Induction of transcription factor Egr-1 gene expression in astrocytoma cells by Murine coronavirus infection

AbstractMouse hepatitis virus (MHV) causes encephalitis and demyelination in the central nervous system (CNS) of susceptible rodents. Astrocytes are one of the major targets for MHV infection in the CNS, and respond to MHV infection by expressing diverse molecules that may contribute to CNS pathogenesis. Here we characterized the activation of an immediate-early transcription factor Egr-1 by MHV infection in an astrocytoma cell line. We found that the expression of Egr-1 was dramatically increased following virus infection. Using various inhibitors of mitogen-activated protein kinases, we identified that the extracellular signal-regulated kinases 1/2 were involved in the activation of Egr-1 transcription by MHV infection. Experiments with ultraviolet light-inactivated virus revealed that the induction of Egr-1 did not require virus replication and was likely mediated during cell entry. We further found that over-expression of Egr-1 suppressed the expression of BNip3, a pro-apoptotic member of the Bcl-2 family. This finding may provide an explanation for our previously observed down-regulation of BNip3 by MHV infection in astrocytoma cells (Cai, Liu, Yu, and Zhang, Virology 316:104–115, 2003). Furthermore, knockdown of Egr-1 by an siRNA inhibited MHV propagation, suggesting the biological relevance of Egr-1 induction to virus replication. In addition, the persistence/demylinating-positive strains (JHM and A59) induced Egr-1 expression, whereas the persistence/demylinating-negative strain (MHV-2) did not. These results indicate a correlation between the ability of MHVs to induce Egr-1 expression and their ability to cause demyelination in the CNS, which may suggest a potential role for the induction of Egr-1 in viral pathogenesis

Association between alcohol consumption during pregnancy and risks of congenital heart defects in offspring: Meta-analysis of epidemiological observational studies

BACKGROUND: To explore the association between maternal alcohol consumption and/or binge drinking and congenital heart defects (CHDs), we conducted a meta-analysis for more sufficient evidence on this issue. METHODS: We searched Medline, EMBASE, and the Cochrane Library from their inceptions to December 2014 for case-control and cohort studies that assessed the association between maternal alcohol consumption and CHD risk. Study-specific relative risk estimates were calculated using random-effect or fixed-effect models. RESULTS: A total of 19 case-control studies and 4 cohort studies were included in the meta-analysis. We observed a null association between maternal alcohol consumption during pregnancy and the risk of CHDs. Even in the analysis of different trimesters of pregnancy, we found little association between the two. CONCLUSIONS: This meta-analysis suggests that maternal alcohol consumption is modestly not associated with the risk of CHDs. However, further investigation is needed to confirm this conclusion

Genomic data for 78 chickens from 14 populations

Background: Since the domestication of the red jungle fowls (Gallus gallus; dating back to~10 000 B.P.) in Asia, domestic chickens (Gallus gallus domesticus) have been subjected to the combined effects of natural selection and human-driven artificial selection; this has resulted in marked phenotypic diversity in a number of traits, including behavior, body composition, egg production, and skin color. Population genomic variations through diversifying selection have not been fully investigated. Findings: The whole genomes of 78 domestic chickens were sequenced to an average of 18-fold coverage for each bird. By combining this data with publicly available genomes of five wild red jungle fowls and eight Xishuangbanna game fowls, we conducted a comprehensive comparative genomics analysis of 91 chickens from 17 populations. After aligning ~21.30 gigabases (Gb) of high-quality data from each individual to the reference chicken genome, we identified ~6.44 million (M) single nucleotide polymorphisms (SNPs) for each population. These SNPs included 1.10 M novel SNPs in 17 populations that were absent in the current chicken dbSNP (Build 145) entries. Conclusions: The current data is important for population genetics and further studies in chickens and will serve as a valuable resource for investigating diversifying selection and candidate genes for selective breeding in chickens.Peer reviewedAnimal Scienc

Neural basis of perceptual learning : structural plasticity and noradrenergic control

Le champ des neurosciences connaît depuis quelques décades un développement très important dans la compréhension des corrélats neuronaux de la perception. Le cerveau adulte répond aux variations de l'environnement et à l'expérience par des modifications fonctionnelles et structurales, regroupées sous le terme générique de plasticité, plasticité qui sous-tend l'apprentissage. Cette plasticité affecte la perception sensorielle, olfactive puisque c'est cette modalité qui va nous intéresser, mais également la perception de stimuli dans d'autres modalités sensorielles. Contrairement à des convictions longtemps érigées en dogme mais maintenant dépassées sur la nature fixe du cerveau, il est établi désormais que le cerveau adulte est capable de générer tout au long de la vie de nouveaux neurones qui s'intègrent dans la circuiterie cérébrale complexe, en particulier dans le bulbe olfactif et pourraient jouer un rôle dans l'apprentissage. Des travaux antérieurs de l'équipe ont démontré que l'acquisition de l'apprentissage perceptif dépend de la présence des neurones formés chez l'adulte. Par ailleurs, les systèmes neuromodulateurs comme les systèmes noradrénergique et cholinergique innervent massivement le bulbe olfactif et en particulier les neurInhibiting noradrenergic fibers duroing post learning discrimination testing lblmocked ones cibles de la neurogenèse adulte, les interneurones granulaires. Ils sont depuis longtemps connus pour leur implication dans les processus d'apprentissage en général et olfactif en particulier. Un objectif de la thèse était de déterminer le pattern temporal et spatial de l'innervation des neurones formés chez l'adulte dans le bulbe olfactif et sa modification potentielle par l'apprentissage, par des approches comportementales combinées à des approches neuro-anatomiques. Un autre objectif était d'évaluer le rôle fonctionnel des contacts noradrénergiques mis en place par l'apprentissage en utilisant l'outil optogénétique. Les résultats indiquent que l'innervation des neurones formés chez l'adulte s'installent dès le huitième jour après la naissance des neurones pour le système cholinergique, comme pour le système noradrénergique. L'apprentissage induit une augmentation massive des contacts noradrénergiques sur les neurones formés chez l'adulte qui n'est pas retrouvée pour les fibres cholinergiques, pointant le système noradrénergique comme un acteur majeur de la plasticité induite par l'apprentissage perceptifThe field of neuroscience has experienced explosive growth over the past decade toward understanding the neural correlates of perception. More specifically, the adult brain responds to environmental experience by significant functional and structural modifications, called "neural plasticity" which underlies learning. A main issue in neuroscience is to understand the cellular basis of perceptive plasticity and subsequent behavioral adaptations. Contrary to previously held beliefs about its static nature, the adult brain is in fact capable of generating new neurons that can integrate into its complex circuitry. The birth of new neurons constitutively occurs in two specific regions of the adult mammalian brain (OB and hippocampal dentate gyrus). Adult neurogenesis is a sophisticated biological process whose function has remained a mystery to neuroscience researchers but a role in learning and memory has been proposed. Previous work in our group have shown that perceptive olfactory learning depends on adult neurogenesis. In addition, neuromodulatory systems, including noradrenergic and cholinergic systems massively innervate the olfactory bulb and more specifically the inhibitory interneurons targeted by adult neurogenesis and are long-known for their role in learning and memory. One objective of the present work was to determine the spatial and temporal pattern of the innervation by noradrenergic and cholinergic inputs of developing adult-born neurons and to investigate its modulation by learning. For that purpose, we used behavioral and neuro-anatomical approaches. Another objective was to assess the functional role of centrifugal contacts using an optogenetic approach. Results indicate that the noradrenergic innervation is selectively increased on adult born neurons following perceptual olfactory learning, a phenomenon that was not observed for cholinergic innervation, pointing the noradrenergic system as a key mechanisms involved in perceptual learning. Interestingly, noradrenergic contacts on neurons born during ontogenesis were not affected by learning, suggesting a very specific part played by adult-born neuron in learning associated plasticity. In the same brains, we have analyzed the structural plasticity induced by learning in adult-born and pre-existing neurons. The major finding is that mirroring the increased number of noradrenergic contacts, learning induced an increase in dendritic spines on adult-born, but not on pre-existing neuron

Bases neurales de l’apprentissage olfactif perceptif : plasticité structurale et contrôle noradrénergique

The field of neuroscience has experienced explosive growth over the past decade toward understanding the neural correlates of perception. More specifically, the adult brain responds to environmental experience by significant functional and structural modifications, called "neural plasticity" which underlies learning. A main issue in neuroscience is to understand the cellular basis of perceptive plasticity and subsequent behavioral adaptations. Contrary to previously held beliefs about its static nature, the adult brain is in fact capable of generating new neurons that can integrate into its complex circuitry. The birth of new neurons constitutively occurs in two specific regions of the adult mammalian brain (OB and hippocampal dentate gyrus). Adult neurogenesis is a sophisticated biological process whose function has remained a mystery to neuroscience researchers but a role in learning and memory has been proposed. Previous work in our group have shown that perceptive olfactory learning depends on adult neurogenesis. In addition, neuromodulatory systems, including noradrenergic and cholinergic systems massively innervate the olfactory bulb and more specifically the inhibitory interneurons targeted by adult neurogenesis and are long-known for their role in learning and memory. One objective of the present work was to determine the spatial and temporal pattern of the innervation by noradrenergic and cholinergic inputs of developing adult-born neurons and to investigate its modulation by learning. For that purpose, we used behavioral and neuro-anatomical approaches. Another objective was to assess the functional role of centrifugal contacts using an optogenetic approach. Results indicate that the noradrenergic innervation is selectively increased on adult born neurons following perceptual olfactory learning, a phenomenon that was not observed for cholinergic innervation, pointing the noradrenergic system as a key mechanisms involved in perceptual learning. Interestingly, noradrenergic contacts on neurons born during ontogenesis were not affected by learning, suggesting a very specific part played by adult-born neuron in learning associated plasticity. In the same brains, we have analyzed the structural plasticity induced by learning in adult-born and pre-existing neurons. The major finding is that mirroring the increased number of noradrenergic contacts, learning induced an increase in dendritic spines on adult-born, but not on pre-existing neuronsLe champ des neurosciences connaît depuis quelques décades un développement très important dans la compréhension des corrélats neuronaux de la perception. Le cerveau adulte répond aux variations de l'environnement et à l'expérience par des modifications fonctionnelles et structurales, regroupées sous le terme générique de plasticité, plasticité qui sous-tend l'apprentissage. Cette plasticité affecte la perception sensorielle, olfactive puisque c'est cette modalité qui va nous intéresser, mais également la perception de stimuli dans d'autres modalités sensorielles. Contrairement à des convictions longtemps érigées en dogme mais maintenant dépassées sur la nature fixe du cerveau, il est établi désormais que le cerveau adulte est capable de générer tout au long de la vie de nouveaux neurones qui s'intègrent dans la circuiterie cérébrale complexe, en particulier dans le bulbe olfactif et pourraient jouer un rôle dans l'apprentissage. Des travaux antérieurs de l'équipe ont démontré que l'acquisition de l'apprentissage perceptif dépend de la présence des neurones formés chez l'adulte. Par ailleurs, les systèmes neuromodulateurs comme les systèmes noradrénergique et cholinergique innervent massivement le bulbe olfactif et en particulier les neurInhibiting noradrenergic fibers duroing post learning discrimination testing lblmocked ones cibles de la neurogenèse adulte, les interneurones granulaires. Ils sont depuis longtemps connus pour leur implication dans les processus d'apprentissage en général et olfactif en particulier. Un objectif de la thèse était de déterminer le pattern temporal et spatial de l'innervation des neurones formés chez l'adulte dans le bulbe olfactif et sa modification potentielle par l'apprentissage, par des approches comportementales combinées à des approches neuro-anatomiques. Un autre objectif était d'évaluer le rôle fonctionnel des contacts noradrénergiques mis en place par l'apprentissage en utilisant l'outil optogénétique. Les résultats indiquent que l'innervation des neurones formés chez l'adulte s'installent dès le huitième jour après la naissance des neurones pour le système cholinergique, comme pour le système noradrénergique. L'apprentissage induit une augmentation massive des contacts noradrénergiques sur les neurones formés chez l'adulte qui n'est pas retrouvée pour les fibres cholinergiques, pointant le système noradrénergique comme un acteur majeur de la plasticité induite par l'apprentissage percepti

Expression of Cellular Oncogene Bcl-xL Prevents Coronavirus-Induced Cell Death and Converts Acute Infection to Persistent Infection in Progenitor Rat Oligodendrocytes

Murine coronavirus mouse hepatitis virus (MHV) causes persistent infection of the central nervous system (CNS) in rodents, which has been associated with demyelination. However, the precise mechanism of MHV persistence in the CNS remains elusive. Here we show that the progenitor oligodendrocytes (central glial 4 [CG-4] cells) derived from newborn rat brain were permissive to MHV infection, which resulted in cell death, although viral replication was restricted. Interestingly, treatment with fetal bovine serum or exogenous expression of cellular oncogene Bcl-xL prevented CG-4 cells from MHV-induced cell death. Significantly, overexpression of Bcl-xL alone was sufficient to convert acute to persistent, nonproductive infection in CG-4 cells. This finding indicates that intracellular factors rather than viral components play a critical role in establishing viral persistence in CNS cells. Although viral genomic RNAs continuously persisted in Bcl-xL-expressing CG-4 cells over 10 passages, infectious virus could no longer be isolated beyond 2 passages of the cell. Such a phenomenon resembles the persistent MHV infection in animal CNS. Thus, the establishment of a persistent, nonproductive infection in CG-4 cells may provide a useful in vitro model for studying viral persistence in animal CNS. The data also suggest that direct virus-host cell interaction is one of the underlying mechanisms that regulate viral persistence in CNS cells