The lncRNA BDNF-AS is an epigenetic regulator in the human amygdala in early onset alcohol use disorders

Translational Psychiatry, Journal Year: 2019, Volume and Issue: 9(1)

Published: Feb. 6, 2019

Abstract Adolescent alcohol drinking is known to contribute the development and severity of use disorders (AUDs) later in adulthood. Recent studies have shown that long non-coding RNAs (lncRNAs) are critical for brain synaptic plasticity. One such lncRNA natural occurring brain-derived neurotrophic factor antisense ( BDNF-AS ) has been regulate BDNF expression. The role molecular mechanisms AUD unknown. Here, we evaluated expression functional postmortem amygdala either early onset or late alcoholics (individuals who began before after 21 years age, respectively) age-matched control subjects. increased but not appears be regulated epitranscriptomically via decreased N 6-methyladenosine on . Upregulation associated with a significant decrease recruitment EZH2, which deposits repressive H3K27 trimethylation (H3K27me3) at regulatory regions gene group. Drinking during adolescence also contributed decreases activity-regulated cytoskeleton-associated protein (ARC) appeared mediated by EZH2 deposition H3K27me3 ARC activity response element. These results suggest an important regulation plasticity epigenetic reprogramming subjects adolescence.

Language: Английский

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GABAA receptor subtypes and benzodiazepine use, misuse, and abuse

Frontiers in Psychiatry, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 12, 2023

Benzodiazepines have been in use for over half a century. While they remain highly prescribed, their unfavorable side-effect profile and abuse liability motivated search alternatives. Most of these efforts focused on the development benzodiazepine-like drugs that are selective specific GABA A receptor subtypes. there is ample evidence subtype-selective ligands great potential providing symptom relief without typical benzodiazepine side-effects, it less clear whether targeting strategies can also reduce misuse potential. This review focuses three properties relevant to DSM-5-TR criteria Sedative, Hypnotic, or Anxiolytic Use Disorder, namely, reinforcing benzodiazepines, maladaptive behaviors related use, tolerance dependence. We existing regarding involvement different subtypes each areas. The reviewed studies suggest α1-containing receptors play an integral role benzodiazepine-induced plasticity reward-related brain areas might be involved dependence benzodiazepines. However, systematic comparison contributions all benzodiazepine-sensitive processes, mechanistic understanding how positive modulation subtype contribute mechanisms underlying definitive answer question chronic any given would result some effects currently lacking from literature. Moreover, non-selective benzodiazepines lead listed DSM remains unexplored. Considering increasing burden abuse, common practice leads severe dependence, current generate free alternatives, urgent need systematic, research provides better including establish informed foundation preclinical clinical efforts.

Language: Английский

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Altered amygdala DNA methylation mechanisms after adolescent alcohol exposure contribute to adult anxiety and alcohol drinking

Neuropharmacology, Journal Year: 2019, Volume and Issue: 157, P. 107679 - 107679

Published: June 20, 2019

Language: Английский

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Genome-wide methylation in alcohol use disorder subjects: implications for an epigenetic regulation of the cortico-limbic glucocorticoid receptors (NR3C1)

Molecular Psychiatry, Journal Year: 2019, Volume and Issue: 26(3), P. 1029 - 1041

Published: June 25, 2019

Abstract Environmental factors, including substance abuse and stress, cause long-lasting changes in the regulation of gene expression brain via epigenetic mechanisms, such as DNA methylation. We examined genome-wide methylation patterns prefrontal cortex (PFC, BA10) 25 pairs control individuals with alcohol use disorder (AUD), using Infinium ® MethylationEPIC BeadChip. identified 5254 differentially methylated CpGs ( p nominal < 0.005). Bioinformatic analyses highlighted biological processes containing genes related to stress adaptation, glucocorticoid receptor (encoded by NR3C1 ). Considering that is a stressor, we focused our attention on regions validated differential several network. Chronic drinking results significant increased exon variant 1 H , particular increase levels 5-hydroxymethylcytosine over 5-methylcytosine. These were associated reduced mRNA protein PFC, well other cortico-limbic AUD subjects when compared controls. Furthermore, show stress-responsive (e.g., CRF POMC FKBP5 ) altered PFC subjects. stress-response also changed hippocampus, region highly susceptible stress. data suggest alcohol-dependent aberrant consequent stress-related might be fundamental pathophysiology lay groundwork for treatments targeting mechanisms regulating AUD.

Language: Английский

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Toxic and Teratogenic Effects of Prenatal Alcohol Exposure on Fetal Development, Adolescence, and Adulthood

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(16), P. 8785 - 8785

Published: Aug. 16, 2021

Prenatal alcohol exposure (PAE) can have immediate and long-lasting toxic teratogenic effects on an individual's development health. As a toxicant, lead to variety of physical neurological anomalies in the fetus that behavioral other impairments which may last lifetime. Recent studies focused identifying mechanisms mediate fetal facilitate persistent health predisposition disease later life. This review focuses contribution epigenetic modifications intercellular transporters like extracellular vesicles toxicity PAE long-term consequences risk disease.

Language: Английский

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α6-Containing GABA_AReceptors: Functional Roles and Therapeutic Potentials

Pharmacological Reviews, Journal Year: 2022, Volume and Issue: 74(1), P. 238 - 270

Published: Jan. 1, 2022

GABA_A receptors containing the α6 subunit are highly expressed in cerebellar granule cells and less abundantly many other neuronal peripheral tissues. Here, we for first time summarize their importance functions of cerebellum nervous system. The is not only involved motor control but also cognitive, emotional, social behaviors. α6βγ2 located at Golgi cell/granule cell synapses enhance precision inputs required timing activity thus cognitive processing adequate responses to our environment. Extrasynaptic α6βδ regulate amount information entering by tonic inhibition cells, optimal functioning enhances input filtering or contrast. complex roles multiple brain can be compromised genetic neurodevelopmental causes that lead a hypofunction α6-containing receptors. Animal models mimicking neuropsychiatric phenotypes suggest compounds selectively activating positively modulating alleviate essential tremor disturbances Angelman Down syndrome as well impaired prepulse disorders reduce migraine trigeminal-related pain via trigeminal ganglia. Genetic studies humans an association human receptor gene with stress-associated disorders. support this conclusion. Neuroimaging post-mortem further involvement various disorders, pointing broad therapeutic potential drugs

Significance Statement

α6-Containing pathophysiological widely unknown, they out mainstream research. Anatomical electrophysiological evidence indicates these have crucial function circuits system, experimental, genetic, post-mortem, pharmacological indicate selective modulation offers prospects variety stress its consequences.

Language: Английский

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Splice-Site Variants in the Gene Encoding GABA-A Receptor Delta Subunit Are Associated with Amphetamine Use in Patients under Methadone Maintenance Treatment

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 24(1), P. 721 - 721

Published: Dec. 31, 2022

Chronic opioid use disorder patients often also other substances such as amphetamines. The gene-based analysis method was applied in the genomic database obtained from our previous study with 343 methadone maintenance treatment (MMT) patients. We found that gene encoding gamma-aminobutyric acid type A receptors (GABA-A receptor) delta subunit isoforms (GABRD) associated amphetamine heroin dependent under MMT Taiwan. total of 15% tested positive for urine toxicology test. Two genetic variants GABRD, rs2889475 and rs2376805, were to be They are located exon 1 splice variant altered amino compositions (T126I, C/T, rs2889475, R252Q, G/A, rs2376805). CC genotype carriers showed a four times higher risk than those TT genotype. GG rs2376805 three AA carriers. To knowledge, this is first report demonstrated an association isoform GABA-A receptor increased Our results suggest may indicators functional role

Language: Английский

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Dietary Supplementation of Methyl Donor l‐Methionine Alters Epigenetic Modification in Type 2 Diabetes

Molecular Nutrition & Food Research, Journal Year: 2019, Volume and Issue: 63(23)

Published: Sept. 18, 2019

Scope The aim of the current study is to evaluate whether l ‐methionine supplementation ( ‐Met‐S) improves type 2 diabetes‐induced alterations in glucose and lipid metabolism by modulating one‐carbon methylation status. Methods Results Diabetes induced male Sprague–Dawley rats using high‐fat diet low dose streptozotocin. At end study, various biochemical parameters, immunoblotting, qRT‐PCR ChIP‐qPCR are performed. first evidence that ‐Met‐S activates p‐AMPK SIRT1, very similar “ metformin ,” provided. altered key metabolites diabetic methionine adenosyl transferase 1A cystathione β synthase expression. shows alleviates increase Forkhead transcription factor 1 expression thereby regulating genes involved (G 6pc, Pdk4 , Pklr) Fasn ). Interestingly, inhibits increased DNMT1 also prevents histone H3K36me2 under condition. ChIP assay persistent abundance on promoter region FOXO1 it recovered ‐Met‐S. Conclusion dietary ‐Met epigenetic levels can be therapeutically exploited for treatment metabolic diseases

Language: Английский

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Epigenetic, transcriptional and phenotypic responses in two generations of Daphnia magna exposed to the DNA methylation inhibitor 5-azacytidine

Current Zoology, Journal Year: 2019, Volume and Issue: 5(3)

Published: July 1, 2019

Abstract The water flea Daphnia magna is a keystone species in freshwater ecosystems and has been widely used as model organism environmental ecotoxicology. This aquatic crustacean sensitive to stressors displays considerable plasticity adapting changing conditions. Part of this may be due epigenetic regulation gene expression, including changes DNA methylation histone modifications. Because the generally hypomethylated genome species, we hypothesized that code have an essential role control modifications might early marker for stress. study aims characterize epigenetic, transcriptional phenotypic responses their causal linkages directly exposed adult (F0) peritoneal neonates (F1) after chronic (7-day) exposure sublethal concentration (10 mg/l) 5-azacytidine, well-studied vertebrate inhibitor. Exposure F0 generation significantly reduced cumulative fecundity, accompanied with differential expression genes one-carbon-cycle metabolic pathway. In epigenome generation, decrease global methylation, but no significant on H3K4me3 or H3K27me3, were observed. F1 offspring reduction identified. results indicate during adulthood result more pronounced effects development though interpretation data should carefully done since both regime developmental period different two generations examined. obtained improve our understanding epigenetics tools developed promote use markers hazard assessment stressors.

Language: Английский

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Data-driven study on resting-state functional magnetic resonance imaging during early abstinence of alcohol dependence in male patients and its predictive value for relapse

BMC Psychiatry, Journal Year: 2022, Volume and Issue: 22(1)

Published: Feb. 22, 2022

Abstract Background Alcohol dependence is a mental disorder with high relapse rate. However, specific neuroimaging biomarkers have not been determined for alcohol and its relapse. We conducted data-driven research to investigate resting-state functional magnetic resonance imaging (rs-fMRI) during early abstinence from potential ability predict Methods Participants included 68 alcohol-dependent patients healthy controls (HCs). The regional homogeneity (ReHo) fractional amplitude of low-frequency fluctuations (fALFF) were compared between the group HCs nonrelapse group. brain regions that presented significantly different ReHo and/or fALFF relapsed nonrelapsed selected as seeds calculate connectivities (FCs). Results During 6-month follow-up period, 52.24% relapsed. A regression model differentiating showed reductions in left postcentral region, right fusiform FC region middle cingulum independently associated dependence, an area under receiver operating characteristic curve (AUC) 0.841. baseline precentral cerebellum was lower than AUC this 0.774. Conclusions Our findings contribute advancing on neurobiological etiology predictive dependence.

Language: Английский

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