose of amyloid-β antibody. Amyloid clearance and recovery of normal neuronal geometries were observed as early as 4 d and lasted at least 32 d after a single treatment. These results demonstrate that, once plaques are cleared, neuronal morphology is self-correcting and that passive antibody treatment has the potential to reverse neuronal damage caused by Alzheimer's disease and, hence, directly impact cognitive decline. Moreover, the rapid normalization of neuritic dystrophy suggests an unexpected degree of plasticity in the adult nervous system.
Neurosteroids Shift Partial Agonist Activation of GABAAReceptor Channels from Low- to High-Efficacy Gating Patterns
Authors: Bianchi Matt T. , Macdonald Robert L.
Published: April 2018

Although GABA activates synaptic (αβγ) GABAAreceptors with high efficacy, partial agonist activation of αβγ isoforms and GABA activation of the primary extrasynaptic (αβδ) GABAAreceptors are limited to low-efficacy activity, characterized by minimal desensitization and brief openings. The unusual sensitivity of αβδ receptor channels to neurosteroid modulation prompted investigation of whether this high sensitivity was dependent on the δ subunit or the low-efficacy channel function that it confers. We show that the isoform specificity (αβδ > αβγ) of neurosteroid modulation could be reversed by conditions that reversed isoform-specific activity modes, including the use of β-alanine to achieve increased efficacy with αβδ receptors and taurine to render αβγ receptors low efficacy. We suggest that neurosteroids preferentially enhance low-efficacy GABAAreceptor activity independent of subunit composition. Allosteric conversion of partial to full agonism may be a general mechanism for reversibly scaling the efficacy of GABAAreceptors to endogenous partial agonists.
Multiple Molecular Determinants for Allosteric Modulation of Alternatively Spliced AMPA Receptors
Authors: Quirk Jennifer C. , Nisenbaum Eric S.
Published: April 2018

Positive allosteric regulation of glutamate AMPA receptors involves conformational changes that can attenuate receptor desensitization and enhance ion flux through the channel pore. Many allosteric modulators (e.g., cyclothiazide and aniracetam) preferentially affect the flip (i) or flop (o) alternatively spliced isoform of AMPA receptors, implicating residues in the flip-flop domain as critical determinants of splice variant sensitivity. Indeed, previous mutational analyses have demonstrated that the differential sensitivity to cyclothiazide and aniracetam depends on a single amino acid, Ser (flip) and Asn (flop), suggesting that this residue may be solely responsible for differences in modulation of AMPA receptor isoforms. The present studies tested this hypothesis by investigating the molecular determinants of modulation of AMPA receptor splice variants by a structurally distinct compound,LY404187, which displays strikingly different and opposing kinetics of allosteric regulation characterized by a time-dependent enhancement in potentiation of homomeric GluR1-GluR4i and a time-dependent reduction in potentiation of GluR1-GluR4o. Site-directed mutagenesis of residues in the flip-flop domain of GluR2 revealed that, although exchange of Asn775 for Ser in GluR2o was sufficient to confer the GluR2i phenotype of potentiation, the corresponding mutation, Ser775Asn, in GluR2i did not impart the GluR2o response. In fact, the GluR2o kinetics of modulation depended on a novel set of substitutions in GluR2i, including Thr765Asn, Pro766Ala, and Val779Leu in combination with Ser775Asn. Collectively, these results show that, unlike cyclothiazide and aniracetam, the residues that confer splice variant differences in modulation byLY404187are not identical and indicate that allosteric regulation of AMPA receptors can arise from multiple molecular determinants.
Adenosinergic Protection of Dopaminergic and GABAergic Neurons against Mitochondrial Inhibition through Receptors Located in the Substantia Nigra and Striatum, Respectively
Authors: Alfinito Peter D. , Wang Sheng-Ping , Manzino Lawrence , Rijhsinghani Sonia , Zeevalk Gail D. , Sonsalla Patricia K.
Published: April 2018

Mitochondrial dysfunction may contribute to dopaminergic (DAergic) cell death in Parkinson's disease and GABAergic cell death in Huntington's disease. In the present work, we tested whether blocking A1receptors could enhance the damage to DAergic and GABAergic neurons caused by mitochondrial inhibition, and whether blocking A2areceptors could protect against damage in this model. Animals received an intraperitoneal injection of 8-cyclopentyl-1,3-dipropylxanthine (CPX) (A1antagonist) or 3,7-dimethyl-1-propargylxanthine (DMPX) (A2aantagonist) 30 min before intrastriatal infusion of malonate (mitochondrial complex II inhibitor). Damage was assessed 1 week later by measuring striatal dopamine, tyrosine hydroxylase (TH), and GABA content. In mice and rats, malonate-induced depletion of striatal dopamine, TH, or GABA was potentiated by pretreatment with 1 mg/kg CPX and attenuated by pretreatment with 5 mg/kg DMPX. To determine the location of the A1and A2areceptors mediating these effects, CPX or DMPX was infused directly into the striatum or substantia nigra of rats 30 min before intrastriatal infusion of malonate. When infused into the striatum, CPX (20 ng) potentiated, whereas DMPX (50 ng) prevented malonate-induced GABA loss, but up to 100 ng of CPX or 500 ng of DMPX did not alter malonate-induced striatal dopamine loss. Intranigral infusion of CPX (100 ng) or DMPX (500 ng), however, did exacerbate and protect, respectively, against malonate-induced striatal dopamine loss. Thus, A1receptor blockade enhances and A2areceptor blockade protects against damage to DAergic and GABAergic neurons caused by mitochondrial inhibition. Interestingly, these effects are mediated by A1and A2areceptors located in the substantia nigra for DAergic neurons and in the striatum for GABAergic neurons.
Activity-Dependent Depression of Excitability and Calcium Transients in the Neurohypophysis Suggests a Model of “Stuttering Conduction”
Authors: Muschol Martin , Kosterin Paul , Ichikawa Michinori , Salzberg B. M.
Published: April 2018

Using millisecond time-resolved optical recordings of transmembrane voltage and intraterminal calcium, we have determined how activity-dependent changes in the population action potential are related to a concurrent modulation of calcium transients in the neurohypophysis. We find that repetitive stimulation dramatically alters the amplitude of the population action potential and significantly increases its temporal dispersion. The population action potentials and the calcium transients exhibit well correlated frequency-dependent amplitude depression, with broadening of the action potential playing only a limited role. High-speed camera recordings indicate that the magnitude of the spike modulation is uniform throughout the neurohypophysis, thereby excluding propagation failure as the underlying mechanism. In contrast, temporal dispersion and latency of the population spike do increase with distance from the stimulation site. This increase is enhanced during repeated stimulation and by raising the stimulation frequency. Changes in Ca influx directly affect the decline in population spike amplitude, consistent with electrophysiological measurements of the local loss of excitability in nerve terminals and varicosities, mediated by a Ca-activated K conductance. Our observations suggest a model of “stuttering conduction”: repeated action potential stimulation causes excitability failures limited to nerve terminals and varicosities, which account for the rapid decline in the population spike amplitude. These failures, however, do not block action potential propagation but generate the cumulative increases in spike latency.
Estradiol Attenuates Programmed Cell Death after Stroke-Like Injury
Authors: Rau Shane W. , Dubal Dena B. , Böttner Martina , Gerhold Lynnette M. , Wise Phyllis M.
Published: April 2018

Estradiol is a known neurotrophic and neuroprotective factor. Our previous work demonstrated that replacement with physiological concentrations of estradiol protects the cortex against middle cerebral artery occlusion (MCAO)-induced cell death. The cerebral cortex exhibits caspase-dependent programmed cell death (PCD) in many models of focal cerebral ischemia. We hypothesized that estradiol attenuates PCD during stroke injury. The current study explored the temporospatial pattern of markers of PCD, their relationship to the evolution of injury, and their modulation by estradiol. Rats were ovariectomized and treated with either estradiol or vehicle. One week later, rats underwent MCAO, and brains were collected at 1, 4, 8, 16, and 24 hr. We assessed the temporospatial evolution of infarction volume, DNA fragmentation, and levels of spectrin cleavage products in ischemic cortex. Estradiol led to a delay and attenuation of injury-mediated DNA fragmentation as early as 8 hr after MCAO. Estradiol also dramatically reduced the level of the 120 kDa caspase-mediated spectrin breakdown product (SBDP120) at 4 hr but not at 8 or 16 hr. The SBDP150, produced by caspase and calpain, showed peak levels at 16 hr but was not altered by estradiol. These results strongly suggest that estradiol protects the ischemic cortex by attenuating PCD, thereby reducing caspase activity, DNA fragmentation, and subsequently, overall cell death. These studies deepen our understanding of the mechanisms underlying estrogen-mediated neuroprotection.
Restoring Tip60 HAT/HDAC2 Balance in the Neurodegenerative Brain Relieves Epigenetic Transcriptional Repression and Reinstates Cognition
Authors: Panikker Priyalakshmi , Xu Song-Jun , Zhang Haolin , Sarthi Jessica , Beaver Mariah , Sheth Avni , Akhter Sunya , Elefant Felice
Published: April 2018

Cognitive decline is a debilitating hallmark during preclinical stages of Alzheimer's disease (AD), yet the causes remain unclear. Because histone acetylation homeostasis is critical for mediating epigenetic gene control throughout neuronal development, we postulated that its misregulation contributes to cognitive impairment preceding AD pathology. Here, we show that disruption of Tip60 histone acetlytransferase (HAT)/histone deacetylase 2 (HDAC2) homeostasis occurs early in the brain of an AD-associated amyloid precursor protein (APP)Drosophilamodel and triggers epigenetic repression of neuroplasticity genes well before Aβ plaques form in male and female larvae. Repressed genes display enhanced HDAC2 binding and reduced Tip60 and histone acetylation enrichment. Increasing Tip60 in the AD-associated APP brain restores Tip60 HAT/HDAC2 balance by decreasing HDAC2 levels, reverses neuroepigenetic alterations to activate synaptic plasticity genes, and reinstates brain morphology and cognition. SuchDrosophilaneuroplasticity gene epigenetic signatures are conserved in male and female mouse hippocampus and their expression and Tip60 function is compromised in hippocampus from AD patients. We suggest that Tip60 HAT/HDAC2-mediated epigenetic gene disruption is a critical initial step in AD that is reversed by restoring Tip60 in the brain.

SIGNIFICANCE STATEMENTMild cognitive impairment is a debilitating hallmark during preclinical stages of Alzheimer's disease (AD), yet its causes remain unclear. Although recent findings support elevated histone deacetylase 2 (HDAC2) as a cause for epigenetic repression of synaptic genes that contribute to cognitive deficits, whether alterations in histone acetlytransferase (HAT) levels that counterbalance HDAC2 repressor action occur and the identity of these HATs remain unknown. We demonstrate that disruption of Tip60 HAT/HDAC2 homeostasis occurs early in the ADDrosophilabrain and triggers epigenetic repression of neuroplasticity genes before Aβ plaques form. Increasing Tip60 in the AD brain restores Tip60 HAT/HDAC2 balance, reverses neuroepigenetic alterations to activate synaptic genes, and reinstates brain morphology and cognition. Our data suggest that disruption of the Tip60 HAT/HDAC2 balance is a critical initial step in AD.
Boulez's Künstlerroman: Using blocs sonores to Overcome Anxieties and Influence in Le marteau sans maître
Authors: Salem Joseph
Published: April 2018

Previous scholarship on Pierre Boulez's Le marteau sans maître celebrates the analytical basis of the piece, with particular emphasis on Boulez's concept of the bloc sonore and its role in Le marteau's design. This article synthesizes aspects of this scholarship with Boulez's personal reflections from the years 1953–55, many of which remain unpublished to this day. Utilizing Boulez's correspondence with Karlheinz Stockhausen and John Cage, as well as his own published writings and the sketches for Le marteau, I present the story of an artist on the path to self-discovery. I also shift the discussion of blocs sonores away from viewing them as musical objects necessary for the analysis of Le marteau to recognizing their significance as a cultural and aesthetic concept at the heart of Boulez's artistic development at this time. Finally, I use the literary trope of “anxiety of influence” to relate Boulez's own maturation to his struggle to escape the shadow and influence of Schoenberg. By humanizing a work that is often cited for its analytical virtuosity and poetic audacity rather than the network of biographical circumstances behind its creation, I attempt to reorient our ears from the rigidness of integral serialism to the broader significance of Boulez's score.
Organisasiaonal on Employee Performance Dimedication Satisfaction Work Vacuum Operating Adat Kerobokankuta Utarabadung
Authors: Sukada I Ketut , Sapta I Ketut Setia , Sudja Nengah
Published: April 2018

This study aims to examine and analyze the influence of Organizational Culture and Organizational Commitment to Job Satisfaction and Employee Performance as a result of the gap of previous research results (research gap) and differences of focus on organizational culture and Organizational Commitment to Job Satisfaction and Employee Performance. This research was conducted at Koperasi Desa Adat Kerobokan Kuta Utara Badung with population and research sample of all employees as many as 60 people. All data obtained from the kuisoner distribution is feasible to be used, then analyzed using a variance based structural equation model known as Partial Least Square (PLS) analysis. The result of research shows that (1) Organizational Culture has positive and significant influence to Job Satisfaction, (2) Organizational Culture has positive and significant influence Employee Performance, (3) Organizational Commitment have positive and significant influence to Job Satisfaction (4) Organizational Commitment have positive and significant on Employee Performance, (5) Job Satisfaction mediates the influence of organizational culture and Organizational Commitment on Employee Performance. The implications of this research that Job Satisfaction and Performance can be applied with respect to Organizational Culture and Organizational Commitment. Employee performance is increasing, job satisfaction is increasing and it can all be improved by taking into account Organizational Culture and Organizational Commitment.
Using Data to Drive Instruction: A Comparative Study of Lexia Scores to Other Reading Assessments, Attendance, Grades, and Behavior
Authors: Sawyer Dr. Felicia , Little Dr. Bobbie , Cantey Dr. Darlene , Martin Principal Lionel
Published: April 2018

The purpose of this study is to analyze student progress after the frequent usage of a computerized reading program that provides phonics instruction and gives students independent practice in basic reading skills. Further, the study observes and analyzes the correlation between student progress in Lexia to progress report grades, report card grades, attendance, office referrals for poor behavior, the Fountas and Pinnell Benchmark Assessment System (BAS) scores, Kindergarten Readiness Assessment (KRA) language and social scores, and the Reading Inventory scores (RI).