bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of surface treatments of AA 2024-T3 aluminum sheet on bonding to epoxy-based film adhesive
Authors: Chiu Hsien-Tang , Liu Yung-Lung , Liao Yean-Ho , Tsai Peir-An
Published: November 2012

Four different surface treatments were performed on aluminum sheets that were then bonded with an epoxy-based film adhesive in an autoclave to achieve good adhesion. Specimens were examined to determine the microstructure of the porous oxide layer on the aluminum sheet surface and its effects on the bonding performance. Based on the failure modes of the bonded surfaces, the peeling strength, and an analysis of the microstructure of the porous oxide layer, this study showed that chromic anodizing the aluminum sheet had the best bonding performance, whereas sulfuric and hard anodizing exhibited the worst bonding performance. Hot etching exhibited a bonding performance somewhere between that of chromic anodizing and that of sulfuric anodizing. The chromic anodizing surface treatment can produce more pores on the oxide layer of aluminum sheet surface, which can enlarge the bonding areas and consequently enhance its bonding performance.
Modeling of tensile modulus of polyolefin-layered silicate nanocomposites: modified micro-mechanical and statistical methods
Authors: Mittal Vikas
Published: November 2012

Applicability and subsequent modification of various composite models for the prediction of the relative tensile modulus of polyolefin nanocomposites has been studied. A number of models, such as the modified Halpin-Tsai, Guth, Mori-Tanaka, Hui and Shia and Takayanagi models, as well as factorial and mixture designs, were considered. Various assumptions in the models, such as uniform shape and size of filler (i.e., complete exfoliation), alignment, as well as interfacial bonding between the components, restrict their application for the prediction of the nanocomposite modulus. The modified Guth model and Halpin-Tsai model, with the ∅m concept, were developed further to incorporate the modulus reduction factors for polyolefin nanocomposites. This allowed the generation of master curves of the modulus reduction factor as a function of the aspect ratio of the filler in the composite. It was observed that the Mori Tanaka model, modified by constructing models of various representative volume elements (RVEs) of the underlying structure of the nanoclay filled polymers, matched the experimental values of the tensile modulus of polyolefin nanocomposites. The modified Hui and Shia model, incorporating the non-bonding interfacial effects, as well as the three component modified Takayanagi model, were also able to predict the tensile modulus of polyolefin nanocomposites efficiently. Factorial and mixture designs did not require the conventionally used assumptions and satisfactorily reflected the material behavior, and were specific to the particular components used to generate nanocomposites. These models were also helpful in predicting the aspect ratio of the filler in the composites, when synergistically combined with other modified models.
Thermal and mechanical characteristics of cement nanocomposites
Authors: Jalal Mostafa , Mansouri Esmaeel
Published: November 2012

Widespread applications and advantages of different types of composite materials have drawn researchers’ attention toward the science and technology of composites. Among these materials, cementitious composites have a special place, as they have many applications in various fields of structural and civil engineering. Due to the importance of cementitious composites and their behavior, investigation of their properties is of great importance. Thus in the present study, thermal and mechanical properties of the self-compacting cementitious composites containing different fractions of nano TiO2 have been investigated. Mechanical properties were assessed through compressive, split tensile and flexural tests. The thermal properties were assessed through thermogravimetric analysis (TGA) and conduction calorimetry tests. Accelerated peak appearance in conduction calorimetry tests and more weight loss in thermogravimetric analysis could indicate that TiO2 nanoparticles could lead to strength development at earlier ages and improve the properties of the self-compacting cementitious composites.
Prediction of tensile capacity of adhesive anchors including edge and group effects using neural networks
Authors: Ozturk Murat
Published: November 2012

Adhesive anchors are widely used in seismic strengthening applications to add new structural members or sections to existing concrete members due to their high tensile and compressive strengths, low cost, and easy and fast installation. To safely design such anchors, it is very important to know their pullout capacity under axial tensile forces. This paper explores the pullout capacity of both single and groups of adhesive anchors loaded in tension in uncracked concrete. Quadruple anchor groups were considered for group effect. To this end, 142 single anchor tests including edge effect (located near a concrete edge) and 175 quadruple group anchor tests (totally 317 tests) were obtained from literature. The formulated three-layered artificial neural network method (ANN) was trained using 75% of the data set by using different learning algorithms. The methods were tested with the remaining 25%. The variables taken into account in this study are anchor diameter, embedment length, concrete compressive strength, concrete body height, edge distance (for single anchors), and anchor spacing (for group anchors). It was determined that experimental data can be estimated to a notably close extent via the ANN model.
Use of marble dust and fly ash in stabilization of base material
Authors: Zorluer Ismail , Demirbas Abdullah
Published: November 2012

Marble dust and fly ash are waste materials and used in various area and industries as an additive material. However, there are still significant amounts of marble dust and fly ash left as waste. Therefore, the reuse of these wastes provides benefits to reduce construction costs and increase sustainability. In this study, a laboratory testing program was conducted on granular soil specimens amended with marble dust and fly ash. The specimens were prepared with granular soil and marble dust-fly ash at different mixing ratios. They were compacted with standard and modified Proctor energies. The specimens were subjected to unconfined compression, California bearing ratio, and freezing-thawing tests. The results of the study show that the strength of a specimen is dependent on the additive ratio, the curing period, compaction energy, and the number of freeze-thaw (F-T) cycles. Generally, unconfined compressive strength (qu) and California bearing ratio (CBR) increased with additive materials, curing times, and high compaction energy. qu decreased and weight loss increased with increasing additives and increasing F-T cycles.
Influence on variation in process parameters for the design of xanthan-gum-facilitated ethyl cellulose microparticles for intestinal specific delivery
Authors: Banerjee Subham , Tiwari Aashish , Yadav Santosh Kumar , Bhattacharya Shiv Sankar , Dagaji Aher Vaibhav , Mondal Pabitra
Published: November 2012

Xanthan-gum-facilitated aspirin-loaded ethyl cellulose microparticles were prepared by multiple-emulsion solvent evaporation technology and the impact on variation in process parameters was investigated systematically. Scanning electron microscopy was performed to determine the surface morphology of the microparticles before and after dissolution study. X-ray diffraction (XRD), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) analysis were performed, and yield value, swelling study, encapsulation efficiency, flow properties and dissolution profiles of the prepared formulations were evaluated. The size of microparticles varied between 247 and 410 μm, and 58.34% drug entrapment efficiency was achieved depending on the variation in process parameters. The drug release in acid solutions was slower than in alkaline solution. The microparticles provided extended drug release in alkaline dissolution medium, and the drug release was found to be controlled by Fickian diffusion mechanism. XRD and DSC analyses revealed the amorphous nature of drug in the microparticles. FTIR data indicated the stable character of the encapsulated drug in the microparticles. Thus, variation in process parameters showed a slow and prolonged release of aspirin in simulated intestinal fluid.
β-Secretase Cleavage of the Fly Amyloid Precursor Protein Is Required for Glial Survival
Authors: Bolkan Bonnie J. , Triphan Tilman , Kretzschmar Doris
Published: November 2012

β-secretase (or BACE1) is the key enzyme in the production of β-amyloid (Aβ), which accumulates in the senile plaques characteristic for Alzheimer's disease. Consequently, the lack of BACE1 prevents β-processing of the amyloid precursor protein and Aβ production, which made it a promising target for drug development. However, the loss of BACE1 is also detrimental, leading to myelination defects and altered neuronal activity, functions that have been associated with the cleavage of Neuregulin and a voltage-gated sodium channel subunit. Here we show that theDrosophilaortholog of BACE, dBACE, is required for glial survival. Cell-specific knockdown experiments reveal that this is a non-cell autonomous function, as a knockdown of dBACE in photoreceptor neurons leads to progressive degeneration of glia in their target zone, the lamina. Interestingly, this phenotype is suppressed by the loss of the fly amyloid precursor protein (APPL), whereas a secretion-deficient form of APPL enhances the degeneration. This shows that full-length APPL in neurons promotes the death of neighboring glial cells and that β-processing of APPL is needed to prevent glial death. These results therefore not only demonstrate a novel function for an APP protein in glia, but they also show this function specifically requires regulation by β-cleavage.
Switching Neuronal Inputs by Differential Modulations of Gamma-Band Phase-Coherence
Authors: Grothe Iris , Neitzel Simon D. , Mandon Sunita , Kreiter Andreas K.
Published: November 2012

Receptive fields (RFs) of cortical sensory neurons increase in size along consecutive processing stages. When multiple stimuli are present in a large visual RF, a neuron typically responds to an attended stimulus as if only that stimulus were present. However, the mechanism by which a neuron selectively responds to a subset of its inputs while discarding all others is unknown. Here, we show that neurons can switch between subsets of their afferent inputs by highly specific modulations of interareal gamma-band phase-coherence (PC). We measured local field potentials, single- and multi-unit activity in two male macaque monkeys (Macaca mulatta) performing an attention task. Two small stimuli were placed on a screen; the stimuli were driving separate local V1 populations, while both were driving the same local V4 population. In each trial, we cued one of the two stimuli to be attended. We found that gamma-band PC of the local V4 population with multiple subpopulations of its V1 input was differentially modulated. It was high with the input subpopulation representing the attended stimulus, while simultaneously it was very low between the same V4 population and the other input-providing subpopulation representing the irrelevant stimulus. These differential modulations, which depend on stimulus relevance, were also found in the locking of spikes from V4 neurons to the gamma-band oscillations of the V1 input subpopulations. This rapid, highly specific interareal locking provides neurons with a powerful dynamic routing mechanism to select and process only the currently relevant signals.
Deficient Use of Visual Information in Estimating Hand Position in Cerebellar Patients
Authors: Taig Efrat , Küper Michael , Theysohn Nina , Timmann Dagmar , Donchin Opher
Published: November 2012

We tested cerebellar degeneration in human patients in a task designed to isolate different aspects of motor planning and found a specific relationship between their ability to do inverse kinematic transformation and sparing of Crus I. Our approach was based on an experimental design introduced by Sober and Sabes (2003, 2005). Their paradigm allows behavioral deficits in planning of movement direction to be dissociated from deficits in generation of motor commands and also allows for the relative role played by visual and proprioceptive information to be quantified. Perturbation of visual information about hand position affected cerebellar degeneration patients (N= 12) and age-matched controls equally in determining movement direction, but had less of an effect in both groups in the transformation of movement direction to motor command. However, when provided with vision of the joints, control participants were more affected in generating the motor command in perturbed trials, and cerebellar degeneration participants were not. Thus, cerebellar patients were less able to use visual information about the joints in generating motor commands. Voxel-based morphometric analysis showed that this inability was primarily correlated with degeneration of Crus I. These results show that the cerebellum plays a role in motor planning, and specifically in the generation of inverse kinematic models for sensorimotor processing. The involvement of Crus I is consistent with an emerging picture in which increasingly posterior lobules of the anterior cerebellar cortex are associated with increasingly complex and abstract aspects of motor behavior.
Attention Selects Informative Neural Populations in Human V1
Authors: Verghese Preeti , Kim Yee-Joon , Wade Alex R.
Published: November 2012

In a neural population driven by a simple grating stimulus, different subpopulations are maximally informative about changes to the grating's orientation and contrast. In theory, observers should attend to the optimal subpopulation when switching between orientation and contrast discrimination tasks. Here we used source-imaged, steady-state visual evoked potentials and visual psychophysics to determine whether this is the case. Observers fixated centrally while static targets were presented bilaterally along with a cue indicating task type (contrast or orientation modulation detection) and task location (left or right). Changes in neuronal activity were measured by quantifying frequency-tagged responses from flickering “reporter” gratings surrounding the targets. To determine the orientation tuning of attentionally modulated neurons, we measured responses for three different probe-reporter angles: 0, 20, and 45°. We estimated frequency-tagged cortical activity using a minimum norm inverse procedure combined with realistic MR-derived head models and retinotopically mapped visual areas. Estimates of neural activity from regions of interest centered on V1 showed that attention to a spatial location clearly increased the amplitude of the neural response in that location. More importantly, the pattern of modulation depended on the task. For orientation discrimination, attentional modulation showed a sharp peak in the population tuned 20° from the target orientation, whereas for contrast discrimination the enhancement was more broadly tuned. Similar tuning functions for orientation and contrast discrimination were obtained from psychophysical adaptation studies. These findings indicate that humans attend selectively to the most informative neural population and that these populations change depending on the nature of the task.
Morphine Withdrawal Enhances Constitutive μ-Opioid Receptor Activity in the Ventral Tegmental Area
Authors: Meye Frank J. , van Zessen Ruud , Smidt Marten P. , Adan Roger A.H. , Ramakers Geert M. J.
Published: November 2012

μ-Opioid receptors (MORs) in the ventral tegmental area (VTA) are pivotally involved in addictive behavior. While MORs are typically activated by opioids, they can also become constitutively active in the absence of any agonist. In the current study, we present evidence that MOR constitutive activity is highly relevant in the mouse VTA, as it regulates GABAergic input to dopamine neurons. Specifically, suppression of MOR constitutive activity with the inverse agonist KC-2-009 enhanced GABAergic neurotransmission onto VTA dopamine neurons. This inverse agonistic effect was fully blocked by the specific MOR neutral antagonist CTOP, which had no effect on GABAergic transmission itself. We next show that withdrawal from chronic morphine further increases the magnitude of inverse agonistic effects at the MOR, suggesting enhanced MOR constitutive activity. We demonstrate that this increase can be an adaptive response to the detrimental elevation in cAMP levels known to occur during morphine withdrawal. These findings offer important insights in the physiological occurrence and function of MOR constitutive activity, and have important implications for therapeutic strategies aimed at normalizing MOR signaling during addiction and opioid overdose.
Region-Specific Hierarchy between Atrophy, Hypometabolism, and β-Amyloid (Aβ) Load in Alzheimer's Disease Dementia
Authors: La Joie Renaud , Perrotin Audrey , Barré Louisa , Hommet Caroline , Mézenge Florence , Ibazizene Méziane , Camus Vincent , Abbas Ahmed , Landeau Brigitte , Guilloteau Denis , de La Sayette Vincent , Eustache Francis , Desgranges Béatrice , Chételat Gaël
Published: November 2012

Gray matter atrophy, glucose hypometabolism, and β-amyloid Aβ deposition are well-described hallmarks of Alzheimer's disease, but their relationships are poorly understood. The present study aims to compare the local levels of these three alterations in humans with Alzheimer's disease. Structural magnetic resonance imaging,18F-fluorodeoxyglucose positron emission tomography (PET), and18F-florbetapir PET data from 34 amyloid-negative healthy controls and 20 demented patients with a high probability of Alzheimer's disease etiology (attested using neuroimaging biomarkers as recently recommended) were analyzed. For each patient and imaging modality, age-adjustedZ-score maps were computed, and direct between-modality voxelwise comparison and correlation analyses were performed. Significant differences in the levels of atrophy, hypometabolism, and Aβ deposition were found in most brain areas, but the hierarchy differed across regions. A cluster analysis revealed distinct subsets of regions: (1) in the hippocampus, atrophy exceeded hypometabolism, whereas Aβ load was minimal; (2) in posterior association areas, Aβ deposition was predominant, together with high hypometabolism and lower but still significant atrophy; and (3) in frontal regions, Aβ deposition was maximal, whereas structural and metabolic alterations were low. Atrophy and hypometabolism significantly correlated in the hippocampus and temporo-parietal cortex, whereas Aβ load was not significantly related to either atrophy or hypometabolism. These findings provide direct evidence for regional variations in the hierarchy and relationships between Aβ load, hypometabolism, and atrophy. Altogether, these variations probably reflect the differential involvement of region-specific pathological or protective mechanisms, such as the presence of neurofibrillary tangles, disconnection, as well as compensation processes.
How Glitter Relates to Gold: Similarity-Dependent Reward Prediction Errors in the Human Striatum
Authors: Kahnt Thorsten , Park Soyoung Q , Burke Christopher J. , Tobler Philippe N.
Published: November 2012

Optimal choices benefit from previous learning. However, it is not clear how previously learned stimuli influence behavior to novel but similar stimuli. One possibility is to generalize based on the similarity between learned and current stimuli. Here, we use neuroscientific methods and a novel computational model to inform the question of how stimulus generalization is implemented in the human brain. Behavioral responses during an intradimensional discrimination task showed similarity-dependent generalization. Moreover, a peak shift occurred, i.e., the peak of the behavioral generalization gradient was displaced from the rewarded conditioned stimulus in the direction away from the unrewarded conditioned stimulus. To account for the behavioral responses, we designed a similarity-based reinforcement learning model wherein prediction errors generalize across similar stimuli and update their value. We show that this model predicts a similarity-dependent neural generalization gradient in the striatum as well as changes in responding during extinction. Moreover, across subjects, the width of generalization was negatively correlated with functional connectivity between the striatum and the hippocampus. This result suggests that hippocampus–striatal connections contribute to stimulus-specific value updating by controlling the width of generalization. In summary, our results shed light onto the neurobiology of a fundamental, similarity-dependent learning principle that allows learning the value of stimuli that have never been encountered.
Dual-Pitch Processing Mechanisms in Primate Auditory Cortex
Authors: Bendor Daniel , Osmanski Michael S. , Wang Xiaoqin
Published: November 2012

Pitch, our perception of how high or low a sound is on a musical scale, is a fundamental perceptual attribute of sounds and is important for both music and speech. After more than a century of research, the exact mechanisms used by the auditory system to extract pitch are still being debated. Theoretically, pitch can be computed using either spectral or temporal acoustic features of a sound. We have investigated how cues derived from the temporal envelope and spectrum of an acoustic signal are used for pitch extraction in the common marmoset (Callithrix jacchus), a vocal primate species, by measuring pitch discrimination behaviorally and examining pitch-selective neuronal responses in auditory cortex. We find that pitch is extracted by marmosets using temporal envelope cues for lower pitch sounds composed of higher-order harmonics, whereas spectral cues are used for higher pitch sounds with lower-order harmonics. Our data support dual-pitch processing mechanisms, originally proposed by psychophysicists based on human studies, whereby pitch is extracted using a combination of temporal envelope and spectral cues.
The β-Secretase-Derived C-Terminal Fragment of βAPP, C99, But Not Aβ, Is a Key Contributor to Early Intraneuronal Lesions in Triple-Transgenic Mouse Hippocampus
Authors: Lauritzen Inger , Pardossi-Piquard Raphaëlle , Bauer Charlotte , Brigham Elizabeth , Abraham Jean-Daniel , Ranaldi Sébastien , Fraser Paul , St-George-Hyslop Peter , Le Thuc Ophelia , Espin Vanessa , Chami Linda , Dunys Julie , Checler Frédéric
Published: November 2012

Triple-transgenic mice (3xTgAD) overexpressing Swedish-mutated β-amyloid precursor protein (βAPPswe), P310L-Tau (TauP301L), and physiological levels of M146V-presenilin-1 (PS1M146V) display extracellular amyloid-β peptides (Aβ) deposits and Tau tangles. More disputed is the observation that these mice accumulate intraneuronal Aβ that has been linked to synaptic dysfunction and cognitive deficits. Here, we provide immunohistological, genetic, and pharmacological evidences for early, age-dependent, and hippocampus-specific accumulation of the β-secretase-derived βAPP fragment C99 that is observed from 3 months of age and enhanced by pharmacological blockade of γ-secretase. Notably, intracellular Aβ is only detectable several months later and appears, as is the case of C99, in enlarged cathepsin B-positive structures, while extracellular Aβ deposits are detected ∼12 months of age and beyond. Early C99 production occurs mainly in the CA1/subicular interchange area of the hippocampus corresponding to the first region exhibiting plaques and tangles in old mice. Furthermore, the comparison of 3xTgAD mice with double-transgenic mice bearing the βAPPsweand TauP301Lmutations but expressing endogenous PS1 (2xTgAD) demonstrate that C99 accumulation is not accounted for by a loss of function triggered by PS1 mutation that would have prevented C99 secondary cleavage by γ-secretase. Together, our work identifies C99 as the earliest βAPP catabolite and main contributor to the intracellular βAPP-related immunoreactivity in 3xTgAD mice, suggesting its implication as an initiator of the neurodegenerative process and cognitive alterations taking place in this mouse model.
Parallel Maturation of Goal-Directed Behavior and Dopaminergic Systems during Adolescence
Authors: Naneix Fabien , Marchand Alain R. , Di Scala Georges , Pape Jean-Rémi , Coutureau Etienne
Published: November 2012

Adolescence is a crucial developmental period characterized by specific behaviors reflecting the immaturity of decision-making abilities. However, the maturation of precise cognitive processes and their neurobiological correlates at this period remain poorly understood. Here, we investigate whether a differential developmental time course of dopamine (DA) pathways during late adolescence could explain the emergence of particular executive and motivational components of goal-directed behavior. First, using a contingency degradation protocol, we demonstrate that adolescent rats display a specific deficit when the causal relationship between their actions and their consequences is changed. When the rats become adults, this deficit disappears. In contrast, actions of adolescents remain sensitive to outcome devaluation or to the influence of a pavlovian-conditioned stimulus. This aspect of cognitive maturation parallels a delayed development of the DA system, especially the mesocortical pathway involved in action adaptation to rule changes. Unlike in striatal and nucleus accumbens regions, DA fibers and DA tissue content continue to increase in the medial prefrontal cortex from juvenile to adult age. Moreover, a sustained overexpression of DA receptors is observed in the prefrontal region until the end of adolescence. These findings highlight the relationship between the emergence of specific cognitive processes, in particular the adaptation to changes in action consequences, and the delayed maturation of the mesocortical DA pathway. Similar developmental processes in humans could contribute to the adolescent vulnerability to the emergence of several psychiatric disorders characterized by decision-making deficits.
DrosophilaPsidin Regulates Olfactory Neuron Number and Axon Targeting through Two Distinct Molecular Mechanisms
Authors: Stephan Daniel , Sánchez-Soriano Natalia , Loschek Laura F. , Gerhards Ramona , Gutmann Susanne , Storchova Zuzana , Prokop Andreas , Kadow Ilona C. Grunwald
Published: November 2012

The formation of neuronal circuits is a key process of development, laying foundations for behavior. The cellular mechanisms regulating circuit development are not fully understood. Here, we reveal Psidin as an intracellular regulator ofDrosophilaolfactory system formation. We show that Psidin is required in several classes of olfactory receptor neurons (ORNs) for survival and subsequently for axon guidance. During axon guidance, Psidin functions as an actin regulator and antagonist of Tropomyosin. Accordingly, Psidin-deficient primary neurons in culture display growth cones with significantly smaller lamellipodia. This lamellipodial phenotype, as well as the mistargeting defectsin vivo, is suppressed by parallel removal of Tropomyosin. In contrast, Psidin functions as the noncatalytic subunit of theN-acetyltransferase complex B (NatB) to maintain the number of ORNs. Psidin physically binds the catalytic NatB subunit CG14222 (dNAA20) and functionally interacts with itin vivo. We define the dNAA20 interaction domain within Psidin and identify a conserved serine as a candidate for phosphorylation-mediated regulation of NatB complex formation. A phosphomimetic mutation of this serine showed severely reduced binding to dNAA20in vitro. In vivo, it fully rescued the targeting defect but not the reduction in neuron numbers. In addition, we show that a different amino acid point mutation shows exactly the opposite effect by rescuing only the cell number but not the axon targeting defect. Together, our data suggest that Psidin plays two independent developmental roles via the acquisition of separate signaling pathways, both of which contribute to the formation of olfactory circuits.
Action-Specific Value Signals in Reward-Related Regions of the Human Brain
Authors: FitzGerald Thomas H. B. , Friston Karl J. , Dolan Raymond J.
Published: November 2012

Estimating the value of potential actions is crucial for learning and adaptive behavior. We know little about how the human brain represents action-specific value outside of motor areas. This is, in part, due to a difficulty in detecting the neural correlates of value using conventional (region of interest) functional magnetic resonance imaging (fMRI) analyses, due to a potential distributed representation of value. We address this limitation by applying a recently developed multivariate decoding method to high-resolution fMRI data in subjects performing an instrumental learning task. We found evidence for action-specific value signals in circumscribed regions, specifically ventromedial prefrontal cortex, putamen, thalamus, and insula cortex. In contrast, action-independent value signals were more widely represented across a large set of brain areas. Using multivariate Bayesian model comparison, we formally tested whether value–specific responses are spatially distributed or coherent. We found strong evidence that both action-specific and action-independent value signals are represented in a distributed fashion. Our results suggest that a surprisingly large number of classical reward-related areas contain distributed representations of action-specific values, representations that are likely to mediate between reward and adaptive behavior.
Aging Differentially Affects the Re-entrainment Response of Central and Peripheral Circadian Oscillators
Authors: Sellix Michael T. , Evans Jennifer A. , Leise Tanya L. , Castanon-Cervantes Oscar , Hill DiJon D. , DeLisser Patrick , Block Gene D. , Menaker Michael , Davidson Alec J.
Published: November 2012

Aging produces a decline in the amplitude and precision of 24 h behavioral, endocrine, and metabolic rhythms, which are regulated in mammals by a central circadian pacemaker within the suprachiasmatic nucleus (SCN) and local oscillators in peripheral tissues. Disruption of the circadian system, as experienced during transmeridian travel, can lead to adverse health consequences, particularly in the elderly. To test the hypothesis that age-related changes in the response to simulated jet lag will reflect altered circadian function, we examined re-entrainment of central and peripheral oscillators from young and old PER2::luciferase mice. As in previous studies, locomotor activity rhythms in older mice required more days to re-entrain following a shift than younger mice. At the tissue level, effects of age on baseline entrainment were evident, with older mice displaying earlier phases for the majority of peripheral oscillators studied and later phases for cells within most SCN subregions. Following a 6 h advance of the light:dark cycle, old mice displayed slower rates of re-entrainment for peripheral tissues but a larger, more rapid SCN response compared to younger mice. Thus, aging alters the circadian timing system in a manner that differentially affects the re-entrainment responses of central and peripheral circadian clocks. This pattern of results suggests that a major consequence of aging is a decrease in pacemaker amplitude, which would slow re-entrainment of peripheral oscillators and reduce SCN resistance to external perturbation.
Cell Lineage Analysis Reveals Three Different Progenitor Pools for Neurosensory Elements in the Otic Vesicle
Authors: Sapède Dora , Dyballa Sylvia , Pujades Cristina
Published: November 2012

In the inner ear, sensory versus neuronal specification is achieved through few well-defined bHLH transcription factors. However, the molecular mechanisms regulating the generation of the appropriate cell type in the correct place and at the correct time are not completely understood yet. Various studies have shown that hair cell- and neuron-specifying genes partially overlap in the otic territory, suggesting that mutual interactions among these bHLH factors could direct the generation of the two cell types from a common neurosensory progenitor. Although there is little evidence for a clonal relationship between macular hair cells and sensory neurons, the existence of a single progenitor able to give both sensory and neuronal cell types remains an open question. Here, we identified a population of common neurosensory progenitors in the zebrafish inner ear and studied the proneural requirement for cell fate decision within this population. Expression analysis reveals that proneural genes for hair cells and neurons overlap within the posteromedial otic epithelium. Combined results from single-cell lineage and functional studies onneurog1andneuroD1further demonstrate the following: (1) in the anterior region of the ear, neuronal and sensory lineages have already segregated at the onset of proneural gene expression and are committed to a given fate very early; (2) in contrast, the posteromedial part of the ear harbors a population of common progenitors giving both neurons and hair cells until late stages; and finally (3)neuroD1is required within this pool of bipotent progenitors to generate the hair cell fate.
Aneuploid Cells Are Differentially Susceptible to Caspase-Mediated Death during Embryonic Cerebral Cortical Development
Authors: Peterson Suzanne E. , Yang Amy H. , Bushman Diane M. , Westra Jurjen W. , Yung Yun C. , Barral Serena , Mutoh Tetsuji , Rehen Stevens K. , Chun Jerold
Published: November 2012

Neural progenitor cells, neurons, and glia of the normal vertebrate brain are diversely aneuploid, forming mosaics of intermixed aneuploid and euploid cells. The functional significance of neural mosaic aneuploidy is not known; however, the generation of aneuploidy during embryonic neurogenesis, coincident with caspase-dependent programmed cell death (PCD), suggests that a cell's karyotype could influence its survival within the CNS. To address this hypothesis, PCD in the mouse embryonic cerebral cortex was attenuated by global pharmacological inhibition of caspases or genetic removal of caspase-3 or caspase-9. The chromosomal repertoire of individual brain cells was then assessed by chromosome counting, spectral karyotyping, fluorescencein situhybridization, and DNA content flow cytometry. Reducing PCD resulted in markedly enhanced mosaicism that was comprised of increased numbers of cells with the following: (1) numerical aneuploidy (chromosome losses or gains); (2) extreme forms of numerical aneuploidy (>5 chromosomes lost or gained); and (3) rare karyotypes, including those with coincident chromosome loss and gain, or absence of both members of a chromosome pair (nullisomy). Interestingly, mildly aneuploid (<5 chromosomes lost or gained) populations remained comparatively unchanged. These data demonstrate functional non-equivalence of distinguishable aneuploidies on neural cell survival, providing evidence that somatically generated, cell-autonomous genomic alterations have consequences for neural development and possibly other brain functions.
CaV1.3-Driven SK Channel Activation Regulates Pacemaking and Spike Frequency Adaptation in Mouse Chromaffin Cells
Authors: Vandael David H. F. , Zuccotti Annalisa , Striessnig Joerg , Carbone Emilio
Published: November 2012

Mouse chromaffin cells (MCCs) fire spontaneous action potentials (APs) at rest. Cav1.3 L-type calcium channels sustain the pacemaker current, and their loss results in depolarized resting potentials (Vrest), spike broadening, and remarkable switches into depolarization block after BayK 8644 application. A functional coupling between Cav1.3 and BK channels has been reported but cannot fully account for the aforementioned observations.

Here, using Cav1.3−/−mice, we investigated the role of Cav1.3 on SK channel activation and how this functional coupling affects the firing patterns induced by sustained current injections. MCCs express SK1–3 channels whose tonic currents are responsible for the slow irregular firing observed at rest. Percentage of frequency increase induced by apamin was found inversely correlated to basal firing frequency. Upon stimulation, MCCs build-up Cav1.3-dependent SK currents during the interspike intervals that lead to a notable degree of spike frequency adaptation (SFA). The major contribution of Cav1.3 to the subthreshold Ca2+charge during an AP-train rather than a specific molecular coupling to SK channels accounts for the reduced SFA of Cav1.3−/−MCCs. Low adaptation ratios due to reduced SK activation associated with Cav1.3 deficiency prevent the efficient recovery of NaVchannels from inactivation. This promotes a rapid decline of AP amplitudes and facilitates early onset of depolarization block following prolonged stimulation. Thus, besides serving as pacemaker, Cav1.3 slows down MCC firing by activating SK channels that maintain NaVchannel availability high enough to preserve stable AP waveforms, even upon high-frequency stimulation of chromaffin cells during stress responses.
LRP1 in Brain Vascular Smooth Muscle Cells Mediates Local Clearance of Alzheimer's Amyloid-β
Authors: Kanekiyo Takahisa , Liu Chia-Chen , Shinohara Mitsuru , Li Jie , Bu Guojun
Published: November 2012

Impaired clearance of amyloid-β (Aβ) is a major pathogenic event for Alzheimer's disease (AD). Aβ depositions in brain parenchyma as senile plaques and along cerebrovasculature as cerebral amyloid angiopathy (CAA) are hallmarks of AD. A major pathway that mediates brain Aβ clearance is the cerebrovascular system where Aβ is eliminated through the blood–brain barrier (BBB) and/or degraded by cerebrovascular cells along the interstitial fluid drainage pathway. An Aβ clearance receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in cerebrovasculature, in particular in vascular smooth muscle cells. Previous studies have indicated a role of LRP1 in endothelial cells in transcytosing Aβ out of the brain across the BBB; however, whether this represents a significant pathway for brain Aβ clearance remains controversial. Here, we demonstrate that Aβ can be cleared locally in the cerebrovasculature by an LRP1-dependent endocytic pathway in smooth muscle cells. The uptake and degradation of both endogenous and exogenous Aβ were significantly reduced in LRP1-suppressed human brain vascular smooth muscle cells. Conditional deletion ofLrp1in vascular smooth muscle cell in amyloid model APP/PS1 mice accelerated brain Aβ accumulation and exacerbated Aβ deposition as amyloid plaques and CAA without affecting Aβ production. Our results demonstrate that LRP1 is a major Aβ clearance receptor in cerebral vascular smooth muscle cell and a disturbance of this pathway contributes to Aβ accumulation. These studies establish critical functions of the cerebrovasculature system in Aβ metabolism and identify a new pathway involved in the pathogenesis of both AD and CAA.
Efficient Coding of Spatial Information in the Primate Retina
Authors: Doi Eizaburo , Gauthier Jeffrey L. , Field Greg D. , Shlens Jonathon , Sher Alexander , Greschner Martin , Machado Timothy A. , Jepson Lauren H. , Mathieson Keith , Gunning Deborah E. , Litke Alan M. , Paninski Liam , Chichilnisky E. J. , Simoncelli Eero P.
Published: November 2012

Sensory neurons have been hypothesized to efficiently encode signals from the natural environment subject to resource constraints. The predictions of this efficient coding hypothesis regarding the spatial filtering properties of the visual system have been found consistent with human perception, but they have not been compared directly with neural responses. Here, we analyze the information that retinal ganglion cells transmit to the brain about the spatial information in natural images subject to three resource constraints: the number of retinal ganglion cells, their total response variances, and their total synaptic strengths. We derive a model that optimizes the transmitted information and compare it directly with measurements of complete functional connectivity between cone photoreceptors and the four major types of ganglion cells in the primate retina, obtained at single-cell resolution. We find that the ganglion cell population exhibited 80% efficiency in transmitting spatial information relative to the model. Both the retina and the model exhibited high redundancy (∼30%) among ganglion cells of the same cell type. A novel and unique prediction of efficient coding, the relationships between projection patterns of individual cones to all ganglion cells, was consistent with the observed projection patterns in the retina. These results indicate a high level of efficiency with near-optimal redundancy in visual signaling by the retina.
Modulation of Top-Down Control of Visual Attention by Cathodal tDCS over Right IPS
Authors: Moos Katharina , Vossel Simone , Weidner Ralph , Sparing Roland , Fink Gereon R.
Published: November 2012

The right intraparietal sulcus (rIPS) is a key region for the endogenous control of selective visual attention in the human brain. Previous studies suggest that the rIPS is especially involved in top-down control and spatial distribution of attention across both visual hemifields. We further explored these attentional functions using transcranial direct current stimulation (tDCS) of the rIPS to modulate behavioral performance in a partial report task. Performance was analyzed according to the theory of visual attention (TVA) (Bundesen, 1990), which provides a computational framework to investigate different parameters of visuo-attentional processing such as top-down control, attentional weighting, capacity of visual short term memory, and processing speed. We investigated the effects of different tDCS current strengths (1 mA and 2 mA) in two experiments: 1 mA tDCS (anodal, cathodal, sham) did not affect any of the TVA parameters, but cathodal 2 mA stimulation significantly enhanced top-down control as evidenced by a reduction of the α parameter of TVA, regardless of hemifield. This differential impact on the top-down control component of attentional processing suggests that the horizontal rIPS is mainly involved in attentional selection as none of the spatial or resource variables of TVA were altered. Furthermore, the data add evidence to previous work highlighting (1) the importance of using appropriate current strength in stimulation protocols, and (2) that the often reported inhibitory effect of cathodal stimulation in e.g., motor tasks might not extend to cognitive paradigms.
Nociceptin/Orphanin FQ Receptor Agonists Attenuate l-DOPA-Induced Dyskinesias
Authors: Marti Matteo , Rodi Donata , Li Qin , Guerrini Remo , Fasano Stefania , Morella Ilaria , Tozzi Alessandro , Brambilla Riccardo , Calabresi Paolo , Simonato Michele , Bezard Erwan , Morari Michele
Published: November 2012

In the present study we investigated whether the neuropeptide nociceptin/orphanin FQ (N/OFQ), previously implicated in the pathogenesis of Parkinson's disease, also affectsl-DOPA-induced dyskinesia. In striatal slices of naive rodents, N/OFQ (0.1–1 μm) prevented the increase of ERK phosphorylation and the loss of depotentiation of synaptic plasticity induced by the D1 receptor agonist SKF38393 in spiny neurons.In vivo, exogenous N/OFQ (0.03–1 nmol, i.c.v.) or a synthetic N/OFQ receptor agonist given systemically (0.01–1 mg/Kg) attenuated dyskinesias expression in 6-hydroxydopamine hemilesioned rats primed withl-DOPA, without causing primary hypolocomotive effects. Conversely, N/OFQ receptor antagonists worsened dyskinesia expression.In vivomicrodialysis revealed that N/OFQ prevented dyskinesias simultaneously with its neurochemical correlates such as the surge of nigral GABA and glutamate, and the reduction of thalamic GABA. Regional microinjections revealed that N/OFQ attenuated dyskinesias more potently and effectively when microinjected in striatum than substantia nigra (SN) reticulata, whereas N/OFQ receptor antagonists were ineffective in striatum but worsened dyskinesias when given in SN. Quantitative autoradiography showed an increase in N/OFQ receptor binding in striatum and a reduction in SN of both unprimed and dyskinetic 6-hydroxydopamine rats, consistent with opposite adaptive changes of N/OFQ transmission. Finally, the N/OFQ receptor synthetic agonist also reduced dyskinesia expression in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated dyskinetic macaques without affecting the global parkinsonian score. We conclude that N/OFQ receptor agonists may represent a novel strategy to counteractl-DOPA-induced dyskinesias. Their action is possibly mediated by upregulated striatal N/OFQ receptors opposing the D1 receptor-mediated overactivation of the striatonigral direct pathway.
Demographic Inference Reveals African and European Admixture in the North AmericanDrosophila melanogasterPopulation
Authors: Duchen Pablo , Živković Daniel , Hutter Stephan , Stephan Wolfgang , Laurent Stefan
Published: November 2012

Drosophila melanogaster spread from sub-Saharan Africa to the rest of the world colonizing new environments. Here, we modeled the joint demography of African (Zimbabwe), European (The Netherlands), and North American (North Carolina) populations using an approximate Bayesian computation (ABC) approach. By testing different models (including scenarios with continuous migration), we found that admixture between Africa and Europe most likely generated the North American population, with an estimated proportion of African ancestry of 15%. We also revisited the demography of the ancestral population (Africa) and found—in contrast to previous work—that a bottleneck fits the history of the population of Zimbabwe better than expansion. Finally, we compared the site-frequency spectrum of the ancestral population to analytical predictions under the estimated bottleneck model.
Genetic Dissection of Peroxisome-Associated Matrix Protein Degradation in Arabidopsis thaliana
Authors: Burkhart Sarah E , Lingard Matthew J , Bartel Bonnie
Published: November 2012

Peroxisomes are organelles that sequester certain metabolic pathways; many of these pathways generate H2O2, which can damage proteins. However, little is known about how damaged or obsolete peroxisomal proteins are degraded. We exploit developmentally timed peroxisomal content remodeling in Arabidopsis thaliana to elucidate peroxisome-associated protein degradation. Isocitrate lyase (ICL) is a peroxisomal glyoxylate cycle enzyme necessary for early seedling development. A few days after germination, photosynthesis begins and ICL is degraded. We previously found that ICL is stabilized when a peroxisome-associated ubiquitin-conjugating enzyme and its membrane anchor are both mutated, suggesting that matrix proteins might exit the peroxisome for ubiquitin-dependent cytosolic degradation. To identify additional components needed for peroxisome-associated matrix protein degradation, we mutagenized a line expressing GFP–ICL, which is degraded similarly to endogenous ICL, and identified persistent GFP-ICLfluorescence (pfl) mutants. We found three pfl mutants that were defective in PEROXIN14 (PEX14/At5g62810), which encodes a peroxisomal membrane protein that assists in importing proteins into the peroxisome matrix, indicating that proteins must enter the peroxisome for efficient degradation. One pfl mutant was missing the peroxisomal 3-ketoacyl-CoA thiolase encoded by the PEROXISOME DEFECTIVE1 (PED1/At2g33150) gene, suggesting that peroxisomal metabolism influences the rate of matrix protein degradation. Finally, one pfl mutant that displayed normal matrix protein import carried a novel lesion in PEROXIN6 (PEX6/At1g03000), which encodes a peroxisome-tethered ATPase that is involved in recycling matrix protein receptors back to the cytosol. The isolation of pex6-2 as a pfl mutant supports the hypothesis that matrix proteins can exit the peroxisome for cytosolic degradation.