bluuebunny/crossref_metadata_2025 huggingface dataset:
Removal of Electrostatically Deposited Powders Using High Intensity Low Frequency Sound, Part 2: Quantification of Adhesive and Cohesive Forces Using Vibration
Authors: Seiffert Gary , Gibbs Barry
Published: March 2011

This is the second of two papers on the controlled removal of electrostatically deposited powder deposits. The research has an industrial application, the cleaning of electrostatic precipitator (ESP) filters in coal-fired power stations. The first paper focused on the removal of powder layers from a metal surface using sound. The aim of the work, reported in this paper, is to quantify the adhesive and cohesive bonding forces formed when powder is electrostatically deposited on to a metal surface by removing deposited layers using vibration. It is these forces that sound must overcome in order to remove deposited layers. It is hoped to establish a link between the layer de-bonding acceleration and de-bonding sound pressure level. Powder layers were electrostatically deposited on to one surface of an aluminium cube. The deposited layers then were removed, using a calibrated vibration table, in order to estimate powder bonding forces.
Adsorption of As(III) Ions onto Iron-Containing Waste Sludge
Authors: Negrea Adina , Lupa Lavinia , Ciopec Mihaela , Lazau Radu , Muntean Cornelia , Negrea Petru
Published: March 2011

The adsorption performance of a low-cost adsorbent (IS), viz. an iron-containing waste sludge arising during a hot-dip galvanizing process, towards the removal of As(III) ions from synthetic aqueous solutions and natural underground water was examined. The adsorption process was best described by the pseudo-second-order kinetic equation. The equilibrium adsorption data were well described by the Langmuir model. The value of the dimensional separation factor, RL, indicated favourable adsorption. The maximum adsorption capacity of IS was 625 μg As(III)/g. The variation in the extent of adsorption with temperature was used to evaluate the thermodynamic parameters for the adsorption process. The values of ΔH0 and ΔG0 obtained demonstrated that the adsorption process was exothermic and spontaneous. The studied material exhibited an excellent As(III) ion adsorption performance from both synthetic solutions and a natural water sample. Moreover, no secondary contaminated substances arise if the exhausted adsorbent is recycled (e.g. in glass applications).
Open Innovation Typology
Authors: Phillips Jeffrey
Published: March 2011

There are many ways an organization can approach innovation. On one end of the spectrum an organization can choose to have everyone submit any idea. On the other, innovation can be generated from a small, dedicated group of specialists. In the middle there are many variations along the way. This paper discusses the open innovation typology and the options for an organization making the decision about the best way to create an innovation infrastructure.
Thermodynamic examination of the pyrophosphate sensor helix in the thiamine pyrophosphate riboswitch
Authors: Furniss Stephanie , Grover Neena
Published: March 2011

Riboswitches are functional mRNA that control gene expression. Thiamine pyrophosphate (TPP) binds tothi-box riboswitch RNA and allosterically inhibits genes that code for proteins involved in the biosynthesis and transport of thiamine. Thiamine binding to the pyrimidine sensor helix and pyrophosphate binding to the pyrophosphate sensor helix cause changes in RNA conformation that regulate gene expression. Here we examine the thermodynamic properties of the internal loop of the pyrophosphate binding domain by comparing the wild-type construct (RNA WT) with six modified 2 × 2 bulged RNA and one 2 × 2 bulged DNA. The wild-type construct retains five conserved bases of the pyrophosphate sensor domain, two of which are in the 2 × 2 bulge (C65 and G66). The RNA WT construct was among the most stable (ΔG°37= −7.7 kcal/mol) in 1 M KCl at pH 7.5. Breaking the A•G mismatch of the bulge decreases the stability of the construct ∼0.5–1 kcal/mol, but does not affect magnesium binding to the RNA WT. Guanine at position 48 is important for RNA–Mg2+interactions of the TPP-binding riboswitch at pH 7.5. In the presence of 9.5 mM magnesium at pH 5.5, the bulged RNA constructs gained an average of 1.1 kcal/mol relative to 1 M salt. Formation of a single A+•C mismatch base pair contributes about 0.5 kcal/mol at pH 5.5, whereas two tandem A+•C mismatch base pairs together contribute about 2 kcal/mol.
An expanded collection and refined consensus model of glmS ribozymes
Authors: McCown Phillip J. , Roth Adam , Breaker Ronald R.
Published: March 2011

Self-cleaving glmS ribozymes selectively bind glucosamine-6-phosphate (GlcN6P) and use this metabolite as a cofactor to promote self-cleavage by internal phosphoester transfer. Representatives of the glmS ribozyme class are found in Gram-positive bacteria where they reside in the 5′ untranslated regions (UTRs) of glmS messenger RNAs that code for the essential enzyme L-glutamine:D-fructose-6-phosphate aminotransferase. By using comparative sequence analyses, we have expanded the number of glmS ribozyme representatives from 160 to 463. All but two glmS ribozymes are present in glmS mRNAs and most exhibit striking uniformity in sequence and structure, which are features that make representatives attractive targets for antibacterial drug development. However, our discovery of rare variants broadens the consensus sequence and structure model. For example, in the Deinococcus-Thermus phylum, several structural variants exist that carry additional stems within the catalytic core and changes to the architecture of core-supporting substructures. These findings reveal that glmS ribozymes have a broader phylogenetic distribution than previously known and suggest that additional rare structural variants may remain to be discovered.
Beryllium Measurement in Commercially Available Wet Wipes
Authors: Youmans-McDonald Linda D. , Brisson Mike , Bernard Maureen , Agrawal Anoop , Cronin John P. , Adams Lori
Published: March 2011

Analysis for beryllium by fluorescence is now an established method which is used in many government run laboratories and commercial facilities. This study investigates the use of this technique using commercially available wet wipes. The fluorescence method is widely documented [1,2] and has been approved as a standard test method by the ASTM International and the National Institute for Occupational Safety and Health. The procedure involves dissolution of samples in an aqueous ammonium bifluoride solution and then adding a small aliquot to a basic hydroxybenzoquinoline sulfonate fluorescent dye, (Berylliant™, Inc., Detection Solution Part #CH-2) and measuring the fluorescence. This method is specific to beryllium. This work will explore the use of three different commercial wipes spiked with beryllium as beryllium acetate or as beryllium oxide and subsequent analysis by optical fluorescence. The effect of possible interfering metals such as Fe, Ti, and Pu in the wipe medium is also examined.
Induction of Hyperphagia and Carbohydrate Intake by μ-Opioid Receptor Stimulation in Circumscribed Regions of Frontal Cortex
Authors: Mena Jesus D. , Sadeghian Ken , Baldo Brian A.
Published: March 2011

Frontal cortical regions are activated by food-associated stimuli, and this activation appears to be dysregulated in individuals with eating disorders. Nevertheless, frontal control of basic unconditioned feeding responses remains poorly understood. Here we show that hyperphagia can be driven by μ-opioid receptor stimulation in restricted regions of ventral medial prefrontal cortex (vmPFC) and orbitofrontal cortex. In bothad libitum-fed and food-restricted male Sprague Dawley rats, bilateral infusions of the μ-opioid agonist [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) markedly increased intake of standard rat chow. When given a choice between palatable fat-enriched versus carbohydrate-enriched test diets, intra-vmPFC DAMGO infusions selectively increased carbohydrate intake, even in rats with a baseline fat preference. Rats also exhibited motor hyperactivity characterized by rapid switching between brief bouts of investigatory and ingestive behaviors. Intra-vmPFC DAMGO affected neither water intake nor nonspecific oral behavior. Similar DAMGO infusions into neighboring areas of lateral orbital or anterior motor cortex had minimal effects on feeding. Neither stimulation of vmPFC-localized δ-opioid, κ-opioid, dopaminergic, serotonergic, or noradrenergic receptors, nor antagonism of D1, 5HT1A, or α- or β-adrenoceptors, reproduced the profile of DAMGO effects. Muscimol-mediated inactivation of the vmPFC, and intra-vmPFC stimulation of κ-opioid receptors or blockade of 5-HT2A (5-hydroxytryptamine receptor 2A) receptors, suppressed motor activity and increased feeding bout duration—a profile opposite to that seen with DAMGO. Hence, μ-opioid-induced hyperphagia and carbohydrate intake can be elicited with remarkable pharmacological and behavioral specificity from discrete subterritories of the frontal cortex. These findings may have implications for understanding affect-driven feeding and loss of restraint in eating disorders.
The RE1 Binding Protein REST Regulates Oligodendrocyte Differentiation
Authors: DeWald Lisa Evans , Rodriguez Justin P. , Levine Joel M.
Published: March 2011

The RE1-silencing transcription factor (REST) represses the expression of neuronal-specific genes in non-neuronal cells by recruiting histone deacetylases (HDACs) and other histone modifying and chromatin remodeling proteins to the DNA. REST regulation of the expression of neuronal genes is required for the orderly developmental transition from a neuroepithelial stem cell to a functional neuron. Here, we examined the expression and function of REST in neonatal rat oligodendrocyte precursor cells (OPCs). OPCs develop from the same neuroepithelial stem cells as neurons, can be reprogrammed to act as neural stem-like cellsin vitro, and require HDAC-mediated gene repression to develop into mature oligodendrocytes. We show that OPCs express functional REST protein and that REST interacts with several neuronal-specific genes whose expression is repressed in OPCs. REST transcript and protein expression increased fourfold during the first 48 h of oligodendrocyte differentiation. During this differentiation, the expression of RE1 containing neuronal genes further decreased as the transcription of oligodendrocyte-specific genes was activated. Expression of a dominant-negative form of REST in OPCs prevented the cells from developing into mature MBP-positive oligodendrocytes. Rather, the cells began to develop a neuronal phenotype characterized by increased expression of neuronal proteins, transcription factors, and cell-type-specific marker antigens. REST overexpression promoted the development of O4-positive pre-oligodendrocytes from OPCs. Together, these results show that REST function is required for the differentiation of OPCs into oligodendrocytes. By regulating the expression of neuronal genes, REST may also regulate the phenotypic plasticity of OPCs.
Ghrelin Inhibits Visceral Afferent Activation of Catecholamine Neurons in the Solitary Tract Nucleus
Authors: Cui Ran Ji , Li Xiaojun , Appleyard Suzanne M.
Published: March 2011

Brainstem A2/C2 catecholamine (CA) neurons in the solitary tract nucleus (NTS) are thought to play an important role in the control of food intake and other homeostatic functions. We have previously demonstrated that these neurons, which send extensive projections to brain regions involved in the regulation of appetite, are strongly and directly activated by solitary tract (ST) visceral afferents. Ghrelin, a potent orexigenic peptide released from the stomach, is proposed to act in part through modulating NTS CA neurons but the underlying cellular mechanisms are unknown. Here, we identified CA neurons using transgenic mice that express enhanced green fluorescent protein driven by the tyrosine hydroxylase promoter (TH-EGFP). We then determined how ghrelin modulates TH-EGFP neurons using patch-clamp techniques in a horizontal brain slice preparation. Ghrelin inhibited the frequency of spontaneous glutamate inputs (spontaneous EPSCs) onto TH-EGFP neurons, including cholecystokinin-sensitive neurons, an effect blocked by the GHSR1 antagonist,d-Lys-3-GHRP-6. This resulted in a decrease in the basal firing rate of NTS TH-EGFP neurons, an effect blocked by the glutamate antagonist NBQX. Ghrelin also dose-dependently inhibited the amplitude of ST afferent evoked EPSCs (ST-EPSCs) in TH-EGFP NTS neurons, decreasing the success rate for ST-evoked action potentials. In addition, ghrelin decreased the frequency of mini-EPSCs suggesting its actions are presynaptic to reduce glutamate release. Last, inhibition by ghrelin of the ST-EPSCs was significantly increased by an 18 h fast. These results demonstrate a potential mechanism by which ghrelin inhibits NTS TH neurons through a pathway whose responsiveness is increased during fasting.
Pharmacological Activation of Kainate Receptors Drives Endocannabinoid Mobilization
Authors: Lourenço Joana , Matias Isabel , Marsicano Giovanni , Mulle Christophe
Published: March 2011

Activation of both presynaptic metabotropic cannabinoid type 1 receptors (CB1s) and ionotropic kainate receptors (KARs) can efficiently modulate GABA release at many synapses of the CNS. The inhibitory effect of kainic acid (KA) has been ascribed to metabotropic actions, and KAR-induced release of secondary neuromodulatory agents may partly mediate these actions. Here, we investigated the involvement of the endocannabinoid system in the modulation of GABAergic synaptic transmission by pharmacological activation of KARs with KA in CA1 pyramidal neurons of the mouse hippocampus. We show that the depression of GABAergic synaptic transmission induced by KA (3 μm) is strongly inhibited by the simultaneous blockade of CB1and GABABreceptors with SR141716A (5 μm) and CGP55845 (5 μm), respectively. KA induces a calcium-dependent mobilization of the endocannabinoid anandamide (AEA) by activation of GluK2-containing KARs in postsynaptic pyramidal neurons. Consistently, the effect of KA is prolonged by the inhibitor of AEA degradation URB597 (1 μm) in a CB1-dependent manner, but it is not altered by blockade of degradation or synthesis of the other main endocannabinoid 2-arachidonoylglycerol (2AG). Hence, our work reveals that the pharmacological activation of KARs leads to the stimulation of secondary metabotropic signaling systems. In addition, these data further underline the profound mechanistic differences between exogenous and endogenous activation of KARs in the hippocampus.
Complement Protein C1q-Mediated Neuroprotection Is Correlated with Regulation of Neuronal Gene and MicroRNA Expression
Authors: Benoit Marie E. , Tenner Andrea J.
Published: March 2011

Activation of the complement cascade, a powerful effector mechanism of the innate immune system, is associated with neuroinflammation but also with elimination of inappropriate synapses during development. Synthesis of C1q, a recognition component of the complement system, occurs in brain during ischemia/reperfusion and Alzheimer's disease, suggesting that C1q may be a response to injury.In vitro, C1q, in the absence of other complement proteins, improves neuronal viability and neurite outgrowth and prevents β-amyloid-induced neuronal death, suggesting that C1q may have a direct neuroprotective role. Here, investigating the molecular basis for this neuroprotectionin vitro, addition of C1q to rat primary cortical neurons significantly upregulated expression of genes associated with cholesterol metabolism, such as cholesterol-25-hydroxylase and insulin induced gene 2, and transiently decreased cholesterol levels in neurons, known to facilitate neurite outgrowth. In addition, the expression of syntaxin-3 and its functional association with synaptosomal-associated protein 25 was increased. C1q also increased the nuclear translocation of cAMP response element-binding protein and CCAAT/enhancer-binding protein-δ (C/EBP-δ), two transcription factors involved in nerve growth factor (NGF) expression and downregulated specific microRNAs, including let-7c that is predicted to target (and thus inhibit) NGF and neurotrophin-3 (NT-3) mRNA. Accordingly, C1q increased expression of NGF and NT-3, and small interfering RNA inhibition of C/EBP-δ, NGF, or NT-3 expression prevented the C1q-dependent neurite outgrowth. No such neuroprotective effect is seen in the presence of C3a or C5a. Finally, the induced neuronal gene expression required conformationally intact C1q. These results show that C1q can directly promote neuronal survival, thereby demonstrating new interactions between immune proteins and neuronal cells that may facilitate neuroprotection.
RTP801/REDD1 Regulates the Timing of Cortical Neurogenesis and Neuron Migration
Authors: Malagelada Cristina , López-Toledano Miguel Angel , Willett Ryan T. , Jin Zong Hao , Shelanski Michael L. , Greene Lloyd A.
Published: March 2011

The generation, differentiation, and migration of newborn neurons are critical features of normal brain development that are subject to both extracellular and intracellular regulation. However, the means of such control are only partially understood. Here, we show that expression of RTP801/REDD1, an inhibitor of mTOR (mammalian target of rapamycin) activation, is regulated during neuronal differentiation and that RTP801 functions to influence the timing of both neurogenesis and neuron migration. RTP801 levels are high in embryonic cortical neuroprogenitors, diminished in newborn neurons, and low in mature neurons. Knockdown of RTP801in vitroandin vivoaccelerates cell cycle exit by neuroprogenitors and their differentiation into neurons. It also disrupts migration of rat newborn neurons to the cortical plate and results in the ectopic localization of mature neurons. On the other hand, RTP801 overexpression delays neuronal differentiation. These findings suggest that endogenous RTP801 plays an essential role in temporal control of cortical development and in cortical patterning.
Memory for the Order of Events in Specific Sequences: Contributions of the Hippocampus and Medial Prefrontal Cortex
Authors: DeVito Loren M. , Eichenbaum Howard
Published: March 2011

Episodic memory involves remembering the incidental order of a series of events that comprise a specific experience. Current models of temporal organization in episodic memory have demonstrated that animals can make memory judgments about the order of serially presented events; however, in these protocols, the animals can judge items based on their relative recency. Thus, it remains unclear as to whether animals use the specific order of items in forming memories of distinct sequences. To resolve this important issue in memory representation, we presented mice repeatedly with two widely separated odor sequences and then tested their natural exploratory preference between pairs of odors selected from within or between sequences. Intact animals preferred to investigate odors that occurred earlier within each sequence, indicating they did remember the order of events within each distinct sequence. In contrast, intact animals did not discriminate between pairs of odors from different sequences. These findings indicate that preferences were not guided by relative recency, which would be expected to support graded discrimination between widely separated events. Furthermore, damage to either the hippocampus or the medial prefrontal cortex eliminated order preference within sequences. Despite the deficit in order memory, control recognition tests showed that normal mice and mice with hippocampal or medial prefrontal damage could correctly identify previously experienced odors compared with novel odors. These findings provide strong evidence that animals form representations of the order of events within specific experiences and that the hippocampus and prefrontal cortex are essential to order memory.
Brain-Generated Estradiol Drives Long-Term Optimization of Auditory Coding to Enhance the Discrimination of Communication Signals
Authors: Tremere Liisa A. , Pinaud Raphael
Published: March 2011

Auditory processing and hearing-related pathologies are heavily influenced by steroid hormones in a variety of vertebrate species, including humans. The hormone estradiol has been recently shown to directly modulate the gain of central auditory neurons, in real time, by controlling the strength of inhibitory transmission via a nongenomic mechanism. The functional relevance of this modulation, however, remains unknown. Here we show that estradiol generated in the songbird homolog of the mammalian auditory association cortex, rapidly enhances the effectiveness of the neural coding of complex, learned acoustic signals in awake zebra finches. Specifically, estradiol increases mutual information rates, coding efficiency, and the neural discrimination of songs. These effects are mediated by estradiol's modulation of both the rate and temporal coding of auditory signals. Interference with the local action or production of estradiol in the auditory forebrain of freely behaving animals disrupts behavioral responses to songs, but not to other behaviorally relevant communication signals. Our findings directly show that estradiol is a key regulator of auditory function in the adult vertebrate brain.
Do All Threats Work the Same Way? Divergent Effects of Fear and Disgust on Sensory Perception and Attention
Authors: Krusemark Elizabeth A. , Li Wen
Published: March 2011

The extant literature indicates that threat enhances cognitive processing and physiological arousal. However, being largely based on fear-relevant processes, this model overlooks other adaptive but inhibitory mechanisms in alternative threat emotions such as disgust. Combining visual event–related potential (VERP) indices (P1 and P250/s) with a simple visual search task, we contrasted behavioral and neural responses to carefully controlled images of fear, disgust, or neutral emotion (as a baseline condition). Consistent with previous findings, fear augmented VERP amplitude and electrical current density in associate visual cortices, paralleled by facilitated object search. Conversely, disgust generated an opposite pattern of effects, reflected by reduced VERP potentials and diminished visual cortical current density along with slowed search time. These results demonstrated suppressed sensory perceptual and attentional processing of disgust information, akin to the central ecological function of disgust to minimize contact with contagious objects to avoid contamination and disease. Notably, the rapid emergence of discrimination between fear and disgust as early as 96 ms after stimulus emphasizes the efficiency of emotional classification not only between threat and nonthreat, but also within the threat domain itself. Finally, a positive correlation between anxiety and behavioral and neural divergence of fear and disgust further indicates that despite their convergence on the core affect of threat, disgust and fear instigate distinct response profiles, providing novel insights into the manifold and sometimes paradoxical symptomology in anxiety disorders.
Tuning of the Human Neocortex to the Temporal Dynamics of Attended Events
Authors: Besle Julien , Schevon Catherine A. , Mehta Ashesh D. , Lakatos Peter , Goodman Robert R. , McKhann Guy M. , Emerson Ronald G. , Schroeder Charles E.
Published: March 2011

Previous studies raise the hypothesis that attentional bias in the phase of neocortical excitability fluctuations (oscillations) represents a fundamental mechanism for tuning the brain to the temporal dynamics of task-relevant event patterns. To evaluate this hypothesis, we recorded intracranial electrocortical activity in human epilepsy patients while they performed an audiovisual stream selection task. Consistent with our hypothesis, (1) attentional modulation of oscillatory entrainment operates in a distinct network of areas including auditory, visual, posterior parietal, inferior motor, inferior frontal and superior midline frontal cortex, (2) the degree of oscillatory entrainment depends on the predictability of the stimulus stream, and (3) the attentional phase shift of entrained oscillation cooccurs with classical attentional effects observed on phase-locked evoked activity in sensory-specific areas but seems to operate on entrained low-frequency oscillations that cannot be explained by sensory activity evoked at the rate of stimulation. Thus, attentional entrainment appears to tune a network of brain areas to the temporal dynamics of behaviorally relevant event streams, contributing to its perceptual and behavioral selection.
Identification ofcis-Elements and Transcription Factors Regulating Neuronal Activity-Dependent Transcription of HumanBDNFGene
Authors: Pruunsild Priit , Sepp Mari , Orav Ester , Koppel Indrek , Timmusk Tõnis
Published: March 2011

Brain-derived neurotrophic factor (BDNF) is an important mediator of activity-dependent functions of the nervous system and its expression is dysregulated in several neuropsychiatric disorders. Regulation of rodentBDNFneuronal activity-dependent transcription has been relatively well characterized. Here, we have studied regulation of humanBDNF(hBDNF) transcription by membrane depolarization of cultured mouse or rat primary cortical neurons expressing hBDNFgene or transfected with hBDNFpromoter constructs, respectively. We identified an asymmetric E-box-like element, PasRE [basic helix-loop-helix (bHLH)-PAS transcription factor response element], in hBDNFpromoter I and demonstrate that binding of this element by bHLH-PAS transcription factors ARNT2 (aryl hydrocarbon receptor nuclear translocator 2) and NPAS4 (neuronal PAS domain protein 4) is crucial for neuronal activity-dependent transcription from promoter I. We show that binding of CREB (cAMP response element-binding protein) to the cAMP/Ca2+-response element (CRE) in hBDNFpromoter IV is critical for activity-dependent transcription from this promoter and that upstream stimulatory factor (USF) transcription factors also contribute to the activation by binding to the upstream stimulatory factor binding element (UBE) in hBDNFpromoter IV. However, we report that full induction of hBDNFexon IV mRNA transcription is dependent on ARNT2 and NPAS4 binding to a PasRE in promoter IV. Finally, we demonstrate that CRE and PasRE elements in hBDNFpromoter IX are required for the induction of this promoter by neuronal activity. Together, the results of this study have identified thecis-elements and transcription factors regulating neuronal activity-dependent transcription of humanBDNFgene.
Cardiopulmonary Arrest and Resuscitation Disrupts Cholinergic Anti-Inflammatory Processes: A Role for Cholinergic α7 Nicotinic Receptors
Authors: Norman Greg J. , Morris John S. , Karelina Kate , Weil Zachary M. , Zhang Ning , Al-Abed Yousef , Brothers Holly M. , Wenk Gary L. , Pavlov Valentin A. , Tracey Kevin J. , DeVries A. Courtney
Published: March 2011

Cardiac arrest is a leading cause of death worldwide. While survival rates following sudden cardiac arrest remain relatively low, recent advancements in patient care have begun to increase the proportion of individuals who survive cardiac arrest. However, many of these individuals subsequently develop physiological and psychiatric conditions that likely result from ongoing neuroinflammation and neuronal death. The present study was conducted to better understand the pathophysiological effects of cardiac arrest on neuronal cell death and inflammation, and their modulation by the cholinergic system. Using a well validated model of cardiac arrest, here we show that global cerebral ischemia increases microglial activation, proinflammatory cytokine mRNA expression (interleukin-1β, interleukin-6, tumor necrosis factor-α), and neuronal damage. Cardiac arrest also induces alterations in numerous cellular components of central cholinergic signaling, including a reduction in choline acetyltransferase enzymatic activity and the number of choline acetyltransferase-positive neurons, as well as, reduced acetylcholinesterase and vesicular acetylcholine transporter mRNA. However, treatment with a selective agonist of the α7 nicotinic acetylcholine receptor, the primary receptor mediating the cholinergic anti-inflammatory pathway, significantly decreases the neuroinflammation and neuronal damage resulting from cardiac arrest. These data suggest that global cerebral ischemia results in significant declines in central cholinergic signaling, which may in turn diminish the capacity of the cholinergic anti-inflammatory pathway to control inflammation. Furthermore, we provide evidence that pharmacological activation of α7 nicotinic acetylcholine receptors provide significant protection against ischemia-related cell death and inflammation within a clinically relevant time frame.
Genetic Influences on Cost-Efficient Organization of Human Cortical Functional Networks
Authors: Fornito Alex , Zalesky Andrew , Bassett Danielle S. , Meunier David , Ellison-Wright Ian , Yücel Murat , Wood Stephen J. , Shaw Karen , O'Connor Jennifer , Nertney Deborah , Mowry Bryan J. , Pantelis Christos , Bullmore Edward T.
Published: March 2011

The human cerebral cortex is a complex network of functionally specialized regions interconnected by axonal fibers, but the organizational principles underlying cortical connectivity remain unknown. Here, we report evidence that one such principle for functional cortical networks involves finding a balance between maximizing communication efficiency and minimizing connection cost, referred to as optimization of network cost-efficiency. We measured spontaneous fluctuations of the blood oxygenation level-dependent signal using functional magnetic resonance imaging in healthy monozygotic (16 pairs) and dizygotic (13 pairs) twins and characterized cost-efficient properties of brain network functional connectivity between 1041 distinct cortical regions. At the global network level, 60% of the interindividual variance in cost-efficiency of cortical functional networks was attributable to additive genetic effects. Regionally, significant genetic effects were observed throughout the cortex in a largely bilateral pattern, including bilateral posterior cingulate and medial prefrontal cortices, dorsolateral prefrontal and superior parietal cortices, and lateral temporal and inferomedial occipital regions. Genetic effects were stronger for cost-efficiency than for other metrics considered, and were more clearly significant in functional networks operating in the 0.09–0.18 Hz frequency interval than at higher or lower frequencies. These findings are consistent with the hypothesis that brain networks evolved to satisfy competitive selection criteria of maximizing efficiency and minimizing cost, and that optimization of network cost-efficiency represents an important principle for the brain's functional organization.
Stochastic Resonance Effects Reveal the Neural Mechanisms of Transcranial Magnetic Stimulation
Authors: Schwarzkopf Dietrich Samuel , Silvanto Juha , Rees Geraint
Published: March 2011

Transcranial magnetic stimulation (TMS) is a popular method for studying causal relationships between neural activity and behavior. However, its mode of action remains controversial, and so far there is no framework to explain its wide range of facilitatory and inhibitory behavioral effects. While some theoretical accounts suggest that TMS suppresses neuronal processing, other competing accounts propose that the effects of TMS result from the addition of noise to neuronal processing. Here we exploited the stochastic resonance phenomenon to distinguish these theoretical accounts and determine how TMS affects neuronal processing. Specifically, we showed that online TMS can induce stochastic resonance in the human brain. At low intensity, TMS facilitated the detection of weak motion signals, but with higher TMS intensities and stronger motion signals, we found only impairment in detection. These findings suggest that TMS acts by adding noise to neuronal processing, at least in an online TMS protocol. Importantly, such stochastic resonance effects may also explain why TMS parameters that under normal circumstances impair behavior can induce behavioral facilitations when the stimulated area is in an adapted or suppressed state.
Submillisecond Firing Synchrony between Different Subtypes of Cortical Interneurons Connected Chemically But Not Electrically
Authors: Hu Hang , Ma Yunyong , Agmon Ariel
Published: March 2011

Synchronous firing is commonly observed in the brain, but its underlying mechanisms and neurobiological meaning remain debated. Most commonly, synchrony is attributed either to electrical coupling by gap junctions or to shared excitatory inputs. In the cerebral cortex and hippocampus, fast-spiking (FS) or somatostatin-containing (SOM) inhibitory interneurons are electrically coupled to same-type neighbors, and each subtype-specific network tends to fire in synchrony. Electrical coupling across subtypes is weak or absent, but SOM–FS and FS–FS pairs are often connected by inhibitory synapses. Theoretical studies suggest that purely inhibitory coupling can also promote synchrony; however, this has not been confirmed experimentally. We recorded from 74 pairs of electrically noncoupled layer 4 interneurons in mouse somatosensory cortexin vitro, and found that tonically depolarized FS–FS and SOM–FS pairs connected by unidirectional or bidirectional inhibitory synapses often fired within 1 ms of each other. Using a novel, jitter-based measure of synchrony, we found that synchrony correlated with inhibitory coupling strength. Importantly, synchrony was resistant to ionotropic glutamate receptors antagonists but was strongly reduced when GABAAreceptors were blocked, confirming that in our experimental system IPSPs were both necessary and sufficient for synchrony. Submillisecond firing lags emerged in a computer simulation of pairs of spiking neurons, in which the only assumed interaction between neurons was by inhibitory synapses. We conclude that cortical interneurons are capable of synchronizing both within and across subtypes, and that submillisecond coordination of firing can arise by mutual synaptic inhibition alone, with neither shared inputs nor electrical coupling.
Development of Single Retinofugal Axon Arbors in Normal and β2 Knock-Out Mice
Authors: Dhande Onkar S. , Hua Ethan W. , Guh Emily , Yeh Jonathan , Bhatt Shivani , Zhang Yueyi , Ruthazer Edward S. , Feller Marla B. , Crair Michael C.
Published: March 2011

The maturation of retinal ganglion cell (RGC) axon projections in the dorsal lateral geniculate nucleus (dLGN) and the superior colliculus (SC) relies on both molecular and activity-dependent mechanisms. Despite the increasing popularity of the mouse as a mammalian visual system model, little is known in this species about the normal development of individual RGC axon arbors or the role of activity in this process. We used a novelin vivosingle RGC labeling technique to quantitatively characterize the elaboration and refinement of RGC axon arbors in the dLGN and SC in wild-type (WT) and β2–nicotinic acetylcholine receptors mutant (β2−/−) mice, which have perturbed retinal waves, during the developmental period when eye-specific lamination and retinotopic refinement occurs. Our results suggest that eye-specific segregation and retinotopic refinement in WT mice are not the result of refinement of richly exuberant arbors but rather the elaboration of arbors prepositioned in the proper location combined with the elimination of inappropriately targeted sparse branches. We found that retinocollicular arbors mature ∼1 week earlier than retinogeniculate arbors, although RGC axons reach the dLGN and SC at roughly the same age. We also observed striking differences between contralateral and ipsilateral RGC axon arbors in the SC but not in the LGN. These data suggest a strong influence of target specific cues during arbor maturation. In β2−/−mice, we found that retinofugal single axon arbors are well ramified but enlarged, particularly in the SC, indicating that activity-dependent visual map development occurs through the refinement of individual RGC arbors.
Difference in Response Reliability Predicted by Spectrotemporal Tuning in the Cochlear Nuclei of Barn Owls
Authors: Steinberg Louisa J. , Peña Jose L.
Published: March 2011

The brainstem auditory pathway is obligatory for all aural information. Brainstem auditory neurons must encode the level and timing of sounds, as well as their time-dependent spectral properties, the fine structure, and envelope, which are essential for sound discrimination. This study focused on envelope coding in the two cochlear nuclei of the barn owl, nucleus angularis (NA) and nucleus magnocellularis (NM). NA and NM receive input from bifurcating auditory nerve fibers and initiate processing pathways specialized in encoding interaural time (ITD) and level (ILD) differences, respectively. We found that NA neurons, although unable to accurately encode stimulus phase, lock more strongly to the stimulus envelope than NM units. The spectrotemporal receptive fields (STRFs) of NA neurons exhibit a pre-excitatory suppressive field. Using multilinear regression analysis and computational modeling, we show that this feature of STRFs can account for enhanced across-trial response reliability, by locking spikes to the stimulus envelope. Our findings indicate a dichotomy in envelope coding between the time and intensity processing pathways as early as at the level of the cochlear nuclei. This allows the ILD processing pathway to encode envelope information with greater fidelity than the ITD processing pathway. Furthermore, we demonstrate that the properties of the STRFs of the neurons can be quantitatively related to spike timing reliability.
Loss of Neuronal Integrity during Progressive HIV-1 Infection of Humanized Mice
Authors: Dash Prasanta K. , Gorantla Santhi , Gendelman Howard E. , Knibbe Jaclyn , Casale George P. , Makarov Edward , Epstein Adrian A. , Gelbard Harris A. , Boska Michael D. , Poluektova Larisa Y.
Published: March 2011

Neuronal damage induced by ongoing human immunodeficiency virus type 1 (HIV-1) infection was investigated in humanized NOD/scid-IL-2Rγcnullmice transplanted at birth with human CD34-positive hematopoietic stem cells. Mice infected at 5 months of age and followed for up to 15 weeks maintained significant plasma viral loads and showed reduced numbers of CD4+T-cells. Prospective serial proton magnetic resonance spectroscopy tests showed selective reductions in corticalN-acetyl aspartate in infected animals. Diffusion tensor imaging revealed structural changes in cortical gray matter. Postmortem immunofluorescence brain tissue examinations for neuronal and glial markers, captured by multispectral imaging microscopy and quantified by morphometric and fluorescence emission, showed regional reduction of neuronal soma and synaptic architectures. This was evidenced by loss of microtubule-associated protein 2, synaptophysin, and neurofilament antigens. This study is the first, to our knowledge, demonstrating lost neuronal integrity after HIV-1 infection in humanized mice. As such, the model permits studies of the relationships between ongoing viral replication and virus-associated neurodegeneration.
Anatomy of Language Impairments in Primary Progressive Aphasia
Authors: Rogalski Emily , Cobia Derin , Harrison Theresa M. , Wieneke Christina , Thompson Cynthia K , Weintraub Sandra , Mesulam M.-Marsel
Published: March 2011

Primary progressive aphasia (PPA) is a clinical dementia syndrome characterized by progressive decline in language function but relative sparing of other cognitive domains. There are three recognized PPA variants: agrammatic, semantic, and logopenic. Although each PPA subtype is characterized by the nature of the principal deficit, individual patients frequently display subtle impairments in additional language domains. The present study investigated the distribution of atrophy related to performance in specific language domains (i.e., grammatical processing, semantic processing, fluency, and sentence repetition) across PPA variants to better understand the anatomical substrates of language. Results showed regionally specific relationships, primarily in the left hemisphere, between atrophy and impairments in language performance. Most notable was the neuroanatomical distinction between fluency and grammatical processing. Poor fluency was associated with regions dorsal to the traditional boundaries of Broca's area in the inferior frontal sulcus and the posterior middle frontal gyrus, whereas grammatical processing was associated with more widespread atrophy, including the inferior frontal gyrus and supramarginal gyrus. Repetition performance was correlated with atrophy in the posterior superior temporal gyrus. The correlation of atrophy with semantic processing impairment was localized to the anterior temporal poles. Atrophy patterns were more closely correlated with domain-specific performance than with subtype. These results show that PPA reflects a selective disruption of the language network as a whole, with no rigid boundaries between subtypes. Further, these atrophy patterns reveal anatomical correlates of language that could not have been surmised in patients with aphasia resulting from cerebrovascular lesions.
Glutamate Receptor δ2 Is Essential for Input Pathway-Dependent Regulation of Synaptic AMPAR Contents in Cerebellar Purkinje Cells
Authors: Yamasaki Miwako , Miyazaki Taisuke , Azechi Hirotsugu , Abe Manabu , Natsume Rie , Hagiwara Teruki , Aiba Atsu , Mishina Masayoshi , Sakimura Kenji , Watanabe Masahiko
Published: March 2011

The number of synaptic AMPA receptors (AMPARs) is the major determinant of synaptic strength and is differently regulated in input pathway-dependent and target cell type-dependent manners. In cerebellar Purkinje cells (PCs), the density of synaptic AMPARs is approximately five times lower at parallel fiber (PF) synapses than at climbing fiber (CF) synapses. However, molecular mechanisms underlying this biased synaptic distribution remain unclear. As a candidate molecule, we focused on glutamate receptor δ2 (GluRδ2 or GluD2), which is known to be efficiently trafficked to and selectively expressed at PF synapses in PCs. We applied postembedding immunogold electron microscopy to GluRδ2 knock-out (KO) and control mice, and measured labeling density for GluA1-4 at three excitatory synapses in the cerebellar molecular layer. In both control and GluRδ2-KO mice, GluA1-3 were localized at PF and CF synapses in PCs, while GluA2-4 were at PF synapses in interneurons. In control mice, labeling density for each of GluA1-3 was four to six times lower at PF-PC synapses than at CF-PC synapses. In GluRδ2-KO mice, however, their labeling density displayed a three- to fivefold increase at PF synapses, but not at CF synapses, thus effectively eliminating input pathway-dependent disparity between the two PC synapses. Furthermore, we found an unexpected twofold increase in labeling density for GluA2 and GluA3, but not GluA4, at PF-interneuron synapses, where we identified low but significant expression of GluRδ2. These results suggest that GluRδ2 is involved in a common mechanism that restricts the number of synaptic AMPARs at PF synapses in PCs and molecular layer interneurons.
A Regret-Induced Status Quo Bias
Authors: Nicolle Antoinette , Fleming Stephen M. , Bach Dominik R. , Driver Jon , Dolan Raymond J.
Published: March 2011

A suboptimal bias toward accepting the status quo option in decision-making is well established behaviorally, but the underlying neural mechanisms are less clear. Behavioral evidence suggests the emotion of regret is higher when errors arise from rejection rather than acceptance of a status quo option. Such asymmetry in the genesis of regret might drive the status quo bias on subsequent decisions, if indeed erroneous status quo rejections have a greater neuronal impact than erroneous status quo acceptances. To test this, we acquired human fMRI data during a difficult perceptual decision task that incorporated a trial-to-trial intrinsic status quo option, with explicit signaling of outcomes (error or correct). Behaviorally, experienced regret was higher after an erroneous status quo rejection compared with acceptance. Anterior insula and medial prefrontal cortex showed increased blood oxygenation level-dependent signal after such status quo rejection errors. In line with our hypothesis, a similar pattern of signal change predicted acceptance of the status quo on a subsequent trial. Thus, our data link a regret-induced status quo bias to error-related activity on the preceding trial.
Postinduction Requirement of NMDA Receptor Activation for Late-Phase Long-Term Potentiation of Developing Retinotectal SynapsesIn Vivo
Authors: Gong Li-qin , He Ling-jie , Dong Zhi-yuan , Lu Xiao-hui , Poo Mu-ming , Zhang Xiao-hui
Published: March 2011

Spaced patterns of repetitive synaptic activation often result in a long-lasting, protein synthesis-dependent potentiation of synaptic transmission, known as late-phase long-term potentiation (L-LTP) that may serve as a substrate for long-term memory. Behavioral studies showed that posttraining blockade of NMDA subtype of the glutamate receptor (NMDAR) impaired long-term memory, although NMDAR activation is generally known to be required during LTP induction. In this study, we found that the establishment of L-LTPin vivorequires NMDAR activation within a critical time window after LTP induction. In the developing visual system ofXenopus laevistadpole, L-LTP of retinotectal synapses could be induced by three episodes of theta burst stimulation (TBS) of the optic nerve with 5 min spacing (“spaced TBS”), but not by three TBS episodes applieden masseor spaced with intervals ≥10 min. Within a time window of ∼30 min after the spaced TBS, local perfusion of the tectum with NMDAR antagonistd-AP5 or Ca2+-chelator EGTA-AM impaired the establishment of L-LTP, indicating the requirement of postinduction activation of NMDAR/Ca2+signaling. Moreover, inhibiting spontaneous spiking activity in the tectum by local application of tetrodotoxin (TTX) prevented L-LTP when TTX was applied for 15 min immediately after the spaced TBS but not 1 h later, whereas the same postinduction TTX application in the retina had no effect. These findings offer new insights into the synaptic basis for the requirement of postlearning activation of NMDARs and point to the importance of postlearning spontaneous circuit activity in memory formation.
Differential Regulation of Dendritic and Axonal Development by the Novel Krüppel-Like Factor Dar1
Authors: Ye Bing , Kim Jung Hwan , Yang Limin , McLachlan Ian , Younger Susan , Jan Lily Yeh , Jan Yuh Nung
Published: March 2011

Dendrites and axons are two major neuronal compartments with differences that are critical for neuronal functions. To learn about the differential regulation of dendritic and axonal development, we conducted a genetic screen inDrosophilaand isolated the dendritic arbor reduction 1 (dar1) mutants, which display defects in dendritic but not axonal growth. Thedar1gene encodes a novel transcription regulator in the Krüppel-like factor family. Neurons lackingdar1function have severely reduced growth of microtubule- but not F-actin-based dendritic branches. In contrast, overexpression of Dar1 dramatically increased the growth of microtubule-based dendritic branches. Our results suggest that Dar1 promotes dendrite growth in part by suppressing the expression of the microtubule-severing protein Spastin. Our study thus uncovers a novel transcriptional program for microtubule regulation that preferentially controls dendrite growth.