bluuebunny/crossref_metadata_2025 huggingface dataset:
Dpp signaling promotes the cuboidal-to-columnar shape transition of Drosophila wing disc epithelia by regulating Rho1
Authors: Widmann Thomas J. , Dahmann Christian
Published: April 2009

Morphogenesis is largely driven by changes in the shape of individual cells. However, how cell shape is regulated in developing animals is not well understood. Here, we show that the onset of TGFβ/Dpp signaling activity correlates with the transition from cuboidal to columnar cell shape in developing Drosophila melanogaster wing disc epithelia. Dpp signaling is necessary for maintaining this elongated columnar cell shape and overactivation of the Dpp signaling pathway results in precocious cell elongation. Moreover, we provide evidence that Dpp signaling controls the subcellular distribution of the activities of the small GTPase Rho1 and the regulatory light chain of non-muscle myosin II (MRLC). Alteration of Rho1 or MRLC activity has a profound effect on apical-basal cell length. Finally, we demonstrate that a decrease in Rho1 or MRLC activity rescues the shortening of cells with compromised Dpp signaling. Our results identify a cell-autonomous role for Dpp signaling in promoting and maintaining the elongated columnar shape of wing disc cells and suggest that Dpp signaling acts by regulating Rho1 and MRLC.
Genetic control of cellular quiescence in S. pombe
Authors: Sajiki Kenichi , Hatanaka Mitsuko , Nakamura Takahiro , Takeda Kojiro , Shimanuki Mizuki , Yoshida Tomoko , Hanyu Yuichiro , Hayashi Takeshi , Nakaseko Yukinobu , Yanagida Mitsuhiro
Published: April 2009

Transition from proliferation to quiescence brings about extensive changes in cellular behavior and structure. However, the genes that are crucial for establishing and/or maintaining quiescence are largely unknown. The fission yeast Schizosaccharomyces pombe is an excellent model in which to study this problem, because it becomes quiescent under nitrogen starvation. Here, we characterize 610 temperature-sensitive mutants, and identify 33 genes that are required for entry into and maintenance of quiescence. These genes cover a broad range of cellular functions in the cytoplasm, membrane and nucleus. They encode proteins for stress-responsive and cell-cycle kinase signaling pathways, for actin-bound and osmo-controlling endosome formation, for RNA transcription, splicing and ribosome biogenesis, for chromatin silencing, for biosynthesis of lipids and ATP, for cell-wall and membrane morphogenesis, and for protein trafficking and vesicle fusion. We specifically highlight Fcp1, a CTD phosphatase of RNA polymerase II, which differentially affects the transcription of genes that are involved in quiescence and proliferation. We propose that the transcriptional role of Fcp1 is central in differentiating quiescence from proliferation.
Complete Absence of KSHV/HHV-8 in Posttransplant Lymphoproliferative Disorders
Authors: Chen Wei , Huang Qin , Zuppan Craig W. , Rowsell Edward H. , Cao Jeffrey D. , Weiss Lawrence M. , Wang Jun
Published: April 2009

Posttransplant lymphoproliferative disorders (PTLDs), a heterogeneous group of monoclonal or polyclonal lesions, occur in immunosuppressed patients after solid organ or bone marrow transplantation. Although most PTLDs are Epstein-Barr virus (EBV)+ and seem to represent EBV-induced proliferations of monoclonal (or less often polyclonal) B, T, or plasma cells, a subset of PTLDs is EBV–. Because Kaposi sarcoma–associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) has been described in association with the development of hematolymphoid and nonhematolymphoid neoplasms in HIV+ patients, we investigated whether there is an association between KSHV/HHV-8 and PTLDs. Formalin-fixed, paraffin-embedded tissue from 52 confirmed PTLD cases were analyzed immunohistochemically for expression of KSHV/HHV-8 latent nuclear antigen (LNA)-1 protein and by polymerase chain reaction–hybridization analysis for the KSHV/HHV-8 genome. The PTLD subtypes included 12 with early lesions (1 plasmacytic hyperplasia and 11 infectious mononucleosis–like), 10 polymorphic, 23 monomorphic (5 Burkitt, 14 diffuse large B-cell lymphoma, 1 plasmacytoma, 1 multiple myeloma, and 2 T-cell), 1 Hodgkin lymphoma (HL), 5 HL-like lesions, and 1 unclassified or other. None of the 51 tested specimens showed expression of KSHV/HHV-8 LNA-1. Furthermore, all 46 specimens tested demonstrated complete absence of the KSHV/HHV-8 genome. Our data clearly indicated that KSHV/HHV-8 is not associated with PTLDs.
Plasma Level of Growth Arrest–Specific 6 (GAS6) Protein and Genetic Variations in the GAS6 Gene in Patients With Acute Coronary Syndrome
Authors: Jiang Lei , Liu Cheng Yun , Yang Qun Fang , Wang Ping , Zhang Wen
Published: April 2009

Growth arrest–specific gene 6 (GAS6) encodes a vitamin K–dependent protein that regulates inflammation, angiogenesis, and atherosclerotic plaque formation. The level of GAS6 expression is associated with plaque stability and stroke. We explored the role of GAS6 in cardiovascular disease, particularly in acute coronary syndrome (ACS). We determined the plasma levels of GAS6 protein by using an enzyme-linked immunosorbent assay method and investigated the role of the single nucleotide polymorphism (c.834+7G>A) in ACS. The median (interquartile range) plasma GAS6 levels were 16.9 μg/L (13–28 μg/L) in healthy control subjects and 10.65 μg/L (5.7–27.5 μg/L) in patients with ACS. The genotype frequencies for GG, AG, and AA, respectively, in patients with ACS were 66% (37/56), 29% (16/56), and 5% (3/56) and were 35% (14/40), 45% (18/40), 20% (8/40) in the control group. The AA genotype and A allele were less frequent in patients with ACS than in control subjects (P < .001). Our study indicates that GAS6 plasma concentrations at admission reflect the presence of common cardiovascular risk factors and can predict cardiovascular events. In addition, the AA genotype and A allele of the GAS6 gene relate to ACS, which may have a protective role against ACS.
Micropapillary Lung Adenocarcinoma
Authors: De Oliveira Duarte Achcar Rosane , Nikiforova Marina N. , Yousem Samuel A.
Published: April 2009

Micropapillary lung adenocarcinoma (MPA) has been reported as an aggressive variant of adenocarcinoma, frequently manifesting at high stage with a poor prognosis. We analyzed the clinical and molecular profile of 15 primary MPAs for K-ras, EGFR, and BRAF mutations and performed fluorescence in situ hybridization for EGFR amplification. In our study, 11 (73%) of 15 MPAs harbored mutually exclusive mutations: 5 (33%) K-ras, 3 (20%) EGFR, and 3 (20%) BRAF. Mutations in all 3 genes occurred in patients with a smoking history and tumors with mucinous differentiation and secondary lepidic, acinar, and solid growth, suggesting that in a Western population, cytomorphologic correlation with genetic mutations is more unpredictable than in Japanese cohorts. We conclude that K-ras, EGFR, and BRAF mutations are disproportionately seen in adenocarcinomas of lung with a dominant micropapillary growth pattern compared with conventional adenocarcinoma in our institutional experience.
Follicular Lymphoma of the Spleen
Authors: Howard Matthew T. , Dufresne Scott , Swerdlow Steven H. , Cook James R.
Published: April 2009

Follicular lymphoma (FL) involving the spleen must be distinguished from reactive hyperplasia and from other lymphomas. A prior study reported that splenic FLs frequently lack BCL2 expression, further complicating diagnosis. We examined 16 cases of splenic FL, including 12 cases initially diagnosed at splenectomy. Two morphologic patterns were identified: one with architectural abnormalities (AA) and one with an extensive architectural preservation (AP) pattern. Newly diagnosed AP cases were associated with older age (P = .051) and grade 1 histologic features (P = .023). All cases displayed a CD10+/BCL2+ phenotype. Cytogenetics and FISH identified IGH/BCL2 or BCL6 translocations in all tested cases. Splenic FLs display phenotypic and cytogenetic findings similar to nodal FLs. However, splenic FLs frequently display an exclusively intrafollicular growth pattern resembling so-called in situ FL. Recognition of subtle FL with preserved architecture is important because patients may have overt FL at other sites or the FL may progress to overt nodal disease.
Usefulness of p16 for Differentiating Primary Pulmonary Squamous Cell Carcinoma From Cervical Squamous Cell Carcinoma Metastatic to the Lung
Authors: Wang Chih-Wei , Wu Tzu-I , Yu Chih-Teng , Wu Yi-Cheng , Teng Yun-Hui , Chin Szu-Ying , Lai Chyong-Huey , Chen Tse-Ching
Published: April 2009

To date, there is no reliable immunohistochemical marker that discriminates between primary pulmonary squamous cell carcinoma (SCC) and cervical SCC metastatic to the lung. In this study, immunohistochemical staining of p16 was performed on 33 primary pulmonary SCCs, 48 primary cervical SCCs, and 17 cases of cervical SCC with pulmonary metastasis. Expression of p16 was noted in 47 cases of cervical SCC (47/48 [98%]), and all were strongly stained. Of the 7 cases of primary pulmonary SCC (7/33 [21%]) in which p16 expression was detected, 3 were weakly positive, 1 was moderately positive, and 3 were strongly positive. Among these p16+ pulmonary SCCs, only 1 showed detectable human papillomavirus DNA. Of the 17 cases of cervical SCC with pulmonary metastasis, all of the pulmonary and cervical tumors were positive for p16. p16 is a useful marker for the discrimination between cervical and pulmonary SCCs. The performance of p16 staining at different cutoff values was also compared.
Immunohistochemical Detection of p63 and XIAP in Thymic Hyperplasia and Thymomas
Authors: Wu Maoxin , Sun Katherine , Gil Joan , Gan Li , Burstein David E.
Published: April 2009

We subjected 23 formalin-fixed, paraffin-embedded tissue blocks (11 cases of thymic hyperplasia and 12 thymomas [3 encapsulated, 8 with capsular invasion, and 1 atypical]) to incubation with monoclonal anti–X-linked inhibitor of apoptosis protein (XIAP) (BD Biosciences, San Jose, CA) and monoclonal anti-p63 (4A4, Santa Cruz, Santa Cruz, CA). Granular or heterogeneous cytoplasmic XIAP staining and nuclear p63 staining were considered positive. We compared thymic hyperplasia with thymoma and capsulated thymoma with thymoma with capsular invasion or atypia.

p63 was positive in virtually all thymic epithelial cells in hyperplasia and thymoma. XIAP was negative in all hyperplasia cases except one. Of 12 thymomas, 9 were XIAP+ with focal/weak to diffuse/strong positivity: 2 of 3 encapsulated and 7 of 8 thymomas with capsular invasion were XIAP+. One atypical thymoma was XIAP–. XIAP expression differed significantly between hyperplasia and thymoma (P = .0007) but not between capsulated and invasive thymomas (P = .3797).

p63 is consistently positive in nonneoplastic and neoplastic thymic epithelium. XIAP expression in thymoma suggests a possible role in the pathogenesis of thymoma and may be helpful in differentiating thymic hyperplasia from thymoma, especially in small biopsy specimens. However, the level of expression does not correlate with capsular invasion or atypia.
Psychometric Properties of the Thai Version of the 8-item Morisky Medication Adherence Scale in Patients with Type 2 Diabetes
Authors: Sakthong Phantipa , Chabunthom Rossamalin , Charoenvisuthiwongs Rungpetch
Published: April 2009

Background

A self-reporting questionnaire is the most convenient and cheapest way to assess medication adherence. A new 8-item self-reported Morisky Medication Adherence Scale (MMAS) has been developed and has shown better psychometric properties than the original 4-item Morisky scale.

Objective

To examine the validity, including convergent known-groups and construct validity, and reliability, including internal consistency and test–retest reliability, of the MMAS in Thai patients with type 2 diabetes.

Methods

The data were derived from a cross-sectional study. In a convenience sample, 303 type 2 diabetic outpatients were interviewed at the General Police Hospital in Bangkok, Thailand, between January and June 2007. Face-to-face interviews included MMAS, medication adherence visual analog scale (MA-VAS), and sociodemographic data. Medical records were reviewed for clinical data such as hemoglobin A1c (A1C) levels.

Results

Internal consistency reliability was moderate (Cronbach's α = 0.61), whereas the test–retest reliability of the MMAS was excellent (intraclass correlation coefficient = 0.83; p < 0.001). Concerning convergent validity, the MMAS had a high correlation with the 3-item Morisky scale (r = 0.77; p < 0.01) and a medium correlation with the MA-VAS (r = 0.57; p < 0 01). Regarding known-groups validity, a significant association between MMAS and A1C levels was found (χ2 = 6.7; p < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value of the MMAS were 51%, 64%, 71%, and 43%, respectively. Our factor analysis showed that the MMAS had 3 dimensions including forgetting to take medications, stopping medications when feeling better or worse, and the complexity of the drug regimen.

Conclusions

The 8-item MMAS can be a tool to aid in assessing medication adherence in diabetes. The poor sensitivity can be improved by increasing the number of the response choices and the cut-off score of the scale and by using specific words in some items. A modified Thai version of the 8-item MMAS may be needed.
Islands of Loneliness: Exploring Social Interaction Through the Autobiographies of Individuals With Autism
Authors: Causton-Theoharis Julie , Ashby Christine , Cosier Meghan
Published: April 2009

Assumptions of difficulties with social interaction, or lack of interest in social interaction, are central to many definitions and conventional understandings of autism. However, many individuals with autism describe a strong craving social interaction. This article uses autobiographical accounts written by individuals who identified as autistic as a source of qualitative research data and specifically explores the ways these texts address issues of social relationships. Using narrative inquiry, the authors explored how individuals with autism described their own notions of and experiences with social interaction. This article discusses the broad themes of (a) the desire to have connections and (b) navigation through the world of people. Last, implications for the education of individuals with autism are considered.
From the Olfactory Bulb to Higher Brain Centers: Genetic Visualization of Secondary Olfactory Pathways in Zebrafish
Authors: Miyasaka Nobuhiko , Morimoto Kozo , Tsubokawa Tatsuya , Higashijima Shin-ichi , Okamoto Hitoshi , Yoshihara Yoshihiro
Published: April 2009

In the vertebrate olfactory system, odor information is represented as a topographic map in the olfactory bulb (OB). However, it remains unknown how this odor map is transferred from the OB to higher olfactory centers. Using genetic labeling techniques in zebrafish, we found that the OB output neurons, mitral cells (MCs), are heterogeneous with respect to transgene expression profiles and spatial distributions. Tracing MC axons at single-cell resolution revealed that (1) individual MCs send axons to multiple target regions in the forebrain; (2) MCs innervating the same glomerulus do not necessarily display the same axon trajectory; (3) MCs innervating distinct glomerular clusters tend to project axons to different, but partly overlapping, target regions; (4) MCs innervating the medial glomerular cluster directly and asymmetrically send axons to the right habenula. We propose that the topographic odor map in the OB is not maintained intact, but reorganized in higher olfactory centers. Moreover, our finding of asymmetric bulbo-habenular projection renders the olfactory system an attractive model for the studies of brain asymmetry and lateralized behaviors.
Specific and Nonspecific Plasticity of the Primary Auditory Cortex Elicited by Thalamic Auditory Neurons
Authors: Ma Xiaofeng , Suga Nobuo
Published: April 2009

The ventral and medial divisions of the medial geniculate body (MGBv and MGBm) respectively are the lemniscal and nonlemniscal thalamic auditory nuclei. Lemniscal neurons are narrowly frequency tuned and provide highly specific frequency information to the primary auditory cortex (AI), whereas nonlemniscal neurons are broadly frequency tuned and project widely to auditory cortical areas including AI. The MGBv and MGBm are presumably different not only in auditory signal processing, but also in eliciting cortical plastic changes. We electrically stimulated MGBv or MGBm neurons and found the following: (1) electric stimulation of narrowly frequency-tuned MGBv neurons evoked the shift of the frequency-tuning curves of AI neurons toward the tuning curves of the stimulated MGBv neurons. This shift was the same as that in the central nucleus of the inferior colliculus and AI elicited by focal electric stimulation of AI or auditory fear conditioning. The widths of the tuning curves of the AI neurons stayed the same or slightly increased. (2) Electric stimulation of broad frequency-tuned MGBm neurons augmented the auditory responses of AI neurons and broadened their frequency-tuning curves which did not shift. These cortical changes evoked by MGBv or MGBm neurons slowly disappeared over 45–60 min after the onset of the electric stimulation. Our findings indicate that lemniscal and nonlemniscal nuclei are indeed different in eliciting cortical plastic changes: the MGBv evokes tone-specific plasticity in AI for adjusting auditory signal processing in the frequency domain, whereas the MGBm evokes nonspecific plasticity in AI for increasing the sensitivity of cortical neurons.
Dopamine D1versus D4Receptors Differentially Modulate the Encoding of Salient versus Nonsalient Emotional Information in the Medial Prefrontal Cortex
Authors: Lauzon Nicole M. , Bishop Stephanie F. , Laviolette Steven R.
Published: April 2009

Dopamine (DA) transmission plays a critical role in the processing of emotionally salient information and in associative learning and memory processes. Within the mammalian brain, neurons within the medial prefrontal cortex (mPFC) are involved critically in the encoding, expression, and extinction of emotionally salient learned information. Within the mPFC, dopaminergic transmission is involved importantly in controlling attentional and motivational processes, particularly within the context of emotionally salient sensory information. Considerable evidence suggests differential roles for DA D1-like versus D2-like receptors, including the D4receptor subtype, in the regulation of neuronal activity and emotional processing within the mPFC. Using an olfactory fear-conditioning assay in rats, we compared the roles of DA D1versus D4receptor activation during the encoding and recall phases of emotional learning and memory. We report that specific activation of DA D4receptors within the mPFC strongly potentiates the salience of normally nonsalient emotional associative fear memories and blocks the encoding of suprathreshold conditioned fear associations. However, D4receptor activation has no effect on the recall of previously learned emotionally salient conditioned memories. In contrast, intra-mPFC D1receptor activation failed to increase the emotional salience of subthreshold fear stimuli but completely blocked the expression of previously learned emotionally relevant information, demonstrating that DA D4versus D1subtype receptor transmission within the mPFC plays distinct functional roles in the processing of emotionally salient versus nonsalient associative information and differentially modulates the encoding versus recall phases of emotional memory within the mPFC.
Adaptable Mechanisms That Regulate the Contrast Response of Neurons in the Primate Lateral Geniculate Nucleus
Authors: Camp Aaron J. , Tailby Chris , Solomon Samuel G.
Published: April 2009

The response of the classical receptive field of visual neurons can be suppressed by stimuli that, when presented alone, cause no change in the discharge rate. This suppression reveals the presence of an extraclassical receptive field (ECRF). In recordings from the lateral geniculate nucleus (LGN) of a New World primate, the marmoset, we characterize the mechanisms that contribute to the ECRF by measuring their spatiotemporal tuning during prolonged exposure to a high-contrast grating (contrast adaptation). The ECRF was strongest in magnocellular cells, where contrast adaptation reduced suppression from the ECRF: adaptation of the ECRF transferred across spatial frequency, temporal frequency, and orientation, but not across space. This implies that the ECRF of LGN cells comprises multiple adaptable mechanisms, each broadly tuned but spatially localized, and consistent with a retinal origin. Signals from the ECRF saturated at high contrasts, and so adaptation of one part of the ECRF brought into its operating range signals from other parts of the visual field. Although the ECRF is adaptable, its major impact during contrast adaptation to a spatially extended pattern was to reduce visual response and hence reduce a neuron's susceptibility to contrast adaptation; in normal viewing, a major role of the ECRF might be to protect visual sensitivity in scenes dominated by high contrast.
Linking the Input to the Output: New Sets of Neurons Complement the Polarization Vision Network in the Locust Central Complex
Authors: Heinze Stanley , Homberg Uwe
Published: April 2009

Polarized light is a key feature of the blue sky, used by many animals as a sensory cue for compass navigation. Like other insects, locusts perceive theE-vector orientation of polarized light with a specialized region of their compound eye, the dorsal rim area. Neurons in the brain relay this information through several processing stages to the central complex. The central complex has a modular neuroarchitecture, composed of vertical columns and horizontal layers. Several types of central-complex neurons respond to dorsally presented, rotatingE-vectors with tonic modulation of their firing frequency. These neurons were found at the input stage of the central complex, as well as near the proposed output stage, where neurons are tuned to form a compass-like representation ofE-vector orientations underlying the columnar organization of the central complex. To identify neurons suited to link input and output elements, we recorded intracellularly from 45 neurons of the central complex. We report several novel types of polarization-sensitive neurons. One of these is suited to fill the gap between input and output stages of the central-complex polarization vision network. Three types of neurons were sensitive to polarized light in only 50% of experiments suggesting that they are recruited to the network depending on behavioral context. Finally, we identified two types of neurons suited to transfer information toward thoracic motor circuits. The data underscore the key role of two subunits of the central complex, the lower division of the central body and the protocerebral bridge, in sky compass orientation.
Systemic Inflammatory Response Reactivates Immune-Mediated Lesions in Rat Brain
Authors: Serres Sébastien , Anthony Daniel C. , Jiang Yanyan , Broom Kerry A. , Campbell Sandra J. , Tyler Damian J. , van Kasteren Sander I. , Davis Benjamin G. , Sibson Nicola R.
Published: April 2009

The potential association between microbial infection and reactivation of a multiple sclerosis (MS) lesion is an important issue that remains unresolved, primarily because of the absence of suitable animal models and imaging techniques. Here, we have evaluated this question in an empirical manner using immunohistochemistry and magnetic resonance imaging (MRI), before and after the induction of a systemic inflammatory response in two distinct models of MS. In a pattern-II-type focal myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis model, systemic endotoxin injection caused an increase in regional cerebral blood volume (rCBV) around the lesion site after 6 h, together with a reduction in the magnetization transfer ratio of the lesioned corpus callosum. These changes were followed by an increase in the diffusion of tissue water within the lesion 24 h after endotoxin challenge and new leukocyte recruitment as revealed both immunohistochemically and by MRI tracking of ultrasmall superparamagnetic iron oxide-labeled macrophages. Importantly, we detectedin vivoexpression of E- and P-selectin in quiescent lesions by MRI-detectable glyconanoparticles conjugated to sialyl LewisX. This finding may explain, at least in part, the ability of quiescent MS lesions to rapidly reinitiate the cell recruitment processes. In a pattern-I-type delayed-type hypersensitivity response model, a similar effect of endotoxin challenge on rCBV was observed, together with delayed breakdown of the blood–brain barrier, showing that systemic infection can alter the pathogenesis of MS-like lesions regardless of lesion etiology. These findings will have important implications for the management and monitoring of individuals with MS.
A Role for the Endocannabinoid System in the Increased Motivation for Cocaine in Extended-Access Conditions
Authors: Orio Laura , Edwards Scott , George Olivier , Parsons Loren H. , Koob George F.
Published: April 2009

Extended access to cocaine produces an increase in cocaine self-administration in rats that mimics aspects of compulsive drug intake in human addicts. Although emerging evidence implicates the endogenous cannabinoid system in aspects of opioid and ethanol addiction, a role of the endocannabinoid system in cocaine addiction remains widely inconclusive. Here, we investigate the effects of systemic and intra-accumbal administration of the CB1 antagonist SR141716A (Rimonabant) on cocaine self-administration (0.5 mg/kg/infusion) under a progressive ratio (PR) schedule in rats with extended [long access (LgA); 6 h/d] or limited [short access (ShA); 1 h/d] access to cocaine. LgA rats, but not ShA rats, showed an increase in cocaine intake as previously reported, and responding for cocaine by LgA rats was higher than in ShA rats under a PR schedule. Systemic SR141716A induced a dramatic dose-dependent decrease in the breakpoint for cocaine by LgA rats, whereas only the highest dose of the antagonist had a significant effect in the ShA group. Anandamide levels in the nucleus accumbens (NAc) shell were decreased in ShA rats but unchanged in LgA rats during cocaine self-administration. Both phosphorylated and total CB1 receptor protein expression were upregulated in LgA rats in the NAc and the amygdala compared with ShA and drug-naive rats, 24 h after last cocaine session. Finally, intra-NAc infusions of SR141716A reduced cocaine breakpoints selectively in LgA animals. These results suggest that neuroadaptations in the endogenous cannabinoid system may be part of the neuroplasticity associated with the development of cocaine addiction.
Phosphatidylinositol 4,5-Bisphosphate-Dependent Interaction of Myelin Basic Protein with the Plasma Membrane in Oligodendroglial Cells and Its Rapid Perturbation by Elevated Calcium
Authors: Nawaz Schanila , Kippert Angelika , Saab Aiman S. , Werner Hauke B. , Lang Thorsten , Nave Klaus-Armin , Simons Mikael
Published: April 2009

Myelin basic protein (MBP) is an essential structural component of CNS myelin. The electrostatic association of this positively charged protein with myelin-forming membranes is a crucial step in myelination, but the mechanism that regulates myelin membrane targeting is not known. Here, we demonstrate that phosphatidylinositol 4,5-bisphosphate (PIP2) is important for the stable association of MBP with cellular membranes. In oligodendrocytes, overexpression of synaptojanin 1-derived phosphoinositide 5-phosphatase, which selectively hydrolyzes membrane PIP2, causes the detachment of MBP from the plasma membrane. In addition, constitutively active Arf6/Q67L induces the formation of PIP2-enriched endosomal vacuoles, leading to the redistribution of MBP to intracellular vesicles. Fluorescence resonance energy transfer imaging revealed an interaction of the PIP2 sensing probe PH-PLCδ1 with wild-type MBP, but not with a mutant MBP isoform that fails to associate with the plasma membrane. Moreover, increasing intracellular Ca2+, followed by phospholipase C-mediated PIP2 hydrolysis, as well as reduction of the membrane charge by ATP depletion, resulted in the dissociation of MBP from the glial plasma membrane. When the corpus callosum of mice was analyzed in acute brain slices by electron microscopy, the reduction of membrane surface charge led to the loss of myelin compaction and rapid vesiculation. Together, these results establish that PIP2 is an essential determinant for stable membrane binding of MBP and provide a novel link between glial phosphoinositol metabolism and MBP function in development and disease.
The Differing Impact of Multisensory and Unisensory Integration on Behavior
Authors: Gingras Guy , Rowland Benjamin A. , Stein Barry E.
Published: April 2009

Pooling and synthesizing signals across different senses often enhances responses to the event from which they are derived. Here, we examine whether multisensory response enhancements are attributable to a redundant target effect (two stimuli rather than one) or if there is some special quality inherent in the combination of cues from different senses. To test these possibilities, the performance of animals in localizing and detecting spatiotemporally concordant visual and auditory stimuli was examined when these stimuli were presented individually (visual or auditory) or in cross-modal (visual–auditory) and within-modal (visual–visual, auditory–auditory) combinations. Performance enhancements proved to be far greater for combinations of cross-modal than within-modal stimuli and support the idea that the behavioral products derived from multisensory integration are not attributable to simple target redundancy. One likely explanation is that whereas cross-modal signals offer statistically independent samples of the environment, within-modal signals can exhibit substantial covariance, and consequently multisensory integration can yield more substantial error reduction than unisensory integration.
Different Pedunculopontine Tegmental Neurons Signal Predicted and Actual Task Rewards
Authors: Okada Ken-ichi , Toyama Keisuke , Inoue Yuka , Isa Tadashi , Kobayashi Yasushi
Published: April 2009

The dopamine system has been implicated in guiding behavior based on rewards. The pedunculopontine tegmental nucleus (PPTN) of the brainstem receives afferent inputs from reward-related structures, including the cerebral cortices and the basal ganglia, and in turn provides strong excitatory projections to dopamine neurons. This anatomical evidence predicts that PPTN neurons may carry reward information. To elucidate the functional role of the PPTN in reward-seeking behavior, we recorded single PPTN neurons while monkeys performed a visually guided saccade task in which the predicted reward value was informed by the shape of the fixation target. Two distinct groups of neurons, fixation target (FT) and reward delivery (RD) neurons, carried reward information. The activity of FT neurons persisted between FT onset and reward delivery, with the level of activity associated with the magnitude of the expected reward. RD neurons discharged phasically after reward delivery, with the levels of activity associated with the actual reward. These results suggest that separate populations of PPTN neurons signal predicted and actual reward values, both of which are necessary for the computation of reward prediction error as represented by dopamine neurons.
Suppression of Amyloid Deposition Leads to Long-Term Reductions in Alzheimer's Pathologies in Tg2576 Mice
Authors: Karlnoski Rachel A. , Rosenthal Arnon , Kobayashi Dione , Pons Jaume , Alamed Jennifer , Mercer Mary , Li Qingyou , Gordon Marcia N. , Gottschall Paul E. , Morgan David
Published: April 2009

In amyloid precursor protein (APP) models of amyloid deposition, the amount of amyloid deposits increase with mouse age. At a first approximation, the extent of amyloid accumulation may either reflect small excesses of production over clearance that accumulate over time or, alternatively, indicate a steady-state equilibrium at that age, reflecting the instantaneous excess of production over clearance, which increases as the organism ages. To discriminate between these options, we reversibly suppressed amyloid deposition in Tg2576 mice with the anti-Aβ antibody 2H6, starting at 8 months, just before the first histological deposits can be discerned. Six months later, we stopped the suppression and monitored the progression of amyloid accumulation in control APP mice and suppressed APP mice over the next 3 months. The accumulation hypothesis would predict that the rate of amyloid from 14 to 17 months would be similar in the suppressed and control mice, while the equilibrium hypothesis would predict that the increase would be faster in the suppressed group, possibly catching up completely with the control mice. The results strongly support the accumulation hypothesis, with no evidence of the suppressed mice catching up with the control mice as predicted by equilibrium models. If anything, there was a slower rate of increase in the suppressed APP mice than the control mice, suggesting that a slow seeding mechanism likely precedes a rapid fibrillogenesis in determining the extent of amyloid deposition.
NADPH Oxidase Is Required for the Sensory Plasticity of the Carotid Body by Chronic Intermittent Hypoxia
Authors: Peng Y.- J. , Nanduri J. , Yuan G. , Wang N. , Deneris E. , Pendyala S. , Natarajan V. , Kumar G. K. , Prabhakar N. R.
Published: April 2009

Respiratory motoneuron response to hypoxia is reflex in nature and carotid body sensory receptor constitutes the afferent limb of this reflex. Recent studies showed that repetitive exposures to hypoxia evokes long term facilitation of sensory nerve discharge (sLTF) of the carotid body in rodents exposed to chronic intermittent hypoxia (CIH). Although studies with anti-oxidants suggested the involvement of reactive oxygen species (ROS)-mediated signaling in eliciting sLTF, the source of and the mechanisms associated with ROS generation have not yet been investigated. We tested the hypothesis that ROS generated by NADPH oxidase (NOX) mediate CIH-evoked sLTF. Experiments were performed onex vivocarotid bodies from rats and mice exposed either to 10 d of CIH or normoxia. Acute repetitive hypoxia evoked a ∼12-fold increase in NOX activity in CIH but not in control carotid bodies, and this effect was associated with upregulation of NOX2 mRNA and protein, which was primarily localized to glomus cells of the carotid body. sLTF was prevented by NOX inhibitors and was absent in mice deficient in NOX2. NOX activation by CIH required 5-HT release and activation of 5-HT2receptors coupled to PKC signaling. Studies with ROS scavengers revealed that H2O2generated from O2·−contributes to sLTF. Priming with H2O2elicited sLTF of carotid bodies from normoxic control rats and mice, similar to that seen in CIH-treated animals. These observations reveal a novel role for NOX-induced ROS signaling in mediating sensory plasticity of the carotid body.
Brain Regions Related to Tool Use and Action Knowledge Reflect Nicotine Dependence
Authors: Yalachkov Yavor , Kaiser Jochen , Naumer Marcus J.
Published: April 2009

In addition to reward- and craving-related processes, habitual mechanisms play an important role in addiction. While the dorsal striatum has been proposed to code for the motivational state of habitual drug-seeking actions, the neural underpinnings of the corresponding drug-taking skills and action knowledge remain poorly understood. We used functional magnetic resonance imaging (fMRI) and a behavioral orientation affordance paradigm to investigate the neural and behavioral correlates of automatized drug-taking actions in nicotine dependence. Smokers exhibited higher fMRI activations than nonsmokers when viewing smoking-related but not when viewing control images. These group differences in fMRI activations were located not only in brain regions associated with craving and habitual learning (left ventral and dorsal striatum, dorsolateral prefrontal cortex, insula, uncus, medial frontal gyrus, right subcallosal gyrus, and bilateral parahippocampal gyrus), but also in a network of brain regions which has been strongly implicated in the encoding of action knowledge and tool use skills (bilateral premotor cortex, left superior parietal lobule, and right lateral cerebellum). A behavioral affordance reaction-time task indicated that smokers, but not nonsmokers, showed an automatized responsiveness to smoking paraphernalia similar to everyday objects. Moreover, smokers showed strong intercorrelations between fMRI activations in tool use-related brain regions, behavioral responsiveness to smoking-related cues, and severity of nicotine dependence. Apparently smoking-related action representations in smokers are stored in brain regions typically representing tool use skills and action knowledge. Most importantly, cortical and behavioral correlates of the respective drug-taking skills vary with the individual degree of nicotine dependence.
Expression of Human Amyloid Precursor Protein in Rat Cortical Neurons Inhibits Calcium Oscillations
Authors: Santos Susana Ferrao , Pierrot Nathalie , Morel Nicole , Gailly Philippe , Sindic Christian , Octave Jean-Noël
Published: April 2009

Synchronous calcium oscillations are observed in primary cultures of rat cortical neurons when mature networks are formed. This spontaneous neuronal activity needs an accurate control of calcium homeostasis. Alteration of intraneuronal calcium concentration is described in many neurodegenerative disorders, including Alzheimer disease (AD). Although processing of amyloid precursor protein (APP) that generates Aβ peptide has critical implications for AD pathogenesis, the neuronal function of APP remains unclear. Here, we report that expression of human APP (hAPP) in rat cortical neurons increases L-type calcium currents, which stimulate SK channels, calcium-dependent K+channels responsible for medium afterhyperpolarization (mAHP). In a neuronal network, increased mAHP in some neurons expressing hAPP leads to inhibition of calcium oscillations in all the cells of the network. This inhibition is independent of production and secretion of Aβ and other APP metabolites. In a neuronal network, reduction of endogenous APP expression using shRNA increases the frequency and reduces the amplitude of calcium oscillations. Altogether, these data support a key role for APP in the control of neuronal excitability.
Ventromedial Prefrontal Cortex Lesions Produce Early Functional Alterations during Remote Memory Retrieval
Authors: Gilboa Asaf , Alain Claude , He Yu , Stuss Donald T. , Moscovitch Morris
Published: April 2009

We examined the role of ventromedial prefrontal cortex (VMPFC) in memory retrieval monitoring. Event-related potentials were recorded while patients with VMPFC lesions and matched controls viewed faces of personal acquaintances, and of famous and nonfamous people, and indicated whether they had personally encountered these individuals. Patients were more likely than controls to make both false positive and false negative errors. Both groups showed a large posterior negative wave peaking at ∼170 ms after face onset (N170). In controls, the N170 was larger for both types of familiar faces, regardless of whether overt recognition occurred. Specifically, personal acquaintances that were erroneously judged as unfamiliar evoked the same electrophysiological response as those who were explicitly recognized. Patients' N170 was not modulated by familiarity suggesting VMPFC lesions disrupt early posterior memory-based preconscious cortical distinctions. Following the N170, there was a significant group difference over frontopolar scalp regions where patients were showing a smaller positive modulation at 230–260 ms for all stimulus types. In patients this modulation correlated highly with reaction times of correct responses, suggesting this early frontal modulation is related to the ability to make rapid correct decisions about memory content. Group differences over anterior sites were also noted at 350 ms after stimulus, reflecting a large sustained negativity of patients' waveforms, equal across conditions. The findings are consistent with a hypothesis of frontally mediated dual-monitoring system. An early automatic (preconscious) component is followed by a late elaborate process. We hypothesize that when both components are damaged, confabulation may occur.
Type A GABA-Receptor-Dependent Synaptic Transmission Sculpts Dendritic Arbor Structure inXenopusTadpolesIn Vivo
Authors: Shen Wanhua , Da Silva Jorge Santos , He Haiyan , Cline Hollis T.
Published: April 2009

The emergence of dendritic arbor structurein vivodepends on synaptic inputs. We tested whether inhibitory GABAergic synaptic transmission regulatesXenopusoptic tectal cell dendritic arbor developmentin vivoby expressing a peptide corresponding to an intracellular loop (ICL) of the γ2 subunit of type A GABA receptors (GABAAR), which is required to anchor GABAAreceptors to the postsynaptic scaffold. Enhanced green fluorescent protein (EGFP)-tagged ICL (EGFP-ICL) was distributed in a punctate pattern at putative inhibitory synapses, identified by vesicular GABA transporter immunoreactive puncta. ICL expression completely blocked GABAAR-mediated transmission in 36% of transfected neurons and significantly reduced GABAAR-mediated synaptic currents relative to AMPA receptor-mediated synaptic currents in the remaining transfected neurons without altering release probability or neuronal excitability. Further analysis of ICL-expressing neurons with residual GABAAR-mediated inputs showed that the capacity of benzodiazepine to enhance GABAergic synaptic responses was reduced in ICL-expressing neurons, indicating that they were likely depleted of γ2 subunit-containing GABAAR. Neurons expressing a mutant form of ICL were comparable to controls.In vivotime-lapse images showed that ICL-expressing neurons have more sparsely branched dendritic arbors, which expand over larger neuropil areas than EGFP-expressing control neurons. Analysis of branch dynamics indicated that ICL expression affected arbor growth by reducing rates of branch addition. Furthermore, we found that decreasing GABAergic synaptic transmission with ICL expression blocked visual experience dependent dendritic arbor structural plasticity. Our findings establish an essential role for inhibitory GABAergic synaptic transmission in the regulation of dendritic structural plasticity inXenopus in vivo.
Pharmacological Analysis Demonstrates Dramatic Alteration of D1Dopamine Receptor Neuronal Distribution in the Rat Analog of l-DOPA-Induced Dyskinesia
Authors: Berthet Amandine , Porras Grégory , Doudnikoff Evelyne , Stark Holger , Cador Martine , Bezard Erwan , Bloch Bertrand
Published: April 2009

We have associated behavioral, pharmacological, and quantitative immunohistochemical study in a rat analog ofl-DOPA-induced dyskinesia to understand whether alterations in dopamine receptor fate in striatal neurons may be involved in mechanisms leading to movement abnormalities. Detailed analysis at the ultrastructural level demonstrates specific alterations of dopamine D1receptor (D1R) subcellular localization in striatal medium spiny neurons inl-DOPA-treated 6-hydroxydopamine-lesioned rats with abnormal involuntary movements (AIMs). This includes exaggerated D1R expression at the plasma membrane. However, D1R retains ability of internalization, as a challenge with the potent D1R agonist SKF-82958 induces a strong decrease of labeling at membrane in animals with AIMs. Since a functional cross talk between D1R and D3R has been suggested, we hypothesized that their coactivation by dopamine derived froml-DOPA might anchor D1R at the membrane. Accordingly, cotreatment withl-DOPA and the D3R antagonist ST 198 restores normal level of membrane-bound D1R. Together, these results demonstrate that AIMs are related to abnormal D1R localization at the membrane and intraneuronal trafficking dysregulation, and suggest that strategies aiming at disrupting the D1R–D3R cross talk might reducel-DOPA-induced dyskinesia by reducing D1R availability at the membrane.
Ensheathing Glia Function as Phagocytes in the AdultDrosophilaBrain
Authors: Doherty Johnna , Logan Mary A. , Taşdemir Özge E. , Freeman Marc R.
Published: April 2009

The mammalian brain contains many subtypes of glia that vary in their morphologies, gene expression profiles, and functional roles; however, the functional diversity of glia in the adultDrosophilabrain remains poorly defined. Here we define the diversity of glial subtypes that exist in the adultDrosophilabrain, show they bear striking similarity to mammalian brain glia, and identify the major phagocytic cell type responsible for engulfing degenerating axons after acute axotomy. We find that neuropil regions contain two different populations of glia: ensheathing glia and astrocytes. Ensheathing glia enwrap major structures in the adult brain, but are not closely associated with synapses. Interestingly, we find these glia uniquely express key components of the glial phagocytic machinery (e.g., the engulfment receptor Draper, and dCed-6), respond morphologically to axon injury, and autonomously require components of the Draper signaling pathway for successful clearance of degenerating axons from the injured brain. Astrocytic glia, in contrast, do not express Draper or dCed-6, fail to respond morphologically to axon injury, and appear to play no role in clearance of degenerating axons from the brain. However, astrocytic glia are closely associated with synaptic regions in neuropil, and express excitatory amino acid transporters, which are presumably required for the clearance of excess neurotransmitters at the synaptic cleft. Together these results argue that ensheathing glia and astrocytes are preprogrammed cell types in the adultDrosophilabrain, with ensheathing glia acting as phagocytes after axotomy, and astrocytes potentially modulating synapse formation and signaling.
Substance P Mediates Excitatory Interactions between Striatal Projection Neurons
Authors: Blomeley Craig P. , Kehoe Laura A. , Bracci Enrico
Published: April 2009

The striatum is the largest nucleus of the basal ganglia, and is crucially involved in motor control. Striatal projection cells are medium-size spiny neurons (MSNs) and form functional GABAergic synapses with other MSNs through their axon collaterals. A subpopulation of MSNs also release substance P (SP), but its role in MSN–MSN communication is unknown. We studied this issue in rat brain slices, in the presence of antagonists for GABA, acetylcholine, dopamine, and opioid receptors; under these conditions, whole-cell paired recordings from MSNs (located <100 μm apart) revealed that, in 31/137 (23%) pairs, a burst of five spikes in a MSN caused significant facilitation (14.2 ± 8.9%) of evoked glutamatergic responses in the other MSN. Reciprocal facilitation of glutamatergic responses was present in 4 of these pairs. These facilitatory effects were maximal when spikes preceded glutamatergic responses by 100 ms, and were completely blocked by the NK1 receptor antagonist L-732,138. Furthermore, in 31/57 (54%) MSNs, a burst of 5 antidromic stimuli delivered to MSN axons in the globus pallidus significantly potentiated glutamatergic responses evoked 250 or 500 ms later by stimulation of the corpus callosum. These effects were larger at 250 than 500 ms intervals, were completely blocked by L-732,138, and facilitated spike generation. These data demonstrate that MSNs facilitate glutamatergic inputs to neighboring MSNs through spike-released SP acting on NK1 receptors. The current view that MSNs form inhibitory networks characterized by competitive dynamics will have to be updated to incorporate the fact that groups of MSNs interact in an excitatory manner.