bluuebunny/crossref_metadata_2025 huggingface dataset:
A Conditionally Integrable Bi-confluent Heun Potential Involving Inverse Square Root and Centrifugal Barrier Terms
Authors: Ishkhanyan Tigran A. , Krainov Vladimir P. , Ishkhanyan Artur M.
Published: April 2018

We present a conditionally integrable potential, belonging to the bi-confluent Heun class, for which the Schrödinger equation is solved in terms of the confluent hypergeometric functions. The potential involves an attractive inverse square root term ~x−1/2with arbitrary strength and a repulsive centrifugal barrier core ~x−2with the strength fixed to a constant. This is a potential well defined on the half-axis. Each of the fundamental solutions composing the general solution of the Schrödinger equation is written as an irreducible linear combination, with non-constant coefficients, of two confluent hypergeometric functions. We present the explicit solution in terms of the non-integer order Hermite functions of scaled and shifted argument and discuss the bound states supported by the potential. We derive the exact equation for the energy spectrum and approximate that by a highly accurate transcendental equation involving trigonometric functions. Finally, we construct an accurate approximation for the bound-state energy levels.
Degradation of Crystal Violet Dye by Fenton and Photo-Fenton Oxidation Processes
Authors: Rehman Faiza , Sayed Murtaza , Khan Javed Ali , Shah Luqman Ali , Shah Noor S. , Khan Hasan M. , Khattak Rozina
Published: April 2018

The oxidative degradation of CV dye in aqueous media has been evaluated using Fenton (Fe2+/H2O2) and photo-Fenton (Fe2+/H2O2/UV) processes. Various operational parameters like H2O2 dosages, Fe2+ dosages and [CV]0 were optimized of both Fenton and photo-Fenton processes for the removal of CV dye from aqueous media. Kinetic results indicated that photo-Fenton process (k
obs=0.0097 min−1, t
1/2=71.45 min) is more effective than Fenton process (k
obs=0.0074 min−1, t
1/2=93.66 min). Second order rate constant of ˙OH radical with CV dye was calculated to be 3.96×109 M−1s−1. De-methylated organic intermediates of CV dye detected by LC-MS and some other intermediates like CH3COO−, HCOO−, NH4
+ and Cl− were identified by ion-chromatography.
Functionalization of Graphene Aerogels and their Applications in Energy Storage and Conversion
Authors: Wang Chen , Fu Qiangang , Wen Dan
Published: April 2018

Functionalized graphene aerogels (GAs) not only own the advantages of the original ones like large specific surface area, three-dimensional porous structures, high specific capacitance and excellent cyclic stability, but also realize the function expansion due to the collective properties endowed via different methods. These characteristics make them advantageous in some promising applications. In this minireview, we focus on the various functionalization methods of GAs and especially their use in the applications of energy storage and conversion like batteries, supercapacitors and fuel cells, etc.
Tarjetas de presentación e identidad. Las colecciones de relatos integrados desde los umbrales
Authors: Sánchez Carbó José
Published: April 2018

Este artículo atiende la solicitud que Gerard Genette plantea en Umbrales sobre la necesidad de analizar género por género las funciones del paratexto. Así, se revisará la función de los paratextos en las colecciones de relatos integrados porque en estos márgenes se ubican claves que anticipan una intención estructural o temática del autor y una forma de lectura propias de la modalidad. En este sentido, de la amplia gama de paratextos, se intentará definir cuáles y cómo contribuyen de forma consistente a prolongar las ideas del autor, reconocer sus efectos en el lector y definir la peculiaridad de la colección integrada.
Metafísica y delirio. El Canto a un dios mineral de Jorge Cuesta
Authors: Sánchez José Israel
Published: April 2018

RESEÑA
La risa en la literatura mexicana: apuntes de poética
Authors: Balderas Chacón Tania
Published: April 2018

RESEÑA
Ortega, Ricoeur y la razón narrativa
Authors: Mendívil José
Published: April 2018

Pretendo aquí mostrar la pertinencia actual del pensamiento de José Ortega y Gasset, precisamente haciendo una comparación con una vía contemporánea paralela en muchos sentidos, la del filósofo francés Paul Ricoeur. La estrategia de caminar desde el presente hacia el pasado de la noción narrativa del sujeto nos permite tener a la vista la actualidad y la profundidad de algunas de las intuiciones del pensador español.
Este tiempo clausurado que no me pertenece: Los años falsos, de Josefina Vicens
Authors: Bustamante Bermúdez Gerardo
Published: April 2018

En 1982, Josefina Vicens dio a conocer su segunda novela titulada Los años falsos. En este artículo se analiza el tema del patriarcado mexicano en las estructuras familiares en donde el poder, la violencia, la infidelidad, la corrupción, el machismo y la subordinación de las mujeres respecto a la autoridad del patriarca constituyen la base de un discurso incisivo en el que Vicens observa las relaciones de género dentro de la familia tradicional mexicana. A lo largo de este texto se habla sobre la identidad asignada al protagonista de la novela, así como la ambigüedad respecto a su construcción de género que, no obstante, queda al margen de sus deseos y posibles realizaciones. Se trata de una vida anulada por una especie de testamento de género por parte del patriarca ausente / presente.
Rubén M. Campos y el contexto literario en la Ciudad de México
Authors: Sol Tlachi Carlomagno
Published: April 2018

Este artículo contextualiza y proporciona características generales de la obra literaria del escritor guanajuatense de filiación modernista Rubén M. Campos. La contextualización se realiza a partir del seguimiento de la evolución del modernismo en tres momentos: sus inicios, con Manuel Gutiérrez Nájera como figura central y hombre fundador de la Revista Azul, publicación en la que se engendra el segundo momento, el decadentismo, con la Revista Moderna y José Juan Tablada al frente de ésta. El decadentismo fue una reacción contra la modernidad, vertido en la constante búsqueda del poeta por la renovación creativa, desarrollada, de preferencia, en la atmósfera de la bohemia. Es aquí donde se desenvuelve la figura de Rubén M. Campos, tópico que el artículo explora y describe a profundidad.
La voz del amauta en el poema Llamado a algunos doctores (Huk Doctorkunaman Qayay)
Authors: Álvarez Rolando
Published: April 2018

En este trabajo, se pretende establecer, algunas relaciones que el poema de José María Arguedas, Llamado a algunos doctores, construye con determinados rasgos del pensamiento mostrado por el autor en Todas las sangres, Los ríos profundos, Warma Kuyay y El zorro de arriba y el zorro de abajo; así como en la mesa redonda sobre Todas las sangres de junio de 1965. Se intenta encontrar, en la voz poética, la voz del amauta, en la forma en que el poeta expresa su relación con la naturaleza y con lo divino.
La fragmentación del discurso: ensayo y literatura Carlos Oliva Mendoza, comp. México, UNAM, 2009
Authors: Sánchez Guerrero José Israel
Published: April 2018

La fragmentación del discurso: ensayo y literatura Carlos Oliva Mendoza, comp. México, UNAM, 2009
Husserl. Elementos de autorreflexión filosófica
Authors: Corona Fernández Javier
Published: April 2018

Este ensayo presenta algunos elementos de la autorreflexión filosófica propuesta por la fenomenología a partir de ciertos puntos de análisis como la denuncia acerca del olvido del mundo de la vida; el señalamiento en torno a la necesidad de una fundamentación humana de la ciencia; la acusación de que la teoría está volcada sobre la facticidad y la concepción de la filosofía como autorreflexión de la humanidad. Tópicos que han colocado a la fenomenología como una de las corrientes protagonistas de la filosofía contemporánea.
Todo lo que se nos brinda...: presentismo y simultaneidad. Fenomenología de lo contemporáneo (collage) y saturación
Authors: Moreno Márquez César
Published: April 2018

Aunque no cabe duda de que el objeto ha sido máximamente relevante como modo de presencia, hay otra modalidad de presencia, no menos decisiva, aunque mucho más desatendida, como es la de simultaneidad de las perspectivas de un objeto (lo que nos conduciría al cubismo) y la contemporaneidad de lo heterogéneo (collage). La atención a lo que supusieron, en tal sentido, algunas prácticas de las vanguardias en el primer tercio del siglo XX, puede resultar muy esclarecedora de cara a la investigación de ciertas experiencias que aunque periféricas o monstruosas son imprescindibles no sólo para una ampliación de las posibilidades del pensar fenomenológico, sino también para la profundización de la problemática filosófica de la hipercomunicación, que caracteriza a nuestro entorno civilizatorio.
Del sentido de la vida Jean Grondin (traducción de Jorge Dávila) Barcelona, Herder, 2005
Authors: Mendoza Mandujano Raúl
Published: April 2018

Reseña de libro Del sentido de la vida Jean Grondin (traducción de Jorge Dávila) Barcelona, Herder, 2005
Microcrack Growth Behavior and CWFS Criterion Parameters Optimization of Granite with PFC
Authors: Miao Shengjun , Wang Hui , Guo Xuelian , Liang Mingchun , Kong Changqing
Published: April 2018

Based on the physical and mechanical parameters obtained in laboratory tests, along with the section scanning of granite specimens, a microgeometric model of the granite particles was established in the Particle Flow Code (PFC) programs. The loading codes were programed and adjusted using the Fish language to simulate both uniaxial and triaxial compression tests. The micromechanical behavior and the evolution of cracks from the microcosm to the macrocosm of the granite were obtained under different loading conditions based on the complete stress-strain curves, Acoustic Emission (AE) monitoring results and crack number obtained from the tests, and PFC simulation. On this basis, the Cohesion Weakening and Friction Strengthening (CWFS) criterion model parameters of the granite were optimized and verified using the stress-strain curves, the relationship between the cracks, friction energy and plastic strain, and Fast Lagrangian Analysis of Continua simulation. The optimized CWFS criterion parameters of initial cohesion, residual cohesion, initial friction angle, and residual friction angle, as well as the critical plastic strain ϵcp and ϵfp of the granite, are 23 MPa, 4.3 MPa, 0°, 46.3°, 0.0015, and 0.0037, respectively. This provides a scientific basis for the establishment of a rock constitutive model during the transfer from open pit to underground mining in the Xingshan Iron Mine in China.
Behavior and Law of Crack Propagation in the Dynamic-Static Superimposed Stress Field
Authors: Yang Renshu , Ding Chenxi , Yang Liyun , Zhang Yufei , Xu Peng
Published: April 2018

The aim of this study is to investigate the behavior and the law of crack propagation, particularly under the dynamic-static superimposed stress field in the poly(methyl methacrylate) specimens. We introduce a novel system of digital laser dynamic caustics experiments with a self-designed dynamic-static loading device. These specimens are divided into three groups and subjected to the static stress field, the dynamic stress field, and the stress superposition field, respectively. The conclusion can be obtained by comparing the crack length and the dynamic stress intensity factor of the main cracks during propagation under the three different stress fields. The static stress field significantly reduces the arrest toughness of the main cracks, which is the main reason for longer crack propagation.
Secondary Nicotinic Synapses on Sympathetic B Neurons and Their Putative Role in Ganglionic Amplification of Activity
Authors: Karila Paul , Horn John P.
Published: April 2018

The strength and number of nicotinic synapses that converge on secretomotor B neurons were assessed in the bullfrog by recording intracellularly from isolated preparations of paravertebral sympathetic ganglia 9 and 10. One input to every B neuron invariably produced a suprathreshold EPSP and was defined as the primary nicotinic synapse. In addition, 93% of the cells received one to four subthreshold inputs that were defined as secondary nicotinic synapses. This contradicts the prevailing view, which has long held that amphibian B neurons are singly innervated. More important, the results revealed that B cells provide the simplest possible experimental system for examining the role of secondary nicotinic synapses on sympathetic neurons. Combining the convergence data with previous estimates of divergence indicates that the average preganglionic B neuron forms connections with 50 ganglionic B neurons and that the majority of these nicotinic synapses are secondary in strength. Secondary EPSPs evoked by low-frequency stimulation ranged from 0.5 to 10 mV in amplitude and had an average quantal content of 1. Nonetheless, secondary synapses could trigger action potentials via four mechanisms: spontaneous fluctuations of EPSP amplitude, two-pulse facilitation, coactivation with other secondary synapses, and coactivation with a slow peptidergic EPSP. The data were used to formulate a stochastic theory of integration, which predicts that ganglia function as amplifiers of the sympathetic outflow. In this two-component scheme, primary nicotinic synapses mediate invariant synaptic gain, and secondary nicotinic synapses mediate activity-dependent synaptic gain. The model also provides a common framework for considering how facilitation, metabotropic mechanisms, and preganglionic oscillators regulate synaptic amplification in sympathetic ganglia.
Spatial Structure of Cone Inputs to Color Cells in Alert Macaque Primary Visual Cortex (V-1)
Authors: Conway Bevil R.
Published: April 2018

The spatial structure of color cell receptive fields is controversial. Here, spots of light that selectively modulate one class of cones (L, M, or S, or loosely red, green, or blue) were flashed in and around the receptive fields of V-1 color cells to map the spatial structure of the cone inputs. The maps generated using these cone-isolating stimuli and an eye-position-corrected reverse correlation technique produced four findings. First, the receptive fields were Double-Opponent, an organization of spatial and chromatic opponency critical for color constancy and color contrast. Optimally stimulating both center and surround subregions with adjacent red and green spots excited the cells more than stimulating a single subregion. Second, red–green cells responded in a luminance-invariant way. For example, red-on-center cells were excited equally by a stimulus that increased L-cone activity (appearing bright red) and by a stimulus that decreased M-cone activity (appearing dark red). This implies that the opponency between L and M is balanced and argues that these cells are encoding a single chromatic axis. Third, most color cells responded to stimuli of all orientations and had circularly symmetric receptive fields. Some cells, however, showed a coarse orientation preference. This was reflected in the receptive fields as oriented Double-Opponent subregions. Fourth, red–green cells often responded to S-cone stimuli. Responses to M- and S-cone stimuli usually aligned, suggesting that these cells might be red–cyan. In summary, red–green (or red–cyan) cells, along with blue–yellow and black–white cells, establish three chromatic axes that are sufficient to describe all of color space.
Functional Anatomy of Nonvisual Feedback Loops during Reaching: A Positron Emission Tomography Study
Authors: Desmurget Michel , Gréa Helena , Grethe Jeff S. , Prablanc Claude , Alexander Garret E. , Grafton Scott T.
Published: April 2018

Reaching movements performed without vision of the moving limb are continuously monitored, during their execution, by feedback loops (designated nonvisual). In this study, we investigated the functional anatomy of these nonvisual loops using positron emission tomography (PET). Seven subjects had to “look at” (eye) or “look and point to” (eye–arm) visual targets whose location either remained stationary or changed undetectably during the ocular saccade (when vision is suppressed). Slightly changing the target location during gaze shift causes an increase in the amount of correction to be generated. Functional anatomy of nonvisual feedback loops was identified by comparing the reaching condition involving large corrections (jump) with the reaching condition involving small corrections (stationary), after subtracting the activations associated with saccadic movements and hand movement planning [(eye–arm–jumping minus eye–jumping) minus (eye–arm–stationary minus eye–stationary)]. Behavioral data confirmed that the subjects were both accurate at reaching to the stationary targets and able to update their movement smoothly and early in response to the target jump. PET difference images showed that these corrections were mediated by a restricted network involving the left posterior parietal cortex, the right anterior intermediate cerebellum, and the left primary motor cortex. These results are consistent with our knowledge of the functional properties of these areas and more generally with models emphasizing parietal–cerebellar circuits for processing a dynamic motor error signal.
Mitochondrial Abnormalities in Alzheimer's Disease
Authors: Hirai Keisuke , Aliev Gjumrakch , Nunomura Akihiko , Fujioka Hisashi , Russell Robert L. , Atwood Craig S. , Johnson Anne B. , Kress Yvonne , Vinters Harry V. , Tabaton Massimo , Shimohama Shun , Cash Adam D. , Siedlak Sandra L. , Harris Peggy L. R. , Jones Paul K. , Petersen Robert B. , Perry George , Smith Mark A.
Published: April 2018

The finding that oxidative damage, including that to nucleic acids, in Alzheimer's disease is primarily limited to the cytoplasm of susceptible neuronal populations suggests that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress of Alzheimer's disease. In this study, we usedin situhybridization to mitochondrial DNA (mtDNA), immunocytochemistry of cytochrome oxidase, and morphometry of electron micrographs of biopsy specimens to determine whether there are mitochondrial abnormalities in Alzheimer's disease and their relationship to oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine. We found that the same neurons showing increased oxidative damage in Alzheimer's disease have a striking and significant increase in mtDNA and cytochrome oxidase. Surprisingly, much of the mtDNA and cytochrome oxidase is found in the neuronal cytoplasm and in the case of mtDNA, the vacuoles associated with lipofuscin. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in Alzheimer's disease.
How Simple Cells Are Made in a Nonlinear Network Model of the Visual Cortex
Authors: Wielaard D. J. , Shelley Michael , McLaughlin David , Shapley Robert
Published: April 2018

Simple cells in the striate cortex respond to visual stimuli in an approximately linear manner, although the LGN input to the striate cortex, and the cortical network itself, are highly nonlinear. Although simple cells are vital for visual perception, there has been no satisfactory explanation of how they are produced in the cortex. To examine this question, we have developed a large-scale neuronal network model of layer 4Cα in V1 of the macaque cortex that is based on, and constrained by, realistic cortical anatomy and physiology. This paper has two aims: (1) to show that neurons in the model respond like simple cells. (2) To identify how the model generates this linearized response in a nonlinear network. Each neuron in the model receives nonlinear excitation from the lateral geniculate nucleus (LGN). The cells of the model receive strong (nonlinear) lateral inhibition from other neurons in the model cortex. Mathematical analysis of the dependence of membrane potential on synaptic conductances, and computer simulations, reveal that the nonlinearity of corticocortical inhibition cancels the nonlinear excitatory input from the LGN. This interaction produces linearized responses that agree with both extracellular and intracellular measurements. The model correctly accounts for experimental results about the time course of simple cell responses and also generates testable predictions about variation in linearity with position in the cortex, and the effect on the linearity of signal summation, caused by unbalancing the relative strengths of excitation and inhibition pharmacologically or with extrinsic current.
Temporal Cues Contribute to Tactile Perception of Roughness
Authors: Cascio Carissa J. , Sathian K.
Published: April 2018

Optimal perception of surface roughness requires lateral movement between skin and surface, suggesting the importance of temporal cues. The roughness of periodic gratings is affected by changing either inter-element spacing (groove width,G) or element width (ridge width,R). Peripheral neural responses to gratings depend quantitatively on a spatial variable,G, and a temporal variable, grating temporal frequency (Ft), with changes inRacting indirectly through concomitant changes inFt. We investigated, psychophysically, the contribution of temporal cues to human tactile perception of roughness, using gratings varying in eitherRorG. Gratings were scanned across the immobile fingerpad with controlled movement speed (S) and contact force. In one experiment, we found that roughness magnitude estimates depended on bothGandFt. In a second experiment, discrimination of the roughness of gratings varying in eitherRorGwas affected by manipulatingFt. Overall, the effect ofGon roughness judgments was much stronger than that ofFt, probably explaining why many previous studies using surfaces that varied only in inter-element spacing led to the conclusion that temporal factors play no role in roughness perception. However, the perceived roughness ofR-varying gratings was determined byFtand not spatial variables. Roughness judgments were influenced byGandFtin a manner entirely consistent with predicted afferent response rates. Thus perceived roughness, like peripheral afferent responses, depends in part on temporal variables.
M Channel KCNQ2 Subunits Are Localized to Key Sites for Control of Neuronal Network Oscillations and Synchronization in Mouse Brain
Authors: Cooper Edward C. , Harrington Emily , Jan Yuh Nung , Jan Lily Y.
Published: April 2018

Mutations in the potassium channel subunit KCNQ2 lead to benign familial neonatal convulsions, a dominantly inherited form of generalized epilepsy. In heterologous cells, KCNQ2 expression yields voltage-gated potassium channels that activate slowly (τ, ∼0.1 sec) at subthreshold membrane potentials. KCNQ2 associates with KCNQ3, a homolog, to form heteromeric channels responsible for the M current (IM) in superior cervical ganglion (SCG) neurons. Muscarinic acetylcholine and peptidergic receptors inhibit SCGIM, causing slow EPSPs and enhancing excitability. Here, we use KCNQ2N antibodies, directed against a conserved N-terminal portion of the KCNQ2 polypeptide, to localize KCNQ2-containing channels throughout mouse brain. We show that KCNQ2N immunoreactivity, although widespread, is particularly concentrated at key sites for control of rhythmic neuronal activity and synchronization. In the basal ganglia, we find KCNQ2N immunoreactivity on somata of dopaminergic and parvalbumin (PV)-positive (presumed GABAergic) cells of the substantia nigra, cholinergic large aspiny neurons of the striatum, and GABAergic and cholinergic neurons of the globus pallidus. In the septum, GABAergic, purinergic, and cholinergic neurons that contribute to the septohippocampal and septohabenular pathways exhibit somatic KCNQ2 labeling. In the thalamus, GABAergic nucleus reticularis neurons that regulate thalamocortical oscillations show strong labeling. In the hippocampus, many PV-positive and additional PV-negative interneurons exhibit strong somatic staining, but labeling of pyramidal and dentate granule somata is weak. There is strong neuropil staining in many regions. In some instances, notably the hippocampal mossy fibers, evidence indicates this neuropil staining is presynaptic.
Alternative Splicing Unmasks Dendritic and Axonal Targeting Signals in Metabotropic Glutamate Receptor 1
Authors: Francesconi Anna , Duvoisin Robert M.
Published: April 2018

Precise targeting of neurotransmitter receptors to different neuronal compartments is a fundamental step for the establishment and function of synaptic circuitry. Group I metabotropic glutamate receptors, mGluR1 and mGluR5, control glutamatergic neurotransmission by acting both postsynaptically and presynaptically. Four alternatively spliced variants of the mGluR1 gene exist, which differ in their signaling properties and subcellular localization. The present study was undertaken to identify the molecular signals responsible for trafficking of these receptors to different neuronal compartments. Here we report that targeting of mGluR1 to dendrites and axons of transfected retina neurons is controlled by alternative splicing. We have identified in the tail of the receptor a tripeptide motif, which is necessary and sufficient to exclude the splice variant mGluR1b from distal dendrites and to drive it to the axon. This motif, which is present in all the mGluR1 receptors, is masked in mGluR1a by a dominant dendritic signal sequence harbored by the extended C-terminal tail of this splice variant. Furthermore, we show that the identified axonal and dendritic targeting signals are also necessary and sufficient to localize mGluR1b and mGluR1a to the apical and basolateral compartment of Madin–Darby canine kidney cells, respectively, consistent with the existence of common trafficking components for polarized targeting in epithelial cells and neurons.
Episodic Bursting Activity and Response to Excitatory Amino Acids in Acutely Dissociated Gonadotropin-Releasing Hormone Neurons Genetically Targeted with Green Fluorescent Protein
Authors: Kuehl-Kovarik M. Cathleen , Pouliot Wendy A. , Halterman Gloriana L. , Handa Robert J. , Dudek F. Edward , Partin Kathryn M.
Published: April 2018

The gonadotropin-releasing hormone (GnRH) system, considered to be the final common pathway for the control of reproduction, has been difficult to study because of a lack of distinguishing characteristics and the scattered distribution of neurons. The development of a transgenic mouse in which the GnRH promoter drives expression of enhanced green fluorescent protein (EGFP) has provided the opportunity to perform electrophysiological studies of GnRH neurons. In this study, neurons were dissociated from brain slices prepared from prepubertal female GnRH-EGFP mice. Both current- and voltage-clamp recordings were obtained from acutely dissociated GnRH neurons identified on the basis of EGFP expression. Most isolated GnRH-EGFP neurons fired spontaneous action potentials (recorded in cell-attached or whole-cell mode) that typically consisted of brief bursts (2–20 Hz) separated by 1–10 sec. At more negative resting potentials, GnRH-EGFP neurons exhibited oscillations in membrane potential, which could lead to bursting episodes lasting from seconds to minutes. These bursting episodes were often separated by minutes of inactivity. Rapid application of glutamate or NMDA increased firing activity in all neurons and usually generated small inward currents (<15 pA), although larger currents were evoked in the remaining neurons. Both AMPA and NMDA receptors mediated the glutamate-evoked inward currents. These results suggest that isolated GnRH-EGFP neurons from juvenile mice can generate episodes of repetitive burst discharges that may underlie the pulsatile secretion of GnRH, and glutamatergic inputs may contribute to the activation of endogenous bursts.
Disease-Specific Human Glycine Receptor α1Subunit Causes Hyperekplexia Phenotype and Impaired Glycine- and GABAA-Receptor Transmission in Transgenic Mice
Authors: Becker Lore , von Wegerer Jörg , Schenkel Johannes , Zeilhofer Hanns-Ulrich , Swandulla Dieter , Weiher Hans
Published: April 2018

Hereditary hyperekplexia is caused by disinhibition of motoneurons resulting from mutations in the ionotropic receptor for the inhibitory neurotransmitter glycine (GlyR). To study the pathomechanisms involvedin vivo, we generated and analyzed transgenic mice expressing the hyperekplexia-specific dominant mutant human GlyR α1subunit 271Q. Tg271Q transgenic mice, in contrast to transgenic animals expressing a wild-type human α1subunit (tg271R), display a dramatic phenotype similar to spontaneous and engineered mouse mutations expressing reduced levels of GlyR. Electrophysiological analysis in the ventral horn of the spinal cord of tg271Q mice revealed a diminished GlyR transmission. Intriguingly, an even larger reduction was found for GABAA-receptor-mediated inhibitory transmission, indicating that the expression of this disease gene not only affects the glycinergic system but also leads to a drastic downregulation of the entire postsynaptic inhibition. Therefore, the transgenic mice generated here provide a new animal model of systemic receptor interaction to study inherited and acquired neuromotor deficiencies at different functional levels and to develop novel therapeutic concepts for these diseases.
How AMPA Receptor Desensitization Depends on Receptor Occupancy
Authors: Robert Antoine , Howe James R.
Published: April 2018

AMPA-type glutamate receptors mediate fast excitatory transmission at many central synapses, and rapid desensitization of these receptors can shape the decay of synaptic currents and limit the fidelity of high-frequency synaptic transmission. Here we use a combination of fast glutamate application protocols and kinetic simulations to determine how AMPA receptor desensitization depends on the number of subunits occupied by glutamate. We show that occupancy of a single subunit is sufficient to desensitize AMPA-type channels and that receptors with one to four glutamates bound enter desensitization at similar rates. We find that recovery from desensitization follows a similar sigmoid time course for channels with two to four glutamates bound but is faster and exponential for singly occupied channels. The results suggest that desensitization, at intermediate and high glutamate concentrations, is accompanied by two conformational changes that slow glutamate dissociation. We propose a kinetic scheme that accurately predicts several types of experimental results and differs significantly from previous models in the assignment of affinities for binding to closed and desensitized states. We conclude that desensitization involves a rearrangement that stabilizes the binding domains of one subunit in each dimer in a partially closed conformation. This stabilization likely results from an interaction at the dimer–dimer interface between the binding domains of adjacent subunits.
Selective Disruption of Stimulus-Reward Learning in Glutamate Receptorgria1Knock-Out Mice
Authors: Mead Andy N. , Stephens David N.
Published: April 2018

Glutamatergic neurotransmission via AMPA receptors has been an important focus of studies investigating neuronal plasticity. AMPA receptor glutamate receptor 1 (GluR1) subunits play a critical role in long-term potentiation (LTP). Because LTP is thought to be the cellular substrate for learning, we investigated whether mice lacking the GluR1 subunit [gria1knock-outs (KO)] were capable of learning a simple cue–reward association, and whether such cues were able to influence motivated behavior. Bothgria1KO and wild-type mice learned to associate a light/tone stimulus with food delivery, as evidenced by their approaching the reward after presentation of the cue. During subsequent testing phases,gria1KO mice also displayed normal approach to the cue in the absence of the reward (Pavlovian approach) and normal enhanced responding for the reward during cue presentations (Pavlovian to instrumental transfer). However, the cue did not act as a reward for learning a new behavior in the KO mice (conditioned reinforcement). This pattern of behavior is similar to that seen with lesions of the basolateral nucleus of the amygdala (BLA), and correspondingly,gria1KO mice displayed impaired acquisition of responding under a second-order schedule. Thus, mice lacking the GluR1 receptor displayed a specific deficit in conditioned reward, suggesting that GluR1-containing AMPA receptors are important in the synaptic plasticity in the BLA that underlies conditioned reinforcement. Immunostaining for GluR2/3 subunits revealed changes in GluR2/3 expression in thegria1KOs in the BLA but not the central nucleus of the amygdala (CA), consistent with the behavioral correlates of BLA but not CA function.
Upregulation of the Hyperpolarization-Activated Cation Current after Chronic Compression of the Dorsal Root Ganglion
Authors: Yao Hang , Donnelly David F. , Ma Chao , LaMotte Robert H.
Published: April 2018

A chronic compression of the DRG (CCD) produces cutaneous hyperalgesia and an enhanced excitability of neuronal somata in the compressed ganglion. The hyperpolarization-activated current (Ih), present in the somata and axons of DRG neurons, acts to induce a depolarization after a hyperpolarizing event and, if upregulated after CCD, may contribute to enhanced neuronal excitability. Whole-cell patch-clamp recordings were obtained from acutely dissociated, retrogradely labeled, cutaneous, adult rat DRG neurons of medium size. Neurons were dissociated from L4and L5control DRGs or DRGs that had each been compressed for 5–7 d by L-shaped rods inserted into the intervertebral foramina.Ih, consisting of a slowly activating inward current during a step hyperpolarization, was recorded from every labeled, medium-sized neuron and was blocked by 1 mmcesium or 15 μmZD7288. Compared with control, CCD increased the current density and rate of activation significantly without changing its reversal potential, voltage dependence of activation, or rate of deactivation. BecauseIhactivation provides a depolarizing current to the neuron, thus enhancing neuronal excitability, our results are consistent with the hypothesis thatIhcontributes to hyperalgesia after CCD-induced nerve injury.
Cell Cycle Regulators in the Neuronal Death Pathway of Amyotrophic Lateral Sclerosis Caused by Mutant Superoxide Dismutase 1
Authors: Nguyen Minh Dang , Boudreau Mathieu , Kriz Jasna , Couillard-Després Sébastien , Kaplan David R. , Julien Jean-Pierre
Published: April 2018

There is growing evidence for involvement of members of the cyclin-dependent kinase (Cdk) family in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults. After our recent report that a deregulation of Cdk5 activity by p25 may contribute to pathogenesis of amyotrophic lateral sclerosis (ALS), we further examined the possible involvement of other Cdks in mice expressing a mutant form of superoxide dismutase (SOD1G37R) linked to ALS. No substantial changes in Cdk2 or Cdk6 distribution and kinase activities were detected in spinal motor neurons from SOD1G37Rmice when compared with normal mice. Of particular interest was the upregulation and mislocalization of Cdk4, a regulator of the G1-S checkpoint of the cell cycle, in motor neurons of SOD1G37Rmice. The increase of Cdk4 activity in SOD1G37Rmice was associated with an increase in nuclear Cdk4, cyclin D1, its coactivator, and with the abnormal phosphorylation of the retinoblastoma (Rb) protein at Cdk phosphorylation sites. Pharmacological treatment of SOD1G37Rmice with minocycline, a compound that attenuates microgliosis and slows down disease, lessened the dysregulation of Cdk5/Cdk4 and the phosphorylation of Rb. Interestingly, phospho-Rb was immunoprecipitated with anti-Cdk4 but not with anti-Cdk5 antibodies, suggesting a key role for Cdk4 in the phosphorylation of Rb. Remarkably, the overexpression of a transgene coding for human neurofilament H, a phosphorylation sink for deregulated Cdk5 activity by p25, resulted in a reduction in levels of nuclear Cdk4 and Rb phosphorylation. These results indicate that a cell cycle signaling at the neuronal G1-S checkpoint subsequent to Cdk5 deregulation may constitute a critical step of the neuronal death pathway in ALS caused by mutant SOD1.
Activation of Microglial Group III Metabotropic Glutamate Receptors Protects Neurons against Microglial Neurotoxicity
Authors: Taylor Deanna L. , Diemel Lara T. , Pocock Jennifer M.
Published: April 2018

A reduction in microglial activation and subsequent neurotoxicity may prove critical for neuroprotection in neurodegenerative diseases. We examined the expression and functionality of group III metabotropic glutamate (mGlu) receptors on microglia. Rat microglia express mRNA and receptor protein for group III mGlu receptors mGlu4, mGlu6, and mGlu8 but not mGlu7. Activation of these receptors on microglia with the specific group III agonists (L)-2-amino-4-phosphono-butyric acid (l-AP-4) or (R,S)-phosphonophenylglycine (RS-PPG) inhibited forskolin-induced cAMP production, linking these receptors to the negative inhibition of adenylate cyclase. These agonists did not induce a fall in mitochondrial membrane potential or apoptosis in the microglia, suggesting that activation of these receptors is not in itself toxic to microglia. Fluorescence-activated cell sorting analysis revealed that activation of group III mGlu receptors induces a mild activation of the microglia, as evidence by their enhanced staining with ED1. However, this activation is not neurotoxic. Agonists of group III mGlu receptors reduced microglial reactivity when they were activated with lipopolysaccharide (LPS), chromogranin A (CGA) or amyloid β peptide 25-35 (Aβ25-35). Furthermore,l-AP-4 orRS-PPG treatment of microglia reduced their neurotoxicity after microglial stimulation with LPS or CGA but not Aβ25-35. Similar results were obtained with microglial conditioned medium or in coculture, suggesting that the activation of microglial group III mGlu receptors may modulate the production of stable neurotoxins from the microglia. These results suggest that selective modulation of microglial group III mGlu receptors may provide a therapeutic target in neuroinflammatory diseases such as Alzheimer's disease.
Phospholemman, a Single-Span Membrane Protein, Is an Accessory Protein of Na,K-ATPase in Cerebellum and Choroid Plexus
Authors: Feschenko Marina S. , Donnet Claudia , Wetzel Randall K. , Asinovski Natalya K. , Jones Larry R. , Sweadner Kathleen J.
Published: April 2018

Phospholemman (FXYD1) is a homolog of the Na,K-ATPase γ subunit (FXYD2), a small accessory protein that modulates ATPase activity. Here we show that phospholemman is highly expressed in selected structures in the CNS. It is most abundant in cerebellum, where it was detected in the molecular layer, in Purkinje neurons, and in axons traversing the granule cell layer. Phospholemman was particularly enriched in choroid plexus, the organ that secretes CSF in the ventricles, where it colocalized with Na,K-ATPase in the apical membrane. It was also enriched, with Na,K-ATPase, in certain tanycytes or ependymal cells of the ventricle wall. Two different experimental approaches demonstrated that phospholemman physically associated with the Na,K-ATPase in cerebellum and choroid plexus: the proteins copurified after detergent treatment and co-immunoprecipitated from solubilized crude membranes using either anti-phospholemman or anti-Na,K-ATPase antibodies. Phospholemman antibodies precipitated all three Na,K-ATPase α subunit isoforms (α1–α3) from cerebellum, indicating that the interaction is not specific to a particular α isoform and consistent with the presence of phospholemman in both neurons and glia. Antibodies against the C-terminal domain of phospholemman reduced Na,K-ATPase activityin vitrowithout effect on Na+affinity. At least two other FXYD family members have been detected in the CNS, suggesting that additional complexity of sodium pump regulation will be found.
Heat Shock Protein 70 Chaperone Overexpression Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model by Reducing Nuclear-Localized Mutant Androgen Receptor Protein
Authors: Adachi Hiroaki , Katsuno Masahisa , Minamiyama Makoto , Sang Chen , Pagoulatos Gerassimos , Angelidis Charalampos , Kusakabe Moriaki , Yoshiki Atsushi , Kobayashi Yasushi , Doyu Manabu , Sobue Gen
Published: April 2018

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR). The nuclear inclusions consisting of the mutant AR protein are characteristic and combine with many components of ubiquitin–proteasome and molecular chaperone pathways, raising the possibility that misfolding and altered degradation of mutant AR may be involved in the pathogenesis. We have reported that the overexpression of heat shock protein (HSP) chaperones reduces mutant AR aggregation and cell death in a neuronal cell model (Kobayashi et al., 2000). To determine whether increasing the expression level of chaperone improves the phenotype in a mouse model, we cross-bred SBMA transgenic mice with mice overexpressing the inducible form of human HSP70. We demonstrated that high expression of HSP70 markedly ameliorated the motor function of the SBMA model mice. In double-transgenic mice, the nuclear-localized mutant AR protein, particularly that of the large complex form, was significantly reduced. Monomeric mutant AR was also reduced in amount by HSP70 overexpression, suggesting the enhanced degradation of mutant AR. These findings suggest that HSP70 overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR, probably caused by enhanced mutant AR degradation. Our study may provide the basis for the development of an HSP70-related therapy for SBMA and other polyQ diseases.
Glutamate Promotes Proliferation of Striatal Neuronal Progenitors by an NMDA Receptor-Mediated Mechanism
Authors: Luk Kelvin C. , Kennedy Timothy E. , Sadikot Abbas F.
Published: April 2018

Increasing evidence suggests that classical neurotransmitters play important roles in the development of the mammalian CNS. We usedin vivoandin vitromodels to identify a novel role for glutamate in striatal neurogenesis mediated by NMDA receptors.In uteroexposure to NMDA receptor antagonists during striatal neurogenesis caused a dramatic reduction in the total number of adult striatal neurons. In contrast, embryos exposed to NMDA receptor antagonists immediately after the main period of neurogenesis showed no significant change in neuronal number in the adult striatum. In addition, examination of embryos shortly after NMDA receptor blockade revealed reduced proliferation in the lateral ganglionic eminence (LGE). In culture, dividing neuronal progenitors derived from the embryonic LGE showed marked reduction in 5′-bromodeoxyuridine (BrdU) uptake when exposed to NMDA receptor antagonists, indicating reduced DNA synthesis. Low concentrations of NMDA significantly increased proliferation, whereas high concentrations were toxic. AMPA–KA receptor antagonists had no significant effect on striatal neuroblast proliferation eitherin vivoorin vitro. These results support the hypothesis that glutamate plays a novel role during early development of the ventral telencephalon, promoting proliferation of striatal neuronal progenitors by an NMDA receptor-dependent mechanism. In contrast, previous findings suggest that proliferation of cortical progenitors derived from the dorsal telencephalon is regulated by activation of AMPA–KA but not NMDA receptors. Heterogeneous responses to glutamate in different germinal zones of the telencephalon may be an important mechanism contributing to generating neuronal diversity in the forebrain.
Proteolipid Protein Gene Mutation Induces Altered Ventilatory Response to Hypoxia in the Myelin-Deficient Rat
Authors: Miller Martha J. , Haxhiu Musa A. , Georgiadis Paraskevi , Gudz Tatyana I. , Kangas Cindy D. , Macklin Wendy B.
Published: April 2018

Pelizaeus Merzbacher disease is an X-linked dysmyelinating disorder of the CNS, resulting from mutations in the proteolipid protein (PLP) gene. An animal model for this disorder, the myelin-deficient (MD) rat, carries a point mutation in thePLPgene and exhibits a phenotype similar to the fatal, connatal disease, including extensive dysmyelination, tremors, ataxia, and death at approximately postnatal day 21 (P21). We postulated that early death might result from disruption of myelinated neural pathways in the caudal brainstem and altered ventilatory response to oxygen deprivation or hypercapnic stimulus. Using barometric plethysmography to measure respiratory function, we found that the MD rat develops lethal hypoxic depression of breathing at P21, but hypercapnic ventilatory response is normal. Histologic examination of the caudal brainstem in the MD rat at this age showed extensive dysmyelination and downregulation of NMDA and to a lesser extent GABAAreceptors on neurons in the nucleus tractus solitarius, hypoglossal nucleus, and dorsal motor nucleus of the vagus. Unexpectedly, immunoreactive PLP/DM20 was detected in neurons in the caudal brainstem. Not all biosynthetic functions and structural elements were altered in these neurons, because phosphorylated and nonphosphorylated neurofilament and choline acetyltransferase expression were comparable between MD and wild-type rats. These findings suggest that PLP is expressed in neurons in the developing brainstem and thatPLPgene mutation can selectively disrupt central processing of afferent neural input from peripheral chemoreceptors, leaving the central chemosensory system for hypercapnia intact.
Estrogen Stimulates Postsynaptic Density-95 Rapid Protein Synthesis via the Akt/Protein Kinase B Pathway
Authors: Akama Keith T. , McEwen Bruce S.
Published: April 2018

Estrogens induce synaptogenesis in the CA1 region of the dorsal hippocampus during the estrous cycle of the female rat. Functional consequences of such estrogen-mediated synaptogenesis include cyclic changes in neurotransmission and memory. At the molecular level, estrogen stimulates the rapid activation of specific signal transduction pathways, and of particular interest is the activation of Akt (protein kinase B), a key signal transduction intermediate that initiates protein translation by alleviating the downstream translational repression of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Using a well establishedin vitromodel system of differentiated NG108-15 neurons to investigate such rapid signaling effects of estrogen, we show that estrogen stimulates the phosphorylation of Akt, an indication of kinase activation, as well as the phosphorylation of 4E-BP1. In turn, the activation of these signaling intermediates suggests a non-genomic mechanism by which estrogen might likewise lead to protein translation of dendrite-localized mRNA transcripts in the hippocampusin vivo. We therefore considered the translation of the dendritic spine scaffolding protein postsynaptic density-95 (PSD-95). Although estrogen does not stimulate a rapid increase in PSD-95 mRNA levels in NG108-15 neurons, we show here that estrogen does however stimulate a rapid increase in PSD-95 new protein synthesisin vitroand that this new protein synthesis is Akt dependent. These results demonstrate an essential role for Akt in estrogen-stimulated dendritic spine protein expression, describe for the first time a signal transduction pathway in PSD-95 expression, and delineate a novel, molecular mechanism by which ovarian hormones might translationally regulate synaptogenesis via activating protein synthesis for dendritic function.