Transcriptomics identifies STAT3 as a key regulator of hippocampal gene expression and anhedonia during withdrawal from chronic alcohol exposure.
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ABSTRACT:
SUBMITTER: Chen WY
PROVIDER: S-EPMC8170676 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Adolescent alcohol use may interfere with neurodevelopment, increasing the likelihood of adult alcohol use disorders (AUDs). We investigated whether adolescent intermittent ethanol (AIE) exposure alters the adult reward response to ethanol. Adolescent rats were administered ethanol once (moderate exposure; Cohort 1) or three times per day (severe exposure; Cohort 2) in a 2 days on/2 days off pattern. In adulthood, subjects responded for electrical stimulation directed at the posterior lateral hypothalamus in a discrete-trial intracranial self-stimulation (ICSS) procedure that provides current-intensity thresholds as a measure of brain reward function. The effects of ethanol administration and withdrawal were assessed. Control rats showed dose-dependent threshold elevations after acute ethanol, indicating reward deficits. A majority of moderately AIE-exposed rats (Cohort 1) showed threshold lowering after ethanol, suggesting ethanol-induced reward enhancement in this sub-set of rats. Rats exposed to severe AIE (Cohort 2) showed no threshold elevation or lowering, suggesting a blunted affective ethanol response. Daily ethanol induced threshold elevations 24h after administration in control rats but not in either group of AIE-exposed rats, suggesting decreased sensitivity to the negative affective state of ethanol withdrawal. Withdrawal from a 4-day ethanol binge produced robust and enduring threshold elevations in all rats, although threshold elevations were diminished in rats exposed to severe AIE. These results indicate that AIE exposure diminished reward deficits associated with ethanol intoxication and withdrawal and may have increased ethanol-induced reward enhancement in a sub-set of rats. In humans, enhanced ethanol reward accompanied by reduced withdrawal severity may contribute to the development of AUDs.
| S-EPMC4020966 | biostudies-literature
Project description:Alcohol withdrawal (AW) after chronic alcohol exposure produces a series of symptoms, with AW-associated seizures being among the most serious and dangerous. However, the mechanism underlying AW seizures has yet to be established. In our mouse model, a sudden AW produced 2 waves of seizures: the first wave includes a surge of multiple seizures that occurs within hours to days of AW, and the second wave consists of sustained expression of epileptiform spikes and wave discharges (SWDs) during a protracted period of abstinence. We revealed that the structural and functional adaptations in newborn dentate granule cells (DGCs) in the hippocampus underlie the second wave of seizures but not the first wave. While the general morphology of newborn DGCs remained unchanged, AW increased the dendritic spine density of newborn DGCs, suggesting that AW induced synaptic connectivity of newborn DGCs with excitatory afferent neurons and enhanced excitability of newborn DGCs. Indeed, specific activation and suppression of newborn DGCs by the chemogenetic DREADD method increased and decreased the expression of epileptiform SWDs, respectively, during abstinence. Thus, our study unveiled that the pathological plasticity of hippocampal newborn DGCs underlies AW seizures during a protracted period of abstinence, providing critical insight into hippocampal neural circuits as a foundation to understand and treat AW seizures.
| S-EPMC6795406 | biostudies-literature
Project description:Single-cell RNA sequencing (scRNA-seq) is a powerful technique for dissecting the complexity of normal and diseased tissues, enabling characterization of cell diversity and heterogeneous phenotypic states in unprecedented detail. However, this technology has been underutilized for exploring the interactions between the host cell and viral pathogens in latently-infected cells. Herein, we use scRNA-seq and single-molecule sensitivity fluorescent in situ hybridization (smFISH) technologies to investigate host single-cell transcriptome changes upon the reactivation of a human neurotropic virus, herpes simplex virus-1 (HSV-1). We identify the stress sensor Growth arrest and DNA damage-inducible 45 beta (Gadd45b) as a critical antiviral host factor that regulates HSV-1 reactivation events in a subpopulation of latently-infected primary neurons. We show that distinct subcellular localization of Gadd45b correlates with the viral late gene expression program, as well as the expression of the viral transcription factor, ICP4. We propose that a hallmark of a "successful" or "aborted" HSV-1 reactivation state in primary neurons is determined by a unique subcellular localization signature of the stress sensor Gadd45b.
| S-SCDT-EMBOR-2021-53543-T | biostudies-other
Project description:RATIONALE:Understanding factors contributing to individual differences in vulnerability to opioid addiction is essential for developing more effective preventions and treatments, yet few reliable behavioral predictors of subsequent opioid self-administration have been identified in rodents. Sensitivity to the acute effects of initial drug exposure predicts later addiction vulnerability in both humans and animals, but the relationship between sensitivity to withdrawal from initial drug exposure and later drug use vulnerability is unclear. OBJECTIVE:The goal of the current study was to evaluate whether the degree of anhedonia experienced during withdrawal from early opioid exposure predicts subsequent vulnerability to opioid self-administration. METHODS:Rats were first tested for withdrawal sensitivity following acute injections of morphine (i.e., "acute dependence"), measured as elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior) during naloxone-precipitated and spontaneous withdrawal. Rats were then tested for addiction-like behavior using various measures of i.v. morphine self-administration (MSA) including acquisition, demand, extinction, and reinstatement induced by morphine, stress, and/or drug-associated cues. RESULTS:Greater naloxone-precipitated withdrawal across repeated morphine injections and greater peak spontaneous withdrawal severity following a single morphine injection were associated with lower addiction-like behavior on multiple MSA measures. Withdrawal-induced anhedonia predicted a wider range of MSA measures than did any individual measure of MSA itself. CONCLUSIONS:Our data establish WIA as one of the first behavioral measures to predict individual differences in opioid SA in rodents. This model promises to be useful for furthering our understanding of behavioral and neurobiological mechanisms underlying vulnerability to opioid addiction.
| S-EPMC7354901 | biostudies-literature
Project description:Alcohol is a psychoactive substance which has detrimental health effects upon consumption. Transcriptome profiling can provide insights into the dynamic changes in global gene expression profiles induced by chronic alcohol exposure and withdrawal. Male and female zebrafish were continually exposed to 0.5% ethanol for a period of 9 weeks. Upon completion of alcohol treatment, the fish were subjected to a withdrawal program for 9 weeks. Brain and liver tissues of control, alcohol exposed and withdrawal fish were isolated and the extracted RNA was sequenced on Illumina HiSeq 2000. The resultant paired end reads were mapped to the zebrafish reference genome (danRer10). The mapped transcripts were quantified for their expression and subjected to differential expression analysis across the three conditions. Gene ontology enrichment analysis of the differentially regulated genes was carried out to identify affected biological processes. The data for this project is available as a GEO dataset under Accession number GSE143416. The gene expression data discussed here accompanies the research article entitled 'Tissue-specific transcriptome recovery on withdrawal from chronic alcohol exposure in zebrafish'.
| S-EPMC7607250 | biostudies-literature
Project description:Alcohol-related liver disease is the most prevalent chronic liver disease worldwide, accounting for 30% of hepatocellular carcinoma (HCC) cases and HCC-specific deaths. However, the knowledge on mechanisms by which alcohol consumption leads to cancer progression and its aggressiveness is limited. Better understanding of the clinical features and the mechanisms of alcohol-induced HCC are of critical importance for prevention and the development of novel treatments. Early stage Huh-7 and advanced SNU449 liver cancer cell lines were subjected to chronic alcohol exposure (CAE), at different doses for 6 months followed by 1-month alcohol withdrawal period. ADH activity and ALDH expression were much lower in SNU449 compared with Huh-7 cells and at the 270 mM dose, CAE decreased cell viability by about 50% and 80%, respectively, in Huh-7 and SNU449 cells but induced mortality only in Huh-7 cells. Thus, Huh-7 may be more vulnerable to ethanol toxicity because of the higher levels of acetaldehyde. CAE induced a dose-dependent increase in cell migration and invasion and also in the expression of cancer stem cells markers (CD133, CD44, CD90). CAE in Huh-7 cells selectively activated ERK1/2 and inhibited GSK3β signaling pathways. Most of the changes induced by CAE were reversed after alcohol withdrawal. Interestingly, we confirmed the increase in CD133 mRNA levels in the tumoral tissue of patients with ethanol-related HCC compared to other HCC etiologies. Our results may explain the benefits observed in epidemiological studies showing a significant increase of overall survival in abstinent compared with non-abstinent patients. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-022-04387-y.
| S-EPMC9205837 | biostudies-literature
Project description:INTRODUCTION:When animals undergo nicotine deprivation, rewards become less rewarding (ie, anhedonia occurs). We searched for tests of whether anhedonia occurs in abstinent smokers. METHODS:The major inclusion criterion was a within-participants comparison of behavioral measures of reward sensitivity or self-reported anhedonia during smoking versus during abstinence among daily smokers. A computerized search of PubMed, PsychInfo, and Cochrane databases and other methods located 13 studies. All but one were laboratory studies. RESULTS:The number of studies and participants were small and the results mixed. In terms of anticipatory anhedonia (ie, wanting a reward), abstinence appeared to decrease willingness to work for immediately available rewards, but did not appear to influence how much adding rewards to a task increased responding. Abstinence also appeared to produce small increases in self-reported anticipatory anhedonia. In terms of consummatory anhedonia (ie, liking a reward), self-report measures found anhedonia decreased pleasure from rewards in some but not all tests. In terms of learning (ie, learning to choose a more frequent reward), abstinence did not reliably decrease allocating responding to high versus low frequency reward options. CONCLUSIONS:Although results were mixed, abstinence appears to increase anticipatory anhedonia. It is unclear if abstinence increases consummatory or reward learning-based anhedonia. Further studies of anhedonia in clinical settings are needed (1) to estimate the reliability and clinical significance of anhedonia as a symptom of tobacco withdrawal, (2) to assess if effects represent withdrawal versus offset processes, and (3) to assess if anhedonia interferes with the ability to stop smoking. IMPLICATIONS:Anticipatory anhedonia appears to be a symptom of tobacco withdrawal and should be added to tobacco withdrawal checklists and diagnostic criteria. Further study of consummatory and learning-based anhedonia is warranted.
| S-EPMC7297016 | biostudies-literature
Project description:BackgroundBaclofen shows potential for rapidly reducing symptoms of severe alcohol withdrawal syndrome (AWS) in people with alcoholism. Treatment with baclofen is easy to manage and rarely produces euphoria or other pleasant effects, or craving for the drug. This is an updated version of the original Cochrane Review published in 2015, Issue 4.ObjectivesTo assess the efficacy and safety of baclofen for people with AWS.Search methodsWe updated our searches of the following databases to March 2017: the Cochrane Drugs and Alcohol Group Specialised Register, CENTRAL, PubMed, Embase, and CINAHL. We also searched registers of ongoing trials. We handsearched the references quoted in the identified trials, and sought information from researchers, pharmaceutical companies, and relevant trial authors about unpublished or uncompleted trials. We placed no restrictions on language.Selection criteriaWe included all randomised controlled clinical trials (RCTs) evaluating baclofen versus placebo or any other treatment for people with AWS. We excluded uncontrolled, non-randomised, or quasi-randomised trials. We included both parallel group and cross-over studies.Data collection and analysisWe used standard methodological procedures expected by Cochrane.Main resultsWe included three RCTs with 141 randomised participants. We did not perform meta-analyses due to the different control interventions. For the comparison of baclofen and placebo (1 study, 31 participants), there was no significant difference in Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) scores (very low quality evidence). For the comparison of baclofen and diazepam (1 study, 37 participants), there was no significant difference in CIWA-Ar scores (very low quality evidence), adverse events (risk difference (RD) 0.00, 95% confidence interval (CI) -0.10 to 0.10; very low quality evidence), dropouts (RD 0.00, 95% CI -0.10 to 0.10; very low quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI -0.10 to 0.10; very low quality evidence). For the comparison of baclofen and chlordiazepoxide (1 study, 60 participants), there was no significant difference in CIWA-Ar scores (mean difference (MD) 1.00, 95% CI 0.70 to 1.30; very low quality evidence), global improvement (MD 0.10, 95% CI -0.03 to 0.23; very low quality evidence), adverse events (RD 2.50, 95% CI 0.88 to 7.10; very low quality of evidence), dropouts (RD 0.00, 95% CI -0.06 to 0.06; very low quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI -0.06 to 0.06; very low quality evidence).Authors' conclusionsNo conclusions can be drawn about the efficacy and safety of baclofen for the management of alcohol withdrawal because we found insufficient and very low quality evidence.
| S-EPMC6483686 | biostudies-literature
Project description:Alcohol withdrawal syndrome (AWS) is a distressing and life-threatening condition that usually affects people who are alcohol dependent when they discontinue or decrease their alcohol consumption. Baclofen shows potential for rapidly reducing symptoms of severe AWS in people with alcoholism. Treatment with baclofen is easy to manage and rarely produces euphoria or other pleasant effects, or craving for the drug. This is an updated version of the original Cochrane Review first published in 2011 and last updated in 2017. To assess the efficacy and safety of baclofen for people with AWS. We updated our searches of the following databases to June 2019: the Cochrane Drugs and Alcohol Group Specialised Register, CENTRAL, PubMed, Embase, and CINAHL. We also searched registers of ongoing trials. We handsearched the references quoted in the identified trials, and sought information from researchers, pharmaceutical companies, and relevant trial authors about unpublished or uncompleted trials. We placed no restrictions on language. We included all randomised controlled clinical trials (RCTs) evaluating baclofen versus placebo or any other treatment for people with AWS. We excluded uncontrolled, non-randomised, or quasi-randomised trials. We included both parallel group and cross-over studies. We used standard methodological procedures expected by Cochrane. We included four RCTs with 189 randomised participants (one RCT new for this update). None of the included studies reported the primary outcomes of alcohol withdrawal seizures, alcohol withdrawal delirium, or craving. For the comparison of baclofen and placebo (1 study, 31 participants), there was no evidence of a difference in Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) scores in eight-hour periods from days one to five (very low-quality evidence). For the comparison of baclofen and diazepam (2 studies, 85 participants), there was no evidence of a difference in change from baseline to days 10 to 15 on CIWA-Ar scores (very low-quality evidence, meta-analysis was not performed due to insufficient data). In one study (37 participants), there was no evidence of a difference in participants with at least one adverse event (risk difference (RD) 0.00, 95% confidence interval (CI) -0.10 to 0.10; very low-quality evidence), dropouts (RD 0.00, 95% CI -0.10 to 0.10; very low-quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI -0.10 to 0.10; very low-quality evidence). For the comparison of baclofen and chlordiazepoxide (1 study, 60 participants), there was no evidence of a difference in difference from baseline to nine-day decremental fixed-dose intervention: CIWA-Ar scores (mean difference (MD) 1.00, 95% CI 0.70 to 1.30; very low-quality evidence), global improvement (MD 0.10, 95% CI -0.03 to 0.23; very low-quality evidence), 14/60 participants with adverse events (RD 2.50, 95% CI 0.88 to 7.10; very low-quality of evidence), dropouts (RD 0.00, 95% CI -0.06 to 0.06; very low-quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI -0.06 to 0.06; very low-quality evidence). None of the RCTs provided information on random sequence generation or allocation concealment, therefore, we assessed them at unclear risk of bias. Two RCTs were not of double-blind design and had a high risk of bias in blinding (Addolorato 2006; Girish 2016). One RCT had more than 5% dropouts with high risk of attrition bias (Lyon 2011). We could not assess reporting bias as none of the prepublished protocols were available. No conclusions can be drawn about the efficacy and safety of baclofen for the management of alcohol withdrawal because we found insufficient and very low-quality evidence.
| S-EPMC6831488 | biostudies-literature
Project description:Although multiple vital genes with strong effects on the tomato (Solanum lycopersicum) ripening process have been identified via the positional cloning of ripening mutants and cloning of ripening-related transcription factors (TFs), recent studies suggest that it is unlikely that we have fully characterized the gene regulatory networks underpinning this process. Here, combining comparative transcriptomics and expression QTLs, we identified 16 candidate genes involved in tomato fruit ripening and validated them through virus-induced gene silencing analysis. To further confirm the accuracy of the approach, one potential ripening regulator, SlWD40 (WD-40 repeats), was chosen for in-depth analysis. Co-expression network analysis indicated that master regulators such as RIN (ripening inhibitor) and NOR (nonripening) as well as vital TFs including FUL1 (FRUITFUL1), SlNAC4 (NAM, ATAF1,2, and CUC2 4), and AP2a (Activating enhancer binding Protein 2 alpha) strongly co-expressed with SlWD40. Furthermore, SlWD40 overexpression and RNAi lines exhibited substantially accelerated and delayed ripening phenotypes compared with the wild type, respectively. Moreover, transcriptome analysis of these transgenics revealed that expression patterns of ethylene biosynthesis genes, phytoene synthase, pectate lyase, and branched chain amino transferase 2, in SlWD40-RNAi lines were similar to those of rin and nor fruits, which further demonstrated that SlWD40 may act as an important ripening regulator in conjunction with RIN and NOR. These results are discussed in the context of current models of ripening and in terms of the use of comparative genomics and transcriptomics as an effective route for isolating causal genes underlying differences in genotypes.
| S-EPMC9434188 | biostudies-literature