PLOS ONE: [sortOrder=DATE_NEWEST_FIRST, from=editorLink, sort=Relevance, q=editor:"Doo-Sup Choi"]PLOShttps://journals.plos.org/plosone/webmaster@plos.orgaccelerating the publication of peer-reviewed sciencehttps://journals.plos.org/plosone/search/feed/atom?sortOrder=DATE_NEWEST_FIRST&unformattedQuery=editor:%22Doo-Sup%20Choi%22&from=editorLink&sort=RelevanceAll PLOS articles are Open Access.https://journals.plos.org/plosone/resource/img/favicon.icohttps://journals.plos.org/plosone/resource/img/favicon.ico2024-03-28T21:26:38ZAn exploratory study of problematic shopping and problematic video gaming in adolescentsNorman R. GreenbergZu Wei ZhaiRani A. HoffSuchitra Krishnan-SarinMarc N. Potenza10.1371/journal.pone.02722282022-08-10T14:00:00Z2022-08-10T14:00:00Z<p>by Norman R. Greenberg, Zu Wei Zhai, Rani A. Hoff, Suchitra Krishnan-Sarin, Marc N. Potenza</p>
Problematic video gaming (PVG) and problematic shopping (PS) are addictive behaviors prevalent in adolescents, characterized by positive and negative reinforcement, and associated with psychosocial impairment. This study examined how PS and PVG relate in adolescents. It also examined how PS interacts with PVG in relation to health/functioning measures. Survey data from 3,657 Connecticut high-school students were evaluated. Chi-square analyses and logistic regression models were used to assess relationships between PS and measures of PVG. Interaction analyses measured effects of PS on relationships between PVG and health/functioning measures. Relative to adolescents without PS, those with PS had 8.79-fold higher odds of exhibiting PVG and were more likely to endorse gaming to relieve anxiety and impairment due to gaming. Interaction analyses revealed that in adolescents with PS, the relationships between PVG and aggressive behaviors, including fighting, serious fighting leading to physical injury, and weapon-carrying, were stronger than in adolescents without PS. PS strongly relates to PVG, and among youth reporting PS, there are stronger associations between PVG and aggressive behaviors. Prevention efforts for adolescents should consider the co-occurrence of PS and PVG. PS and PVG may be linked by negative reinforcement and propensities for aggressive and addictive behaviors, suggesting that further research should explore possible interventions targeting stress management and maladaptive coping.Processing incomplete questionnaire data into continuous digital biomarkers for addiction monitoringAndreas ZetterströmGunnar DahlbergSara LundqvistMarkku D. HämäläinenMaria WinkvistFred NybergKarl Andersson10.1371/journal.pone.02714652022-07-14T14:00:00Z2022-07-14T14:00:00Z<p>by Andreas Zetterström, Gunnar Dahlberg, Sara Lundqvist, Markku D. Hämäläinen, Maria Winkvist, Fred Nyberg, Karl Andersson</p>
Purpose <p>eHealth systems allow efficient daily smartphone-based collection of self-reported data on mood, wellbeing, routines, and motivation; however, missing data is frequent. Within addictive disorders, missing data may reflect lack of motivation to stay sober. We hypothesize that qualitative questionnaire data contains valuable information, which after proper handling of missing data becomes more useful for practitioners.</p> Methods <p>Anonymized data from daily questionnaires containing 11 questions was collected with an eHealth system for 751 patients with alcohol use disorder (AUD). Two digital continuous biomarkers were composed from 9 wellbeing questions (WeBe-i) and from two questions representing motivation/self-confidence to remain sober (MotSC-i). To investigate possible loss of information in the process of composing the digital biomarkers, performance of neural networks to predict exacerbation events (relapse) in alcohol use disorder was compared.</p> Results <p>Long short-term memory (LSTM) neural networks predicted a coming exacerbation event 1–3 days (AUC 0.68–0.70) and 5–7 days (AUC 0.65–0.68) in advance on unseen patients. The predictive capability of digital biomarkers and raw questionnaire data was equal, indicating no loss of information. The transformation into digital biomarkers enable a continuous graphical display of each patient’s clinical course and a combined interpretation of qualitative and quantitative aspects of recovery on a time scale.</p> Conclusion <p>By transforming questionnaire data with large proportion of missing data into continuous digital biomarkers, the information captured by questionnaires can be more easily used in clinical practice. Information, assessed by the capability to predict exacerbation events of AUD, is preserved when processing raw questionnaire data into digital biomarkers.</p>Systems genetics analysis of the LXS recombinant inbred mouse strains:Genetic and molecular insights into acute ethanol toleranceRichard A. RadcliffeRobin DowellAaron T. OdellPhillip A. RichmondBeth BennettColin LarsonKaterina KechrisLaura M. SabaPratyaydipta RudraShi Wen10.1371/journal.pone.02402532020-10-23T14:00:00Z2020-10-23T14:00:00Z<p>by Richard A. Radcliffe, Robin Dowell, Aaron T. Odell, Phillip A. Richmond, Beth Bennett, Colin Larson, Katerina Kechris, Laura M. Saba, Pratyaydipta Rudra, Shi Wen</p>
We have been using the Inbred Long- and Short-Sleep mouse strains (ILS, ISS) and a recombinant inbred panel derived from them, the LXS, to investigate the genetic underpinnings of acute ethanol tolerance which is considered to be a risk factor for alcohol use disorders (AUDs). Here, we have used RNA-seq to examine the transcriptome of whole brain in 40 of the LXS strains 8 hours after a saline or ethanol “pretreatment” as in previous behavioral studies. Approximately 1/3 of the 14,184 expressed genes were significantly heritable and many were unique to the pretreatment. Several thousand <i>cis</i>- and <i>trans</i>-eQTLs were mapped; a portion of these also were unique to pretreatment. Ethanol pretreatment caused differential expression (DE) of 1,230 genes. Gene Ontology (GO) enrichment analysis suggested involvement in numerous biological processes including astrocyte differentiation, histone acetylation, mRNA splicing, and neuron projection development. Genetic correlation analysis identified hundreds of genes that were correlated to the behaviors. GO analysis indicated that these genes are involved in gene expression, chromosome organization, and protein transport, among others. The expression profiles of the DE genes and genes correlated to AFT in the ethanol pretreatment group (AFT-Et) were found to be similar to profiles of HDAC inhibitors. <i>Hdac1</i>, a <i>cis</i>-regulated gene that is located at the peak of a previously mapped QTL for AFT-Et, was correlated to 437 genes, most of which were also correlated to AFT-Et. GO analysis of these genes identified several enriched biological process terms including neuron-neuron synaptic transmission and potassium transport. In summary, the results suggest widespread genetic effects on gene expression, including effects that are pretreatment-specific. A number of candidate genes and biological functions were identified that could be mediating the behavioral responses. The most prominent of these was <i>Hdac1</i> which may be regulating genes associated with glutamatergic signaling and potassium conductance.Brain regional gene expression network analysis identifies unique interactions between chronic ethanol exposure and consumptionMaren L. SmithMarcelo F. LopezAaron R. WolenHoward C. BeckerMichael F. Miles10.1371/journal.pone.02333192020-05-29T14:00:00Z2020-05-29T14:00:00Z<p>by Maren L. Smith, Marcelo F. Lopez, Aaron R. Wolen, Howard C. Becker, Michael F. Miles</p>
Progressive increases in ethanol consumption is a hallmark of alcohol use disorder (AUD). Persistent changes in brain gene expression are hypothesized to underlie the altered neural signaling producing abusive consumption in AUD. To identify brain regional gene expression networks contributing to progressive ethanol consumption, we performed microarray and scale-free network analysis of expression responses in a C57BL/6J mouse model utilizing chronic intermittent ethanol by vapor chamber (CIE) in combination with limited access oral ethanol consumption. This model has previously been shown to produce long-lasting increased ethanol consumption, particularly when combining oral ethanol access with repeated cycles of intermittent vapor exposure. The interaction of CIE and oral consumption was studied by expression profiling and network analysis in medial prefrontal cortex, nucleus accumbens, hippocampus, bed nucleus of the stria terminalis, and central nucleus of the amygdala. Brain region expression networks were analyzed for ethanol-responsive gene expression, correlation with ethanol consumption and functional content using extensive bioinformatics studies. In all brain-regions studied the largest number of changes in gene expression were seen when comparing ethanol naïve mice to those exposed to CIE and drinking. In the prefrontal cortex, however, unique patterns of gene expression were seen compared to other brain-regions. Network analysis identified modules of co-expressed genes in all brain regions. The prefrontal cortex and nucleus accumbens showed the greatest number of modules with significant correlation to drinking behavior. Across brain-regions, however, many modules with strong correlations to drinking, both baseline intake and amount consumed after CIE, showed functional enrichment for synaptic transmission and synaptic plasticity.Cardiac vagal dysfunction moderates patterns of craving across the day in moderate to heavy consumers of alcoholRhiannon E. MayhughPaul J. LaurientiJason FanningLise GauvinKeri J. HeilmanStephen W. PorgesW. Jack Rejeski10.1371/journal.pone.02004242018-07-17T14:00:00Z2018-07-17T14:00:00Z<p>by Rhiannon E. Mayhugh, Paul J. Laurienti, Jason Fanning, Lise Gauvin, Keri J. Heilman, Stephen W. Porges, W. Jack Rejeski</p>
Background <p>Alcohol craving, a known correlate of vulnerability to Alcohol Use Disorder (AUD), has been found to be inversely related to cardiac vagal tone (CVT). Here we examine how resting CVT, CVT reactivity to a postural challenge, and their interaction influence craving during imposed alcohol abstinence and their usual drinking among moderate to heavy drinkers.</p> Methods <p>Participants were recruited from the local community (final n = 29) and assessed for CVT functioning via respiratory sinus arrhythmia (RSA) at rest (RSA-rest) and during a postural challenge (RSA-react). Craving intensity was assessed throughout the day during 3-day periods of imposed alcohol abstinence (abstained days) and drinking as usual (normal days) via Ecological Momentary Assessment (EMA). Multilevel statistical modeling assessed relationships between patterns of CVT and diurnal craving. The primary hypothesis of interest was that the interaction of RSA-rest with RSA-react would be significantly associated with increased craving across the day.</p> Results <p>Overall, craving increased throughout the day and significantly decreased after drinking (p < 0.001). There was a significant interaction between RSA-rest and RSA-react with plots revealing that this effect was driven by an aberrant craving pattern among participants with higher RSA-rest and a sluggish vagal brake in response to a postural shift—atypical RSA-react.</p> Conclusion <p>Although additional research is needed to corroborate these findings, our results suggest that moderate-heavy drinkers characterized by higher RSA-rest and atypical RSA-react exhibit aberrant patterns of craving across the day that may represent a risk factor for AUD.</p>Impaired Reality Testing in Mice Lacking Phospholipase Cβ1: Observed by Persistent Representation-Mediated Taste AversionHea-jin KimHae-Young Koh10.1371/journal.pone.01463762016-01-05T14:00:00Z2016-01-05T14:00:00Z<p>by Hea-jin Kim, Hae-Young Koh</p>
Hallucinations and delusions are the most prominent symptoms of schizophrenia and characterized by impaired reality testing. Representation-mediated taste aversion (RMTA) has been proposed as a potential behavioral assessment of reality testing and has been applied to a neurodevelopmental rat model of schizophrenia. However, the theory underlying this approach has not been generalized yet with any demonstration of impaired reality testing in other animal models of schizophrenia, such as genetically-modified mice. We devised a RMTA procedure for mice that combines a Pavlovian association protocol pairing odor conditioned stimulus (CS) with sugar reward unconditioned stimulus (US), and a conditioned taste aversion (CTA) method. In this RMTA paradigm, we compared performances of wild-type (PLCβ1<sup>+/+</sup>) mice and phospholipase C β1 knock-out (PLCβ1<sup>-/-</sup>) mice which are known as one of the genetic models for schizophrenia. With a minimal amount of initial odor-sugar associative training, both PLCβ1<sup>+/+</sup> and PLCβ1<sup>-/-</sup> mice were able to form an aversion to the sugar reward when the odor CS predicting sugar was paired with nausea. With an extended initial training, however, only PLCβ1<sup>-/-</sup> mice could form a RMTA. This persistent RMTA displayed by PLCβ1<sup>-/-</sup> mice shows their inability to distinguish real sugar from the CS-evoked representation of sugar at a stage in associative learning where wild-type mice normally could differentiate the two. These results demonstrate an impaired reality testing first observed in a genetic mouse model of schizophrenia, and suggest that RMTA paradigm may, with general applicability, allow diverse biological approaches to impaired reality testing.Striatal-Enriched Protein Tyrosine Phosphatase Controls Responses to Aversive Stimuli: Implication for Ethanol DrinkingRémi LegasteloisEmmanuel DarcqScott A. WegnerPaul J. LombrosoDorit Ron10.1371/journal.pone.01274082015-05-20T14:00:00Z2015-05-20T14:00:00Z<p>by Rémi Legastelois, Emmanuel Darcq, Scott A. Wegner, Paul J. Lombroso, Dorit Ron</p>
The STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific phosphatase whose dysregulation in expression and/or activity is associated with several neuropsychiatric disorders. We recently showed that long-term excessive consumption of ethanol induces a sustained inhibition of STEP activity in the dorsomedial striatum (DMS) of mice. We further showed that down-regulation of STEP expression in the DMS, and not in the adjacent dorsolateral striatum, increases ethanol intake, suggesting that the inactivation of STEP in the DMS contributes to the development of ethanol drinking behaviors. Here, we compared the consequence of global deletion of the <i>STEP</i> gene on voluntary ethanol intake to the consumption of an appetitive rewarding substance (saccharin) or an aversive solution (quinine or denatonium). Whereas saccharin intake was similar in STEP knockout (KO) and wild type (WT) littermate mice, the consumption of ethanol as well as quinine and denatonium was increased in STEP KO mice. These results suggested that the aversive taste of these substances was masked upon deletion of the <i>STEP</i> gene. We therefore hypothesized that STEP contributes to the physiological avoidance towards aversive stimuli. To further test this hypothesis, we measured the responses of STEP KO and WT mice to lithium-induced conditioned place aversion (CPA) and found that whereas WT mice developed lithium place aversion, STEP KO mice did not. In contrast, conditioned place preference (CPP) to ethanol was similar in both genotypes. Together, our results indicate that STEP contributes, at least in part, to the protection against the ingestion of aversive agents.Olfactory Marker Protein Expression Is an Indicator of Olfactory Receptor-Associated Events in Non-Olfactory TissuesNaNa KangHyerin KimYoonGyu JaeNaHye LeeCheol Ryong KuFrank MargolisEun Jig LeeYoung Yil BahkMin-Soo KimJaeHyung Koo10.1371/journal.pone.01160972015-01-30T14:00:00Z2015-01-30T14:00:00Z<p>by NaNa Kang, Hyerin Kim, YoonGyu Jae, NaHye Lee, Cheol Ryong Ku, Frank Margolis, Eun Jig Lee, Young Yil Bahk, Min-Soo Kim, JaeHyung Koo</p>
Olfactory receptor (OR)-associated events are mediated by well-conserved components in the olfactory epithelium, including olfactory G-protein (G<sub>olf</sub>), adenylate cyclase III (ACIII), and olfactory marker protein (OMP). The expression of ORs has recently been observed in non-olfactory tissues where they are involved in monitoring extracellular chemical cues. The large number of OR genes and their sequence similarities illustrate the need to find an effective and simple way to detect non-olfactory OR-associated events. In addition, expression profiles and physiological functions of ORs in non-olfactory tissues are largely unknown. To overcome limitations associated with using OR as a target protein, this study used OMP with G<sub>olf</sub> and ACIII as targets to screen for potential OR-mediated sensing systems in non-olfactory tissues. Here, we show using western blotting, real-time PCR, and single as well as double immunoassays that ORs and OR-associated proteins are co-expressed in diverse tissues. The results of immunohistochemical analyses showed OMP (+) cells in mouse heart and in the following cells using the corresponding marker proteins c-kit, keratin 14, calcitonin, and GFAP in mouse tissues: interstitial cells of Cajal of the bladder, medullary thymic epithelial cells of the thymus, parafollicular cells of the thyroid, and Leydig cells of the testis. The expression of ORs in OMP (+) tissues was analyzed using a refined microarray analysis and validated with RT-PCR and real-time PCR. Three ORs (olfr544, olfr558, and olfr1386) were expressed in the OMP (+) cells of the bladder and thyroid as shown using a co-immunostaining method. Together, these results suggest that OMP is involved in the OR-mediated signal transduction cascade with olfactory canonical signaling components between the nervous and endocrine systems. The results further demonstrate that OMP immunohistochemical analysis is a useful tool for identifying expression of ORs, suggesting OMP expression is an indicator of potential OR-mediated chemoreception in non-olfactory systems.The Smartphone Addiction Scale: Development and Validation of a Short Version for AdolescentsMin KwonDai-Jin KimHyun ChoSoo Yang10.1371/journal.pone.00835582013-12-31T14:00:00Z2013-12-31T14:00:00Z<p>by Min Kwon, Dai-Jin Kim, Hyun Cho, Soo Yang</p>
Objective <p>This study was designed to investigate the revised and short version of the smartphone addiction scale and the proof of its validity in adolescents. In addition, it suggested cutting off the values by gender in order to determine smartphone addiction and elaborate the characteristics of smartphone usage in adolescents.</p> Method <p>A set of questionnaires were provided to a total of 540 selected participants from April to May of 2013. The participants consisted of 343 boys and 197 girls, and their average age was 14.5 years old. The content validity was performed on a selection of shortened items, while an internal-consistency test was conducted for the verification of its reliability. The concurrent validity was confirmed using SAS, SAPS and KS-scale. Receiver operating characteristics analysis was conducted to suggest cut-off.</p> Results <p>The 10 final questions were selected using content validity. The internal consistency and concurrent validity of SAS were verified with a Cronbach's alpha of 0.911. The SAS-SV was significantly correlated with the SAS, SAPS and KS-scale. The SAS-SV scores of gender (p<.001) and self-evaluation of smartphone addiction (p<.001) showed significant difference. The ROC analysis results showed an area under a curve (AUC) value of 0.963(0.888–1.000), a cut-off value of 31, sensitivity value of 0.867 and specificity value of 0.893 in boys while an AUC value of 0.947(0.887–1.000), a cut-off value of 33, sensitivity value of 0.875, and a specificity value of 0.886 in girls.</p> Conclusions <p>The SAS-SV showed good reliability and validity for the assessment of smartphone addiction. The smartphone addiction scale short version, which was developed and validated in this study, could be used efficiently for the evaluation of smartphone addiction in community and research areas.</p>Fyn-Dependent Gene Networks in Acute Ethanol SensitivitySean P. FarrisMichael F. Miles10.1371/journal.pone.00824352013-11-29T14:00:00Z2013-11-29T14:00:00Z<p>by Sean P. Farris, Michael F. Miles</p>
Studies in humans and animal models document that acute behavioral responses to ethanol are predisposing factor for the risk of long-term drinking behavior. Prior microarray data from our laboratory document strain- and brain region-specific variation in gene expression profile responses to acute ethanol that may be underlying regulators of ethanol behavioral phenotypes. The non-receptor tyrosine kinase Fyn has previously been mechanistically implicated in the sedative-hypnotic response to acute ethanol. To further understand how Fyn may modulate ethanol behaviors, we used whole-genome expression profiling. We characterized basal and acute ethanol-evoked (3 g/kg) gene expression patterns in nucleus accumbens (NAC), prefrontal cortex (PFC), and ventral midbrain (VMB) of control and <i>Fyn</i> knockout mice. Bioinformatics analysis identified a set of <i>Fyn</i>-related gene networks differently regulated by acute ethanol across the three brain regions. In particular, our analysis suggested a coordinate basal decrease in myelin-associated gene expression within NAC and PFC as an underlying factor in sensitivity of <i>Fyn</i> null animals to ethanol sedation. An <i>in silico</i> analysis across the BXD recombinant inbred (RI) strains of mice identified a significant correlation between <i>Fyn</i> expression and a previously published ethanol loss-of-righting-reflex (LORR) phenotype. By combining PFC gene expression correlates to <i>Fyn</i> and LORR across multiple genomic datasets, we identified robust <i>Fyn</i>-centric gene networks related to LORR. Our results thus suggest that multiple system-wide changes exist within specific brain regions of <i>Fyn</i> knockout mice, and that distinct <i>Fyn</i>-dependent expression networks within PFC may be important determinates of the LORR due to acute ethanol. These results add to the interpretation of acute ethanol behavioral sensitivity in Fyn kinase null animals, and identify <i>Fyn</i>-centric gene networks influencing variance in ethanol LORR. Such networks may also inform future design of pharmacotherapies for the treatment and prevention of alcohol use disorders.Gene Expression in Brain and Liver Produced by Three Different Regimens of Alcohol Consumption in Mice: Comparison with Immune ActivationElizabeth Osterndorff-KahanekIgor PonomarevYuri A. BlednovR. Adron Harris10.1371/journal.pone.00598702013-03-29T14:00:00Z2013-03-29T14:00:00Z<p>by Elizabeth Osterndorff-Kahanek, Igor Ponomarev, Yuri A. Blednov, R. Adron Harris</p>
Chronically available alcohol escalates drinking in mice and a single injection of the immune activator lipopolysaccharide can mimic this effect and result in a persistent increase in alcohol consumption. We hypothesized that chronic alcohol drinking and lipopolysaccharide injections will produce some similar molecular changes that play a role in regulation of alcohol intake. We investigated the molecular mechanisms of chronic alcohol consumption or lipopolysaccharide insult by gene expression profiling in prefrontal cortex and liver of C57BL/6J mice. We identified similar patterns of transcriptional changes among four groups of animals, three consuming alcohol (vs water) in different consumption tests and one injected with lipopolysaccharide (vs. vehicle). The three tests of alcohol consumption are the continuous chronic two bottle choice (Chronic), two bottle choice available every other day (Chronic Intermittent) and limited access to one bottle of ethanol (Drinking in the Dark). Gene expression changes were more numerous and marked in liver than in prefrontal cortex for the alcohol treatments and similar in the two tissues for lipopolysaccharide. Many of the changes were unique to each treatment, but there was significant overlap in prefrontal cortex for Chronic-Chronic Intermittent and for Chronic Intermittent-lipopolysaccharide and in liver all pairs showed overlap. In silico cell-type analysis indicated that lipopolysaccharide had strongest effects on brain microglia and liver Kupffer cells. Pathway analysis detected a prefrontal cortex-based dopamine-related (PPP1R1B, DRD1, DRD2, FOSB, PDNY) network that was highly over-represented in the Chronic Intermittent group, with several genes from the network being also regulated in the Chronic and lipopolysaccharide (but not Drinking in the Dark) groups. Liver showed a CYP and GST centered metabolic network shared in part by all four treatments. We demonstrate common consequences of chronic alcohol consumption and immune activation in both liver and brain and show distinct genomic consequences of different types of alcohol consumption.Expression of Ethanol-Induced Behavioral Sensitization Is Associated with Alteration of Chromatin Remodeling in MiceBéatrice BotiaRémi LegasteloisStéphanie Alaux-CantinMickaël Naassila10.1371/journal.pone.00475272012-10-22T14:00:00Z2012-10-22T14:00:00Z<p>by Béatrice Botia, Rémi Legastelois, Stéphanie Alaux-Cantin, Mickaël Naassila</p>
Background <p>Ethanol-induced behavioral sensitization (EIBS) is proposed to play a role in early and recurring steps of addiction. EIBS does not occur uniformly in all animals even from the same inbred strain. Since recent data demonstrate that epigenetic mechanisms are likely to be involved in the development and the persistence of ethanol-related behaviors, we explored the involvement of epigenetic mechanisms in ethanol response after EIBS development.</p> Methodology <p>DBA/2J mice were i.p. injected with saline or ethanol (2 g/kg) once a day for 10 consecutive days. At day 17, ethanol-treated mice were split in resistant and sensitized groups. Brains were then removed 30 min after a saline or 2 g/kg ethanol challenge to assess <i>i)</i> gene expression using PCR array targeting 84 epigenetic-related genes and <i>ii)</i> histone deacetylases (HDAC), histone acetylases (HAT) and DNA methyltransferases (DNMT) activities as well as H4K12 acetylation.</p> Principal Findings <p>Acute ethanol administration decreased <i>dnmt1, esco2</i> and <i>rps6ka5</i> genes expression. These genes were similarly altered in sensitized but not in resistant mice after an ethanol challenge, suggesting that resistant mice were tolerant to the transcriptional outcomes of an ethanol challenge. Whereas global HAT or DNMT activity was not affected, global HDAC activity was reduced after an acute ethanol injection. HDAC inhibition occurred in all ethanol-treated mice but with a lesser extent in sensitized animals. As a consequence, H4 acetylation was specifically potentiated in the core of the Nac proportionally to the striatal HDAC activity decrease.</p> Conclusions/Significance <p>The present study highlights that the contrasted behavioral response to an ethanol challenge between resistant and sensitized mice may be mediated by epigenetic mechanisms occurring specifically in the striatum. Here we show that vulnerability to ethanol dependence and relapse could be, at least in part, due to individual variability in acute ethanol-induced epigenetic response.</p>Neurogenomic Evidence for a Shared Mechanism of the Antidepressant Effects of Exercise and Chronic Fluoxetine in MiceGuo-Jen HuangEyal Ben-DavidAgnès Tort PiellaAndrew EdwardsJonathan FlintSagiv Shifman10.1371/journal.pone.00359012012-04-25T14:00:00Z2012-04-25T14:00:00Z<p>by Guo-Jen Huang, Eyal Ben-David, Agnès Tort Piella, Andrew Edwards, Jonathan Flint, Sagiv Shifman</p>
Several different interventions improve depressed mood, including medication and environmental factors such as regular physical exercise. The molecular pathways underlying these effects are still not fully understood. In this study, we sought to identify shared mechanisms underlying antidepressant interventions. We studied three groups of mice: mice treated with a widely used antidepressant drug – fluoxetine, mice engaged in voluntary exercise, and mice living in an enriched environment. The hippocampi of treated mice were investigated at the molecular and cellular levels. Mice treated with fluoxetine and mice who exercised daily showed, not only similar antidepressant behavior, but also similar changes in gene expression and hippocampal neurons. These changes were not observed in mice with environmental enrichment. An increase in neurogenesis and dendritic spine density was observed following four weeks of fluoxetine treatment and voluntary exercise. A weighted gene co-expression network analysis revealed four different modules of co-expressed genes that were correlated with the antidepressant effect. This network analysis enabled us to identify genes involved in the molecular pathways underlying the effects of fluoxetine and exercise. The existence of both neuronal and gene expression changes common to antidepressant drug and exercise suggests a shared mechanism underlying their effect. Further studies of these findings may be used to uncover the molecular mechanisms of depression, and to identify new avenues of therapy.Mapping Functional Brain Activation Using [<sup>14</sup>C]-Iodoantipyrine in Male Serotonin Transporter Knockout MiceRaina D. PangZhuo WangLauren P. KlosinskiYumei GuoDavid H. HermanTansu CelikelHong Wei DongDaniel P. Holschneider10.1371/journal.pone.00238692011-08-23T14:00:00Z2011-08-23T14:00:00Z<p>by Raina D. Pang, Zhuo Wang, Lauren P. Klosinski, Yumei Guo, David H. Herman, Tansu Celikel, Hong Wei Dong, Daniel P. Holschneider</p>
Background <p>Serotonin transporter knockout mice have been a powerful tool in understanding the role played by the serotonin transporter in modulating physiological function and behavior. However, little work has examined brain function in this mouse model. We tested the hypothesis that male knockout mice show exaggerated limbic activation during exposure to an emotional stressor, similar to human subjects with genetically reduced transcription of the serotonin transporter.</p> Methodology/Principal Findings <p>Functional brain mapping using [<sup>14</sup>C]-iodoantipyrine was performed during recall of a fear conditioned tone. Regional cerebral blood flow was analyzed by statistical parametric mapping from autoradiographs of the three-dimensionally reconstructed brains. During recall, knockout mice compared to wild-type mice showed increased freezing, increased regional cerebral blood flow of the amygdala, insula, and barrel field somatosensory cortex, decreased regional cerebral blood flow of the ventral hippocampus, and conditioning-dependent alterations in regional cerebral blood flow in the medial prefrontal cortex (prelimbic, infralimbic, and cingulate). Anxiety tests relying on sensorimotor exploration showed a small (open field) or paradoxical effect (marble burying) of loss of the serotonin transporter on anxiety behavior, which may reflect known abnormalities in the knockout animal's sensory system. Experiments evaluating whisker function showed that knockout mice displayed impaired whisker sensation in the spontaneous gap crossing task and appetitive gap cross training.</p> Conclusions <p>This study is the first to demonstrate altered functional activation in the serotonin transporter knockout mice of critical nodes of the fear conditioning circuit. Alterations in whisker sensation and functional activation of barrel field somatosensory cortex extend earlier reports of barrel field abnormalities, which may confound behavioral measures relying on sensorimotor exploration.</p>The Temporal Structure of Vertical Arm MovementsJérémie GaveauCharalambos Papaxanthis10.1371/journal.pone.00220452011-07-12T14:00:00Z2011-07-12T14:00:00Z<p>by Jérémie Gaveau, Charalambos Papaxanthis</p>
The present study investigates how the CNS deals with the omnipresent force of gravity during arm motor planning. Previous studies have reported direction-dependent kinematic differences in the vertical plane; notably, acceleration duration was greater during a downward than an upward arm movement. Although the analysis of acceleration and deceleration phases has permitted to explore the integration of gravity force, further investigation is necessary to conclude whether feedforward or feedback control processes are at the origin of this incorporation. We considered that a more detailed analysis of the temporal features of vertical arm movements could provide additional information about gravity force integration into the motor planning. Eight subjects performed single joint vertical arm movements (45° rotation around the shoulder joint) in two opposite directions (upwards and downwards) and at three different speeds (slow, natural and fast). We calculated different parameters of hand acceleration profiles: movement duration (MD), duration to peak acceleration (D PA), duration from peak acceleration to peak velocity (D PA-PV), duration from peak velocity to peak deceleration (D PV-PD), duration from peak deceleration to the movement end (D PD-End), acceleration duration (AD), deceleration duration (DD), peak acceleration (PA), peak velocity (PV), and peak deceleration (PD). While movement durations and amplitudes were similar for upward and downward movements, the temporal structure of acceleration profiles differed between the two directions. More specifically, subjects performed upward movements faster than downward movements; these direction-dependent asymmetries appeared early in the movement (i.e., before PA) and lasted until the moment of PD. Additionally, PA and PV were greater for upward than downward movements. Movement speed also changed the temporal structure of acceleration profiles. The effect of speed and direction on the form of acceleration profiles is consistent with the premise that the CNS optimises motor commands with respect to both gravitational and inertial constraints.