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The outbreak of COVID-19 between 2020 and 2022 highlighted the significant role of news media as a tool of communication among different social actors. Due to the novelty of the virus, most citizens turned to official news outlets to obtain reliable information about the disease and pandemic regulations. Therefore, a content analysis of news coverage in different countries provides insight into their Quadruple Helix dynamics, which reflects new patterns of knowledge democracy under consideration of the media-based public sphere. This article aims to trace the patterns of prevalent topics related to COVID-19 news in Turkish and British mainstream news agencies between September 2020 and March 2022. By deploying content analysis, this research endeavours to elicit public discourses created around the pandemic. These media agencies engaged in critical commentary on the pandemic situation and the policies enacted during this period, updating citizens with the latest information. However, the differences in the political and social structures of each country influence their Quadruple Helix knowledge exchange, which has a high impact on transformation processes.

BackgroundDespite the worldwide growth in mobile health (mHealth) tools and the possible benefits for both patients and health care providers, the adoption of mHealth is low, and only a limited number of studies have examined the intention to download mHealth apps. ObjectiveIn this study, we investigated individuals’ preferences in the adoption of a health app. MethodsWe conducted a discrete choice experimental study in 3 countries (Spain: n=800, Germany: n=800, and the Netherlands: n=416) with 4 different attributes and levels (ie, price: €1.99 vs €4.99 [a currency exchange rate of €1=US $1.09 is applicable] vs for free, data protection: data protection vs no information, recommendation: patients’ association vs doctors, and manufacturer: medical association vs pharmaceutical company). Participants were randomly assigned. For the analyses, we used the conditional logistic model separately for each country. ResultsThe results showed that price and data protection were considered important factors that significantly increased the probability to download an mHealth app. In general, the source of the recommendation and the manufacturer affected the probability to download the mHealth app less. However, in Germany and the Netherlands, we found that if the app was manufactured by a pharmaceutical company, the probability to download the mHealth app decreased. ConclusionsmHealth tools are highly promising to reduce health care costs and increase the effectiveness of traditional health interventions and therapies. Improving data protection, reducing costs, and creating sound business models are the major driving forces to increase the adoption of mHealth apps in the future. It is thereby essential to create trustworthy standards for mobile apps, whereby prices, legislation concerning data protection, and health professionals can have a leading role to inform the potential consumers.

There are different crisis periods in the world that significantly affect financial and economic markets and require some transformations. In these crisis periods, countries re-transform their financial and economic structures in line with the dimensions and effects of the crisis. In this context, countries implement different financial and economic policies such as supplying resources to the market, changing interest rates, trying to increase or decrease the inflation rate, and intervention in the markets. The COVID-19 pandemic, which emerged at the end of 2019 and made itself felt significantly in the first quarter of 2020, emerged as one of the different crises faced by countries in the world, and its effects were much larger and more inclusive. With the emergence of the pandemic, all countries started to implement financial and economic policies to reduce the effects of the pandemic, while trying to balance their existing financial and economic markets. Countries have had to create very inclusive financial and economic policies, especially due to the supply and demand-side shocks created by the pandemic, the slowdown in working life due to quarantine periods, and the fact that some sectors have come to a standstill. In this study, the effects of the Covid-19 pandemic on Turkey's macroeconomic indicators will be examined and evaluated comparatively according to the Quadruple Helix Model.

BackgroundDespite the worldwide growth in using COVID-19 contact tracing apps (CTAs) and the potential benefits for citizens, governments, health care professionals, businesses, and other organizations, only a few studies have examined the factors affecting the levels of willingness to download a CTA. ObjectiveThis study aimed to investigate individuals’ preferences in the willingness to download a health app. MethodsWe conducted an experimental study in 2 countries, the Netherlands (N=62) and Turkey (N=83), using 4 different vignettes (ie, data protection, manufacturer, reward, and gaming models) with different attributes. Participants were randomly assigned to 1 of the conditions within the vignettes. ResultsThe results showed that data protection and gaming elements are factors that influence the willingness to download a COVID-19 CTA. More specifically, we see that data protection is an important factor explaining the willingness to download the app in Turkey, whereas including gaming elements significantly affects the willingness to download the app in the Netherlands. ConclusionsCOVID-19 CTAs are highly promising to reduce the spread of the virus and make it easier to open up society faster, especially because they can be used quickly and share information rapidly. COVID-19 CTA developers must ensure that their apps satisfactorily and sufficiently address ethical considerations, even in times of crisis. Furthermore, integrating gaming elements in the CTA could enhance the willingness to download the CTA.

IntroductionHigh levels of adoption and usage for the COVID Tracing Apps (CTA) among the population is a stipulated prerequisite for success of the implementation of these apps, aiming to mitigate the pandemic and track spreading of the virus more efficient and effectively. In the current study, the main objective was to investigate individuals' preferences in the intention to download a COVID-19 tracing app in a pilot-study in both the Netherlands and Turkey.MethodsWe conducted a discrete choice experimental study through an online survey in two countries (the Netherlands [N = 62] and Turkey [N = 83]), with four different attributes: (1) data protection (data protection vs. no information), (2) manufacturer (government vs. company), (3) reward (no reward vs. voucher as a reward) and (4) gaming (no gaming elements vs. gaming elements). Participants were recruited among a student population.ResultsThe results showed that data protection is one of the most important factors that significantly increases the probability to adopt a CTA. In general, the manufacturer, reward or gaming affected the probability to download the CTA less.DiscussionsHealth authorities worldwide have generally released high quality CTA, although scientific studies assessing the most important factors that describe and predict the intention to download is limited. Sensitive personal data is collected through these apps, and may potentially threaten privacy, equality and fairness, which are important attributes to take into account when developing or launching a CTA, following the results of this study.

Streptomycetes are an important source of natural products potentially applicable in the pharmaceutical industry. Many of these drugs are secondary metabolites whose biosynthetic genes are very often poorly expressed under laboratory cultivation conditions. In many cases, antibiotic-resistant mutants exhibit increased production of natural drugs, which facilitates the identification and isolation of new substances. In this study, we report the induction of a type II polyketide synthase gene cluster in the marine strain Streptomyces albus subsp. chlorinus through the selection of streptomycin-resistant mutants, resulting in overproduction of the novel compound fredericamycin C2 (1). Fredericamycin C2 (1) is structurally related to the potent antitumor drug lead fredericamycin A.

Herbicides with new modes of action and safer toxicological and environmental profiles are needed to manage the evolution of weeds that are resistant to commercial herbicides. The unparalleled structural diversity of natural products makes these compounds a promising source for new herbicides. In 2009, a novel nucleoside phytotoxin, albucidin, with broad activity against grass and broadleaf weeds was isolated from a strain of Streptomyces albus subsp. chlorinus NRRL B-24108. Here, we report the identification and heterologous expression of the previously uncharacterized albucidin gene cluster. Through a series of gene inactivation experiments, a minimal set of albucidin biosynthetic genes was determined. Based on gene annotation and sequence homology, a model for albucidin biosynthesis was suggested. The presented results enable the construction of producer strains for a sustainable supply of albucidin for biological activity studies.

Adult stem cells including multipotent mesenchymal stromal cells (MSC) acquire a high amount of DNA-damage due to their prolonged lifespan. MSC may exert specific mechanisms of resistance to avoid loss of functional activity. We have previously shown that resistance of MSC is associated with an induction of p53 and proliferation arrest upon genotoxic damage. Hypoxia may also contribute to resistance in MSC due to the low oxygen tension in the niche. In this study we characterized the role of p53 and contribution of hypoxia in resistance of MSC to genotoxic damage. MSC exhibited increased resistance to cisplatin induced DNA-damage. This resistance was associated with a temporary G2/M cell cycle arrest, induction of p53- and p21-expression and reduced cyclin B / cdk1-levels upon subapoptotic damage. Resistance of MSC to cisplatin was increased at hypoxic conditions i. e. oxygen

A continuous monitoring of the whole tumor burden of individuals in orthotopic tumor models is a desirable aim and requires non-invasive imaging methods. Here we investigated whether quantification of a xenograft tumor intrinsic fluorescence signal can be used to evaluate tumor growth and response to chemotherapy. Stably fluorescence protein (FP) expressing cell clones of colorectal carcinoma and germ cell tumor lines were generated by lentiviral transduction using the FPs eGFP, dsRed2, TurboFP635, and mPlum. Applying subcutaneous tumor models in different experimental designs, specific correlations between measured total fluorescence intensity (FI) and the tumor volume (V) could be established. The accuracy of correlation of FI and V varied depending on the cell model used. The application of deep-red FP expressing xenografts (TurboFP635, mPlum) was observed to result in improved correlations. This was also reflected by the results of a performed error analysis. In a model of visceral growing mPlum tumors, measurements of FI could be used to follow growth and response to chemotherapy. However, in some cases final necropsy revealed the existence of additional, deeper located tumors that had not been detected in vivo by their mPlum signal. Consistently, only the weights of the tumors that were detected in vivo based on their mPlum signal correlated with FI. In conclusion, as long as tumors are visualized by their fluorescence signal the FI can be used to evaluate tumor burden. Deep-red FPs are more suitable for in vivo applications as compared to eGFP and dsRed2.

Background: Chronic opioid exposure leads to hedonic deficits and enhanced vulnerability to addiction, which are observed and even strengthen after a period of abstinence, but the underlying circuit mechanisms are poorly understood. In this study, using both molecular and behavioral approaches, we tested the hypothesis that neurons expressing mu opioid receptors (MORs) in the dorsal raphe nucleus (DRN) are involved in addiction vulnerability associated with morphine abstinence., Methods: MOR-Cre mice were exposed to chronic morphine and then went through spontaneous withdrawal for 4 weeks, a well-established mouse model of morphine abstinence. We studied DRN-MOR neurons of abstinent mice using 1) viral translating ribosome affinity for transcriptome profiling, 2) fiber photometry to measure neuronal activity, and 3) an opto-intracranial self-stimulation paradigm applied to DRN-MOR neurons to assess responses related to addiction vulnerability including persistence to respond, motivation to obtain the stimulation, self-stimulation despite punishment, and cue-induced reinstatement., Results: DRN-MOR neurons of abstinent animals showed a downregulation of genes involved in ion conductance and MOR-mediated signaling, as well as altered responding to acute morphine. Opto-intracranial self-stimulation data showed that abstinent animals executed more impulsive-like and persistent responses during acquisition and scored higher on addiction-like criteria., Conclusions: Our data suggest that protracted abstinence to chronic morphine leads to reduced MOR function in DRN-MOR neurons and abnormal self-stimulation of these neurons. We propose that DRN-MOR neurons have partially lost their reward-facilitating properties, which in turn may lead to increased propensity to perform addiction-related behaviors., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Bipolar disorder (BD) is a chronic and severe psychiatric disorder associated with significant medical morbidity and reduced life expectancy. In this study, we assessed accelerated epigenetic aging in individuals with BD using various DNA methylation (DNAm)-based markers. For this purpose, we used five epigenetic clocks (Horvath, Hannum, EN, PhenoAge, and GrimAge) and a DNAm-based telomere length clock (DNAmTL). DNAm profiles were obtained using Infinium MethylationEPIC Arrays from whole-blood samples of 184 individuals with BD. We also estimated blood cell counts based on DNAm levels for adjustment. Significant correlations between chronological age and each epigenetic age estimated using the six different clocks were observed. Following adjustment for blood cell counts, we found that the six epigenetic AgeAccels (age accelerations) were significantly associated with the body mass index. GrimAge AgeAccel was significantly associated with male sex, smoking status and childhood maltreatment. DNAmTL AgeAccel was significantly associated with smoking status. Overall, this study showed that distinct epigenetic clocks are sensitive to different aspects of aging process in BD. Further investigations with comprehensive epigenetic clock analyses and large samples are required to confirm our findings of potential determinants of an accelerated epigenetic aging in BD., Competing Interests: Declaration of Competing Interest None to be declared in links with this study., (Copyright © 2023. Published by Elsevier B.V.)

Just over 20 years ago, molecular biologists Leonie Ringrose and Renato Paro published an article with a provocative title, "Remembering Silence", in BioEssays. The article focused on how epigenetic elements could return to their silent state, operationally defined as their epigenetic status before their modulation by experimental or environmental factors. Though Ringrose and Paro's article was on fruit flies and factors affecting embryological growth, the article asked a question of considerable importance to rapidly expanding research in neuroepigenetics on the correlation between trauma and neuropsychiatric risk: If you experience a traumatic event and, as a result, acquire an epigenetic trait that is considered pathological, can you free yourself of that trait? Ultimately, we are interested in how a return to silence is envisioned in neuroepigenetics research, how interventions purported to bring about that silence might function, and what this might mean for people who live in the aftermath of trauma., (© 2023 The Authors. BioEssays published by Wiley Periodicals LLC.)

While depression and chronic pain are frequently comorbid, underlying neuronal circuits and their psychopathological relevance remain poorly defined. Here we show in mice that hyperactivity of the neuronal pathway linking the basolateral amygdala to the anterior cingulate cortex is essential for chronic pain-induced depression. Moreover, activation of this pathway in naive male mice, in the absence of on-going pain, is sufficient to trigger depressive-like behaviors, as well as transcriptomic alterations that recapitulate core molecular features of depression in the human brain. These alterations notably impact gene modules related to myelination and the oligodendrocyte lineage. Among these, we show that Sema4a, which was significantly upregulated in both male mice and humans in the context of altered mood, is necessary for the emergence of emotional dysfunction. Overall, these results place the amygdalo-cingulate pathway at the core of pain and depression comorbidity, and unravel the role of Sema4a and impaired myelination in mood control., (© 2023. The Author(s).)

What sets someone on a life trajectory? This question is at the heart of studies of 21st-century neurosciences that build on scientific models developed over the last 150 years that attempt to link psychopathology risk and human development. Historically, this research has documented persistent effects of singular, negative life experiences on people's subsequent development. More recently, studies have documented neuromolecular effects of early life adversity on life trajectories, resulting in models that frame lives as disproportionately affected by early negative experiences. This view is dominant, despite little evidence of the stability of the presumably early-developed molecular traits and their potential effects on phenotypes. We argue that in the context of gaps in knowledge and the need for scientists to reason across molecular and phenotypic scales, as well as time spans that can extend beyond an individual's life, specific interpretative frameworks shape the ways in which individual scientific findings are assessed. In the process, scientific reasoning oscillates between understandings of cellular homeostasis and organisms' homeorhesis, or life trajectory. Biologist and historian François Jacob described this framework as the "attitude" that researchers bring to bear on their "objects" of study. Through an analysis of, first, historical and contemporary scientific literature and then ethnographic research with neuroscientists, we consider how early life trauma came to be associated with specific psychological and neurobiological effects grounded in understandings of life trajectories. We conclude with a consideration of the conceptual, ontological, and ethical implications of interpreting life trajectories as the result of the persistence of long-embodied biological traits, persistent life environments, or both., (© 2022. Springer Nature Switzerland AG.)

Next-generation sequencing now enables the rapid and affordable production of reliable biological data at multiple molecular levels, collectively referred to as "omics". To maximize the potential for discovery, computational biologists have created and adapted integrative multi-omic analytical methods. When applied to diseases with traceable pathophysiology such as cancer, these new algorithms and statistical approaches have enabled the discovery of clinically relevant molecular mechanisms and biomarkers. In contrast, these methods have been much less applied to the field of molecular psychiatry, although diagnostic and prognostic biomarkers are similarly needed. In the present review, we first briefly summarize main findings from two decades of studies that investigated single molecular processes in relation to mood disorders. Then, we conduct a systematic review of multi-omic strategies that have been proposed and used more recently. We also list databases and types of data available to researchers for future work. Finally, we present the newest methodologies that have been employed for multi-omics integration in other medical fields, and discuss their potential for molecular psychiatry studies., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Childhood abuse significantly increases the lifetime risk of negative mental health outcomes. The oxytocinergic system, which plays a role in complex social and emotional behaviors, has been shown to be sensitive to early-life experiences. While previous studies have investigated the relationship between early-life adversity and oxytocin, they did so with peripheral samples. We, therefore, aimed to characterize the relationship between early-life adversity and oxytocin receptor (OXTR) expression in the brain, using post-mortem human samples, as well as a rodent model of naturally occurring variation in early-life environment. Focusing on the dorsal anterior cingulate cortex, we compared OXTR expression and epigenetic regulation between MDD suicides with (N = 26) and without history of childhood abuse (N = 24), as well as psychiatrically healthy controls (N = 23). We also compared Oxtr expression in the cingulate cortex of adult rats raised by dams displaying high (N = 13) and low levels (N = 12) of licking and grooming (LG) behavior. Overall, our results indicate that childhood abuse associates with an upregulation of OXTR expression, and that similarly, this relationship is also observed in the cingulate cortex of adult rats raised by low-LG dams. Additionally, we found an effect of rs53576 genotype on expression, showing that carriers of the A variant also show upregulated OXTR expression. The effects of early-life adversity and rs53576 genotype on OXTR expression are, however, not explained by differences in DNA methylation within and around the MT region of the OXTR gene., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The mu opioid receptor (MOR) is a G protein-coupled receptor that plays an essential role in reward and hedonic processes, and that has been implicated in disorders such as depression and addiction. Over the last decade, several brain imaging studies in depressed patients have consistently found that dysregulation of MOR function occurs in particular in the anterior insular cortex, an important brain site for the perception of internal states and emotional regulation. To investigate molecular mechanisms that may underlie these effects, here we assessed genetic polymorphisms, expression, and functional G-protein coupling of MOR in a large post-mortem cohort (N = 95) composed of depressed individuals who died by suicide, and healthy controls. Results indicated that depression, but not comorbid substance use disorder or acute opiate consumption, was associated with increased MOR activity. This effect was partly explained by a specific increase in expression of the inhibitory alpha G-protein subunit GNAI2. Consistent with previous neuroimaging studies, our findings support the notion that enhanced endogenous opioidergic tone in the anterior insula may buffer negative affective states in depressed individuals, a mechanism that could potentially contribute to the antidepressant efficacy of emerging opioid-based medications.

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context. Additionally, we find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides insights into genomic brain regulation as a function of early-life experience.

Objectives: Psychological pain increases the risk of suicidal ideas and acts, and represents a potential therapeutic target. However, the mechanisms of mental pain remain unclear. Here, we assessed the peripheral transcriptomic and central neural correlates of mental pain during a depressive episode., Methods: 172 adult un-medicated depressed patients were recruited. Leucocytes were extracted for RNA quantification at baseline (T0) and after 8 weeks (T8) of an antidepressant treatment. Ninety-nine genes of the cortisol, immune, opioid, serotonergic, and kynurenine systems were a priori selected, and 41 were sufficiently expressed to be analyzed. At both T0 and T8, mean level of mental pain over the last 15 days was measured with a visual analog scale. A subset of 38 patients was additionally scanned with Magnetic Resonance Imaging at T0. Resting-state sequences of 4 networks (default-mode, basal ganglia, central executive, salience) were examined., Results: Mean psychological pain scores significantly decreased between T0 and T8. At conservative p-corrected levels, T0 mental pain was significantly correlated with 11 brain clusters encompassing the prefrontal, parietal, and temporal cortices, the striatum, and the cerebellum. There was no direct association between peripheral gene expression and mean mental pain at any time points or in terms of temporal changes. However, expressions of 5HTR2B at p-corrected levels, and 5HTR3A, TPH1, and OPRL1 were correlated with the activity of several identified brain clusters at T0. Finally, while suicidal ideas and mental pain were correlated, the neural and molecular correlates of suicidal ideas were not the same., Conclusion: Our study suggests that the serotonergic and nociceptin systems are associated with the activity of a cortico-subcortical brain network underlying the perception of mental pain during depression. Mental pain may be a necessary but insufficient condition for the emergence of suicidal ideation during depression., Competing Interests: Declaration of Competing Interest All authors have no conflict of interest to report., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aberrant gene expression can contribute to brain and nervous system dysfunction that causes many psychiatric illnesses. Here, we review how transcriptomic approaches have deepened our understanding of the neurobiological underpinnings of psychiatric disorders and how they have to the identification of biomarkers for these disorders, with a focus on their relevance to suicide and suicide behaviors. We begin by providing an overview of the genetic, transcriptomic, and epigenetic factors (including non-coding RNAs) implicated in suicide and their roles in the regulation of gene expression. Then, we highlight the unique benefits and limitations of using either postmortem brain or peripheral tissues in transcriptomic analyses. We examine the current shift from candidate gene to genome-wide approaches in psychiatric research, which are concurrently emerging with the increased consideration of the Research Domain Criteria (RDoC) framework for classifying mental illnesses. Furthermore, we discuss the use of transcription networks and how they can be integrated into multiomic analyses. Finally, we end by highlighting recent findings of peripheral markers of suicide risk identified through the use of transcriptomic tools. Technological advancements and increased accessibility of these technologies are drastically shaping the current research landscape. We present an overview of the significant changes currently taking place to usher in a new era of psychiatric research., (© 2018 Wiley Periodicals, Inc.)

In the past decade, considerable attention has been drawn to social interactions and behaviors as sources of pleasurable (social reward) and painful (social pain) emotional states. While the role of the opioid system in the regulation of reward and pain processes has long been recognized, it has more recently been investigated and characterized in the specific context of social experiences across several mammalian species. Accordingly, the present narrative review provides a comprehensive summary of studies detailing how the opioid system controls social reward and social pain. From a translational and pathophysiological perspective, we further discuss how opioid-dependent regulation of social behaviors may contribute to depressive illness and suicidal behaviors, and ultimately provide innovative therapeutic opportunities., (© 2018 Wiley Periodicals, Inc.)

With more than 800,000 deaths by suicide each year and 20 to 30 times more suicide attempts worldwide, suicide is a major public health problem. Current treatments of SB are mainly based on pharmacological treatments that are not specific of SB (e.g. antidepressants), and new therapeutic targets are urgently needed. Recent data strengthen the ancient conception pain (social, psychic, physical) that is at the core of the suicidal process and should be incorporated in the clinical assessment of suicide risk. Then, the mechanisms involved in the regulation of pain may open new avenues regarding therapeutic perspectives. Opiates appear to be a promising candidate in treatment of SB. Indeed, since the last two decades, growing evidences suggest an implication of the opioid system in the pathophysiology of SB, this conduct to the elaboration of randomized controlled trials (RCTs) using opiates in patients with SB. Results suggesting an anti-suicidal effect of buprenorphine and the potential opioidergic-related anti-suicidal effect of ketamine both contribute to the growing interest in opiates use in SB. In this review, we will summarize a large part of the evidence that leads researchers and clinicians to be interested in the use of opiates for SB treatment and discuss on new opioid pharmacological options for suicidal patients.

Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.

Glial dysfunction is a major pathophysiological feature of mood disorders. While altered astrocyte (AS) and oligodendrocyte-lineage (OL) functions have been associated with depression, the crosstalk between these glial cell types has never been assessed in that context. AS are potent regulators of myelination, in part through gap junction (GJ) channels formed by the heterotypic coupling of AS-specific (Cx30 and Cx43) and OL-specific (Cx32 and Cx47) connexins. This study therefore aimed at addressing the integrity of AS/OL coupling in the anterior cingulate cortex (ACC) of depressed suicides. Using immunofluorescence and confocal imaging, we characterized the distribution of Cx30 and mapped its expression onto OL somas, myelinated axons, and brain vasculature in postmortem brain samples from depressed suicides (N = 48) and matched controls (N = 23). Differential gene expression of key components of the GJ nexus was also screened through RNA-sequencing previously generated by our group, and validated by quantitative real-time PCR. We show that Cx30 expression localized onto OL cells and myelinated fibers is decreased in deep cortical layers of the ACC in male-depressed suicides. This effect was associated with decreased expression of OL-specific connexins, as well as the downregulation of major connexin-interacting proteins essential for the scaffolding, trafficking, and function of GJs. These results provide a first evidence of impaired AS/OL GJ-mediated communication in the ACC of individuals with mood disorders. These changes in glial coupling are likely to have significant impact on brain function, and may contribute to the altered OL function previously reported in this brain region.

Background: Experiences of abuse and neglect during childhood are major predictors of the emergence of depressive and suicidal behaviors throughout life. The underlying biological mechanisms, however, remain poorly understood. Here, we focused on the opioid system as a potential brain substrate mediating these effects., Methods: Postmortem samples from three brain structures regulating social bonds and emotions were analyzed. Groups were constituted of depressed individuals who died by suicide, with or without a history of severe child abuse, and of psychiatrically healthy control subjects. Expression of opioid peptides and receptors was measured using real-time polymerase chain reaction. DNA methylation, a major epigenetic mark, was investigated using targeted bisulfite sequencing and characterized at functional level using in vitro reporter assays. Finally, oxidative bisulfite sequencing was used to differentiate methylation and hydroxymethylation of DNA., Results: A history of child abuse specifically associated in the anterior insula with a downregulation of the kappa opioid receptor (Kappa), as well as decreased DNA methylation in the second intron of the Kappa gene. In vitro assays further showed that this intron functions as a genomic enhancer where glucocorticoid receptor binding regulates Kappa expression, unraveling a new mechanism mediating the well-established interactions between endogenous opioids and stress. Finally, results showed that child abuse is associated in the Kappa intron with a selective reduction in levels of DNA hydroxymethylation, likely mediating the observed downregulation of the receptor., Conclusions: Altogether, our findings uncover new facets of Kappa physiology, whereby this receptor may be epigenetically regulated by stressful experiences, in particular as a function of early social life., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. Despite the widespread use of these drugs, the mechanism underlying their therapeutic action in this pain context remains partly elusive. The present study combined data collected in male and female mice from a model of neuropathic pain and data from the clinical setting to understand how antidepressant drugs act. We show two distinct mechanisms by which the selective inhibitor of serotonin and noradrenaline reuptake duloxetine and the tricyclic antidepressant amitriptyline relieve neuropathic allodynia. One of these mechanisms is acute, central, and requires descending noradrenergic inhibitory controls and α 2A adrenoceptors, as well as the mu and delta opioid receptors. The second mechanism is delayed, peripheral, and requires noradrenaline from peripheral sympathetic endings and β 2 adrenoceptors, as well as the delta opioid receptors. We then conducted a transcriptomic analysis in dorsal root ganglia, which suggested that the peripheral component of duloxetine action involves the inhibition of neuroimmune mechanisms accompanying nerve injury, including the downregulation of the TNF-α-NF-κB signaling pathway. Accordingly, immunotherapies against either TNF-α or Toll-like receptor 2 (TLR2) provided allodynia relief. We also compared duloxetine plasma levels in the animal model and in patients and we observed that patients' drug concentrations were compatible with those measured in animals under chronic treatment involving the peripheral mechanism. Our study highlights a peripheral neuroimmune component of antidepressant drugs that is relevant to their delayed therapeutic action against neuropathic pain. SIGNIFICANCE STATEMENT In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. However, the mechanism by which antidepressant drugs can relieve neuropathic pain remained in part elusive. Indeed, preclinical studies led to contradictions concerning the anatomical and molecular substrates of this action. In the present work, we overcame these apparent contradictions by highlighting the existence of two independent mechanisms. One is rapid and centrally mediated by descending controls from the brain to the spinal cord and the other is delayed, peripheral, and relies on the anti-neuroimmune action of chronic antidepressant treatment., (Copyright © 2018 the authors 0270-6474/18/389935-21$15.00/0.)

Long non-coding RNAs (lncRNAs) are an emerging class of regulatory RNA that may be implicated in psychiatric disorders. Here we performed RNA-sequencing in the rostral anterior cingulate cortex of 26 depressed suicides and 24 matched controls. We first performed differential lncRNA expression analysis, and then conducted Weighted Gene Co-expression Network Analysis (WGCNA) to identify co-expression modules associating with depression and suicide. We identified 23 differentially expressed lncRNAs (FDR < 0.1) as well as their differentially expressed overlapping and antisense protein-coding genes. Several of these overlapping or antisense genes were associated with interferon signaling, which is a component of the innate immune response. Using WGCNA, we identified modules of highly co-expressed genes associated with depression and suicide and found protein-coding genes highly connected to differentially expressed lncRNAs within these modules. These protein-coding genes were located distal to their associated lncRNAs and were found to be part of several GO terms enriched in the significant modules, which include: cytoskeleton organization, plasma membrane, cell adhesion, nucleus, DNA-binding, and regulation of dendrite development and morphology. Altogether, we report that lncRNAs are differentially expressed in the brains of depressed individuals who died by suicide and may represent regulators of important molecular functions and biological processes.

Background: Antidepressant treatment is associated with a high rate of poor response, and thus, biomarker development is warranted., Methods: We aimed to synthesize studies investigating gene expression, small RNAs, and epigenomic biomarkers of antidepressant response. We conducted a narrative review of the literature., Results: Firstly, we detailed the challenges involved, in terms of biological tissues, relevant study time frames, and mandatory statistical tools. Secondly we synthesized results obtained in gene expression studies, focusing mainly on genome-wide studies, particularly small non-coding RNA, including micro-RNA and other small RNA species. In addition, we reviewed the potential biomarkers of antidepressant response arising from studies investigating DNA methylation variation and histone modifications., Limitations: We did not conduct a meta-analysis due to the heterogeneity of the study., Conclusion: Although promising, the field of gene expression and epigenomic biomarkers of antidepressant response is still in its infancy, and needs further development to define useful biomarkers in clinical practice., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Early life adversity remains a significant risk factor for the development of a host of negative behavioural and pathological outcomes in adulthood long after the stressor is over. Recent evidence indicates that these lasting effects of ELS may occur via alterations in the epigenetic landscape. Here, we review the main findings of the effects of early life adversity on DNA methylation, histone post-translational modification, and non-coding RNAs in the context of psychiatric disease in animal models and human cohorts. We specifically explore how early life adversity alters epigenetic patterns in both a global manner, and in specific candidate genes that play a role in relevant systems such as the hypothalamic-pituitary-adrenal axis, as well as neurotransmitter and neuroendocrine signalling. We also discuss how individual factors, such as genetics, sex, and age, as well as the type, and timing of early life adversity, can create differential susceptibility and significantly moderate outcomes. Although challenges remain in deciphering the complexity of how the early environment interacts with individual factors to determine epigenetic patterns, as well as how to translate these mechanistic findings into clinically relevant populations, the reviewed literature sheds light on the potential of the field to identify effective interventions for vulnerable individuals., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Pain associates both sensory and emotional aversive components, and often leads to anxiety and depression when it becomes chronic. Here, we characterized, in a mouse model, the long-term development of these sensory and aversive components as well as anxiodepressive-like consequences of neuropathic pain and determined their electrophysiological impact on the anterior cingulate cortex (ACC, cortical areas 24a/24b). We show that these symptoms of neuropathic pain evolve and recover in different time courses following nerve injury in male mice. In vivo electrophysiological recordings evidence an increased firing rate and bursting activity within the ACC when anxiodepressive-like consequences developed, and this hyperactivity persists beyond the period of mechanical hypersensitivity. Whole-cell patch-clamp recordings also support ACC hyperactivity, as shown by increased excitatory postsynaptic transmission and contribution of NMDA receptors. Optogenetic inhibition of the ACC hyperactivity was sufficient to alleviate the aversive and anxiodepressive-like consequences of neuropathic pain, indicating that these consequences are underpinned by ACC hyperactivity. SIGNIFICANCE STATEMENT Chronic pain is frequently comorbid with mood disorders, such as anxiety and depression. It has been shown that it is possible to model this comorbidity in animal models by taking into consideration the time factor. In this study, we aimed at determining the dynamic of different components and consequences of chronic pain, and correlated them with electrophysiological alterations. By combining electrophysiological, optogenetic, and behavioral analyses in a mouse model of neuropathic pain, we show that the mechanical hypersensitivity, ongoing pain, anxiodepressive consequences, and their recoveries do not necessarily exhibit temporal synchrony during chronic pain processing, and that the hyperactivity of the anterior cingulate cortex is essential for driving the emotional impact of neuropathic pain., (Copyright © 2018 the authors 0270-6474/18/383102-14$15.00/0.)

Preclinical and clinical studies have demonstrated that the kappa opioid receptor (KOR) regulates reward, hedonic tone and emotions. At therapeutic level, on-going clinical trials are assessing the potential of targeting the KOR for the management of depression, anxiety disorders and substance use disorders. However, genetic polymorphisms in the KOR gene that potentially contribute to its implication in these phenotypes have been poorly studied. Here we investigated an insertion-deletion in the promoter region of KOR (rs35566036), recently associated with alcohol addiction, in a cohort of depressed subjects who died by suicide, as well as psychiatrically healthy individuals. Focusing on 3 brain regions (anterior insula, anterior cingulate cortex, and mediodorsal thalamus), we characterized the functional impact of this structural variant on the expression and patterns of DNA methylation of the KOR gene, using qPCR and targeted Bisulfite-Sequencing, respectively. While there was no significant change in the expression of KOR as a function of the insertion-deletion, or as a function of disease status in any brain region, we found that this variant strongly determines DNA methylation in KOR promoter, leading to a significant decrease in methylation levels of 8 nearby CpG dinucleotides located approximately 500 base pairs upstream the transcription start site. In addition, our results suggest a possible association between the insertion-deletion and depression; however, this result should be tested in larger populations. In sum, in this study we uncovered an epigenetic mechanism potentially contributing to KOR dysfunction in carriers of the insertion-deletion., (Copyright © 2018. Published by Elsevier B.V.)

Substance use disorders (SUD) and behavioral addictions are devastating conditions that impose a severe burden on all societies, and represent difficult challenges for clinicians. Therefore, biomarkers are urgently needed to help predict vulnerability, clinical course, and response to treatment. Here, we elaborate on the potential for addiction biomarker discovery of the opioid system, particularly within the emerging framework aiming to probe opioid function in peripheral tissues. Mu, delta, and kappa opioid receptors all critically regulate neurobiological and behavioral processes that define addiction, and are also targeted by major pharmacotherapies used in the management of patients with SUD. We propose that opioid biomarkers may have the potential to improve and guide diagnosis and therapeutic decisions in the addiction field., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Child abuse has devastating and long-lasting consequences, considerably increasing the lifetime risk of negative mental health outcomes such as depression and suicide. Yet the neurobiological processes underlying this heightened vulnerability remain poorly understood. The authors investigated the hypothesis that epigenetic, transcriptomic, and cellular adaptations may occur in the anterior cingulate cortex as a function of child abuse., Method: Postmortem brain samples from human subjects (N=78) and from a rodent model of the impact of early-life environment (N=24) were analyzed. The human samples were from depressed individuals who died by suicide, with (N=27) or without (N=25) a history of severe child abuse, as well as from psychiatrically healthy control subjects (N=26). Genome-wide DNA methylation and gene expression were investigated using reduced representation bisulfite sequencing and RNA sequencing, respectively. Cell type-specific validation of differentially methylated loci was performed after fluorescence-activated cell sorting of oligodendrocyte and neuronal nuclei. Differential gene expression was validated using NanoString technology. Finally, oligodendrocytes and myelinated axons were analyzed using stereology and coherent anti-Stokes Raman scattering microscopy., Results: A history of child abuse was associated with cell type-specific changes in DNA methylation of oligodendrocyte genes and a global impairment of the myelin-related transcriptional program. These effects were absent in the depressed suicide completers with no history of child abuse, and they were strongly correlated with myelin gene expression changes observed in the animal model. Furthermore, a selective and significant reduction in the thickness of myelin sheaths around small-diameter axons was observed in individuals with history of child abuse., Conclusions: The results suggest that child abuse, in part through epigenetic reprogramming of oligodendrocytes, may lastingly disrupt cortical myelination, a fundamental feature of cerebral connectivity.

Suicide is a major public health concern and a leading cause of death in most societies. Suicidal behaviour is complex and heterogeneous, likely resulting from several causes. It associates with multiple factors, including psychopathology, personality traits, early-life adversity and stressful life events, among others. Over the past decades, studies in fields ranging from neuroanatomy, genetics and molecular psychiatry have led to a model whereby behavioural dysregulation, including suicidal behaviour (SB), develops as a function of biological adaptations in key brain systems. More recently, the unravelling of the unique epigenetic processes that occur in the brain has opened promising avenues in suicide research. The present review explores the various facets of the current knowledge on suicidality and discusses how the rapidly evolving field of neurobehavioural epigenetics may fuel our ability to understand, and potentially prevent, SB.

Addiction is a chronic brain disorder that progressively invades all aspects of personal life. Accordingly, addiction to opiates severely impairs interpersonal relationships, and the resulting social isolation strongly contributes to the severity and chronicity of the disease. Uncovering new therapeutic strategies that address this aspect of addiction is therefore of great clinical relevance. We recently established a mouse model of heroin addiction in which, following chronic heroin exposure, 'abstinent' mice progressively develop a strong and long-lasting social avoidance phenotype. Here, we explored and compared the efficacy of two pharmacological interventions in this mouse model. Because clinical studies indicate some efficacy of antidepressants on emotional dysfunction associated with addiction, we first used a chronic 4-week treatment with the serotonergic antidepressant fluoxetine, as a reference. In addition, considering prodepressant effects recently associated with kappa opioid receptor signaling, we also investigated the kappa opioid receptor antagonist norbinaltorphimine (norBNI). Finally, we assessed whether fluoxetine and norBNI could reverse abstinence-induced social avoidance after it has established. Altogether, our results show that two interspaced norBNI administrations are sufficient both to prevent and to reverse social impairment in heroin abstinent animals. Therefore, kappa opioid receptor antagonism may represent a useful approach to alleviate social dysfunction in addicted individuals., (© 2016 Society for the Study of Addiction.)

Introduction: Energy drinks are popular beverages that are supposed to counteract sleepiness, increase energy, maintain alertness and reduce symptoms of hangover. Cognitive enhancing seems to be related to many compounds such as caffeine, taurine and vitamins. Currently, users mostly combine psychostimulant effects of energy drinks to counteract sedative effects of alcohol. However, recent literature suggests that this combination conducts to feel less intoxicated but still impaired. The goal of the present article is to review cognitive impact and subjective awareness in case of caffeinated alcoholic beverage (CAB) intoxication., Method: PubMed (January 1960 to March 2016) database was searched using the following terms: cognitive impairments, alcohol, energy drinks; cognition, alcohol, caffeine., Results: 99 papers were found but only 12 randomized controlled studies which explored cognitive disorders and subjective awareness associated with acute CAB or AED (alcohol associated with energy drinks) intoxication were included., Discussion: The present literature review confirmed that energy drinks might counteract some cognitive deficits and adverse effects of alcohol i.e. dry mouth, fatigue, headache, weakness, and perception of intoxication due to alcohol alone. This effect depends on alcohol limb but disappears when the complexity of the task increases, when driving for example. Moreover, studies clearly showed that CAB/AEDs increase impulsivity which conducts to an overconsumption of alcohol and enhanced motivation to drink compared to alcohol alone, potentiating the risk of developing addictive behaviors. This is a huge problem in adolescents with high impulsivity and immature decision making processes., Conclusion: Although energy drinks counteract some cognitive deficits due to alcohol alone, their association promotes the risk of developing alcohol addiction. As a consequence, it is necessary to better understand the neurobiological mechanisms underlying these interactions in order to better prevent the development of alcohol dependence., (Copyright © 2017 Elsevier Inc. All rights reserved.)

5-Hydroxymethylcytosine (5hmC) is a recently characterized epigenetic mark that is particularly abundant in brain tissue and that regulates gene transcription. We have recently begun to understand the important role of 5hmC in brain development, plasticity and disease, but there are currently little data on 5hmC alterations in psychiatric illnesses. Here we report what we believe to be the first genome-wide analysis of 5hmC in the depressed brain. Using AbaSI sequencing, we investigated 5hmC in the prefrontal cortex of depressed (N=19) and psychiatrically healthy controls (N=19). Consistent with previous global 5hmC analyses in other phenotypes, and likely owing to the inter-individual variability in 5hmC content, the distribution of 5hmC across chromosomes and genomic features was not different between groups. We did, however, find 550 CpGs with suggestive evidence of differential hydroxymethylation. Of these, we validated CpGs in the gene body of myosin XVI (MYO16) and insulin-degrading enzyme using targeted oxidative bisulfite sequencing. Furthermore, the enrichment of 5hmC was also associated with changes in the expression of these two genes in depressed suicides. Together, our results present a novel mechanism linking increased 5hmC to depression and provide a framework for future research in this field.

Background: Epigenetic modifications of DNA, such as 5-methylcytosine and 5-hydroxymethycytosine, play important roles in development and disease. Here, we present a cost-effective and versatile methodology for the analysis of DNA methylation in targeted genomic regions, which comprises multiplexed, PCR-based preparation of bisulfite DNA libraries followed by customized MiSeq sequencing., Results: Using bisulfite and oxidative bisulfite conversion of DNA, we have performed multiplexed targeted sequencing to analyse several kilobases of genomic DNA in up to 478 samples, and achieved high coverage data of 5-methylcytosine and 5-hydroxymethycytosine at single-base resolution. Our results demonstrate the ability of this methodology to detect all levels of cytosine modifications at greater than 100× coverage in large sample sets at low cost compared to other targeted methods., Conclusions: This approach can be applied to multiple settings, from candidate gene to clinical studies, and is especially useful for validation of differentially methylated or hydroxymethylated regions following whole-genome analyses.

Investigating 5-methylcytosine (5mC) has led to many hypotheses regarding molecular mechanism underlying human diseases and disorders. Many of these studies, however, utilize bisulfite conversion alone, which cannot distinguish 5mC from its recently discovered oxidative product, 5-hydroxymethylcytosine (5hmC). Furthermore, previous array-based technologies do not have the necessary probes to adequately investigate both modifications simultaneously. In this manuscript, we used technical replicates of DNA from human brain, human blood, and human saliva, in combination with oxidative bisulfite conversion and Illumina's Infinium MethylationEPIC array, to analyze 5mC and 5hmC at more than 650 000 and 450 000 relevant loci, respectively, in the human genome. We show the presence of loci with detectable 5mC and 5hmC to be equally distributed across chromosomes and genomic features, while also being present in genomic regions with transcriptional regulatory properties. We also describe 2528 5hmC sites common across tissue types that show a strong association with immune-related functions. Lastly, in human brain, we show that 5hmC accounts for one-third of the total signal from bisulfite-converted data. As such, not only do our results confirm the efficacy and sensitivity of pairing oxidative bisulfite conversion and the EPIC array to detect 5mC and 5hmC in all three tissue types, but they also highlight the importance of dissociating 5hmC from 5mC in future studies related to cytosine modifications., (© The Author 2016. Published by Oxford University Press. All rights reserved.)

Introduction: Many epidemiological studies have revealed a frequent co-occurrence of psychiatric and substance use disorders. The term used in the literature to refer to this co-occurrence is dual diagnosis. The high prevalence of dual diagnosis has led physicians to observe the effects of medication prescribed to treat psychiatric disorders on the co-occurring substance use disorder and vice versa. The concept of medications between psychiatric and addictive disorders stems from these clinical observations, alongside which, however, it has developed from the observation that both psychiatric and substance use disorders share common neurobiological pathways and trigger common cognitive disorders. This has led researchers to develop medications on the basis of neurobiological and cognitive rationales., Material and Method: In our article, we review peculiar medications based on neurobiological and cognitive rationales and that have an impact in both psychiatric and addictive disorders., Results: We highlight how interesting these new prescriptions are for clinical observation and for the treatment of patients suffering from dual diagnosis., Conclusion: We then go on to discuss the interest in them from the perspective of clinical practice and clinical research, in that the development of medications to treat dual diagnosis helps to further our knowledge of both psychiatric and substance use disorders.

The nociceptin/orphanin FQ (N/OFQ)-Nociceptin Opiod-like Peptide (NOP) receptor system is a critical mediator of physiological and pathological processes involved in emotional regulation and drug addiction. As such, this system may be an important biological substrate underlying psychiatric conditions that contribute to the risk of suicide. Thus, the goal of the present study was to characterize changes in human N/OFQ and NOP signaling as a function of depression, addiction and suicide. We quantified the expression of N/OFQ and NOP by RT-PCR in the anterior insula, the mediodorsal thalamus, and the dorsal anterior cingulate cortex (dACC) from a large sample of individuals who died by suicide and matched psychiatrically-healthy controls. Suicides displayed an 18% decrease in the expression of N/OFQ in the dACC that was not accounted for by current depressive or substance use disorders at the time of death. Therefore, our results suggest that dysregulation of the N/OFQ-NOP system may contribute to the neurobiology of suicide, a hypothesis that warrants further exploration., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Rationale: Opiate addiction is a brain disorder emerging through repeated intoxication and withdrawal episodes. Epidemiological studies also indicate that chronic exposure to opiates may lead in susceptible individuals to the emergence of depressive symptoms, strongly contributing to the severity and chronicity of addiction. We recently established a mouse model of heroin abstinence, characterized by the development of depressive-like behaviors following chronic heroin exposure., Objectives: While genetic factors regulating immediate behavioral responses to opiates have been largely investigated, little is known about their contribution to long-term emotional regulation during abstinence. Here, we compared locomotor stimulation and physical dependence induced by heroin exposure, as well as emotional dysfunction following abstinence, across mice strains with distinct genetic backgrounds., Methods: Mice from three inbred strains (C57BL/6J, Balb/cByJ, and 129S2/SvPas) were exposed to an escalating chronic heroin regimen (10-50 mg/kg). Independent cohorts were used to assess drug-induced locomotor activity during chronic treatment, naloxone-precipitated withdrawal at the end of chronic treatment, and emotional-like responses after a 4-week abstinence period., Results: Distinct behavioral profiles were observed across strains during heroin treatment, with no physical dependence and low locomotor stimulation in 129S2/SvPas. In addition, different behavioral impairments developed during abstinence across the three strains, with increased despair-like behavior in 129S2/SvPas and Balb/cByJ, and low sociability in 129S2/SvPas and C57BL/6J., Conclusions: Our results indicate that depressive-like behaviors emerge during heroin abstinence, whatever the severity of immediate behavioral responses to the drug. In addition, inbred mouse strains will allow studying several aspects of mood-related deficits associated with addiction.

Childhood maltreatment (CM) is all too frequent among western societies, with an estimated prevalence of 10 to 15%. CM associates with increased risk of several psychiatric disorders, and therefore represents a worrying public and socioeconomic burden. While associated clinical outcomes are well characterized, determining by which mechanisms early-life adverse experiences affect mental health over the lifespan is a major challenge. Epigenetic mechanisms, in particular DNA methylation, represent a form of molecular memory that may modify brain function over extended periods of time, as well as serve as a bio-marker of behavioral phenotypes associated with CM. Here, we review human studies suggesting that DNA methylation is a crucial substrate mediating neurobiological consequences of CM throughout life, thereby potentiating maladaptive behavioral patterns and psychopathological risk.

Comorbidity is a major issue in psychiatry that notably associates with more severe symptoms, longer illness duration, and higher service utilization. Therefore, identifying key clusters of comorbidity and exploring the underlying pathophysiological mechanisms represent important steps toward improving mental health care. In the present review, we focus on the frequent association between addiction and depression. In particular, we summarize the large body of evidence from preclinical models indicating that the kappa opioid receptor (KOR), a member of the opioid neuromodulatory system, represents a central player in the regulation of both reward and mood processes. Current data suggest that the KOR modulates overlapping neuronal networks linking brainstem monoaminergic nuclei with forebrain limbic structures. Rewarding properties of both drugs of abuse and natural stimuli, as well as the neurobiological effects of stressful experiences, strongly interact at the level of KOR signaling. In addiction models, activity of the KOR is potentiated by stressors and critically controls drug-seeking and relapse. In depression paradigms, KOR signaling is responsive to a variety of stressors, and mediates despair-like responses. Altogether, the KOR represents a prototypical substrate of comorbidity, whereby life experiences converge upon common brain mechanisms to trigger behavioral dysregulation and increased risk for distinct but interacting psychopathologies.

Addiction is a chronic disorder involving recurring intoxication, withdrawal, and craving episodes. Escaping this vicious cycle requires maintenance of abstinence for extended periods of time and is a true challenge for addicted individuals. The emergence of depressive symptoms, including social withdrawal, is considered a main cause for relapse, but underlying mechanisms are poorly understood. Here we establish a mouse model of protracted abstinence to heroin, a major abused opiate, where both emotional and working memory deficits unfold. We show that delta and kappa opioid receptor (DOR and KOR, respectively) knockout mice develop either stronger or reduced emotional disruption during heroin abstinence, establishing DOR and KOR activities as protective and vulnerability factors, respectively, that regulate the severity of abstinence. Further, we found that chronic treatment with the antidepressant drug fluoxetine prevents emergence of low sociability, with no impact on the working memory deficit, implicating serotonergic mechanisms predominantly in emotional aspects of abstinence symptoms. Finally, targeting the main serotonergic brain structure, we show that gene knockout of mu opioid receptors (MORs) in the dorsal raphe nucleus (DRN) before heroin exposure abolishes the development of social withdrawal. This is the first result demonstrating that intermittent chronic MOR activation at the level of DRN represents an essential mechanism contributing to low sociability during protracted heroin abstinence. Altogether, our findings reveal crucial and distinct roles for all three opioid receptors in the development of emotional alterations that follow a history of heroin exposure and open the way towards understanding opioid system-mediated serotonin homeostasis in heroin abuse.

Background: Bisulfite sequencing is the most efficient single nucleotide resolution method for analysis of methylation status at whole genome scale, but improved quality control metrics are needed to better standardize experiments., Results: We describe BisQC, a step-by-step method for multiplexed bisulfite-converted DNA library construction, pooling, spike-in content, and bioinformatics. We demonstrate technical improvements for library preparation and bioinformatic analyses that can be done in standard laboratories. We find that decoupling amplification of bisulfite converted (bis) DNA from the indexing reaction is an advantage, specifically in reducing total PCR cycle number and pre-selecting high quality bis-libraries. We also introduce a progressive PCR method for optimal library amplification and size-selection. At the sequencing stage, we thoroughly test the benefits of pooling non-bis DNA library with bis-libraries and find that BisSeq libraries can be pooled with a high proportion of non-bis DNA libraries with minimal impact on BisSeq output. For informatics analysis, we propose a series of optimization steps including the utilization of the mitochondrial genome as a QC standard, and we assess the validity of using duplicate reads for coverage statistics., Conclusion: We demonstrate several quality control checkpoints at the library preparation, pre-sequencing, post-sequencing, and post-alignment stages, which should prove useful in determining sample and processing quality. We also determine that including a significant portion of non-bisulfite converted DNA with bisulfite converted DNA has a minimal impact on usable bisulfite read output.