Cell-Type-Specific Epigenetic Priming of Gene Expression in Nucleus Accumbens by Cocaine
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PROVIDER: PRJNA1136526 | ENA |
REPOSITORIES: ENA
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Project description:A hallmark of addiction is the ability of drugs of abuse to trigger relapse after periods of prolonged abstinence. Here, we describe a novel epigenetic mechanism whereby chronic cocaine exposure causes lasting chromatin and downstream transcriptional modifications in the nucleus accumbens (NAc), a critical brain region controlling motivation. We link prolonged withdrawal from cocaine to the depletion of the histone variant H2A.Z, coupled with increased genome accessibility and latent priming of gene transcription, in D1 dopamine receptor-expressing medium spiny neurons (D1 MSNs) that relate to aberrant gene expression upon drug relapse. The histone chaperone ANP32E removes H2A.Z from chromatin, and we demonstrate that D1 MSN-selective Anp32e knockdown prevents cocaine-induced H2A.Z depletion and blocks cocaine’s rewarding actions. By contrast, very different effects of cocaine exposure, withdrawal, and relapse were found for D2 MSNs. These findings establish histone variant exchange as an important mechanism and clinical target engaged by drugs of abuse to corrupt brain function and behavior.
2024-10-09 | GSE272369 | GEO
Project description:A hallmark of addiction is the ability of drugs of abuse to trigger relapse after periods of prolonged abstinence. Here, we describe a novel epigenetic mechanism whereby chronic cocaine exposure causes lasting chromatin and downstream transcriptional modifications in the nucleus accumbens (NAc), a critical brain region controlling motivation. We link prolonged withdrawal from cocaine to the depletion of the histone variant H2A.Z, coupled with increased genome accessibility and latent priming of gene transcription, in D1 dopamine receptor-expressing medium spiny neurons (D1 MSNs) that relate to aberrant gene expression upon drug relapse. The histone chaperone ANP32E removes H2A.Z from chromatin, and we demonstrate that D1 MSN-selective Anp32e knockdown prevents cocaine-induced H2A.Z depletion and blocks cocaine’s rewarding actions. By contrast, very different effects of cocaine exposure, withdrawal, and relapse were found for D2 MSNs. These findings establish histone variant exchange as an important mechanism and clinical target engaged by drugs of abuse to corrupt brain function and behavior.
2024-10-09 | GSE272458 | GEO
Project description:Cell-Type-Specific Epigenetic Priming of Gene Expression in Nucleus Accumbens by Cocaine [ATAC-seq]
| PRJNA1136908 | ENA
Project description:DNA methylation profiling of nucleus Accumbens of rats that self administered cocaine, were subjected to 30 withdrawal days, were treated with aCSF, RG108 or SAM and were subjected to extinction tests. The groups consist of: 1. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 30 days, were injected in the nucleus accumbens with aCSF and were subjected to an extinction test for assessment of cue-induced cocaine-seeking behavior (aCSF) 2. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 30 days, were injected in the nucleus accumbens with RG108 and were subjected to an extinction test for assessment of cue-induced cocaine-seeking behavior (RG108) 3. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 30 days, were injected in the nucleus accumbens with SAM and were subjected to an extinction test for assessment of cue-induced cocaine-seeking behavior (SAM)
2015-02-27 | E-GEOD-66347 | biostudies-arrayexpress
Project description:Cocaine use disorder (CUD) is a chronic neuropsychiatric condition characterized by a compulsion to use cocaine, resulting from enduring cellular and molecular adaptations. Among substance use disorders (SUDs), CUD is notable for its rising prevalence and the lack of approved pharmacotherapies. The nucleus accumbens (NAc), integral to the brain's reward circuitry, plays a crucial role in the initiation and continuation of maladaptive behaviors intrinsic to CUD. Leveraging advancements in neuroproteomics, we undertook an in-depth proteomic analysis of the NAc in a mouse model that spans membrane, cytosolic, nuclear, and chromatin compartments. Our study unveils immediate and sustained proteomic modifications post-cocaine exposure and during prolonged withdrawal. We identify congruent protein regulatory patterns during initial cocaine exposure and re-exposure post-withdrawal, contrasted against distinct patterns during withdrawal. Pronounced proteomic shifts within the membrane compartment indicate adaptive and long-lasting molecular responses prompted by cocaine withdrawal. Additionally, we describe protein translocation events between soluble-nuclear and chromatin-bound compartments, providing novel insight into intracellular protein dynamics post-cocaine exposure. Together, our findings illuminate the intricate proteomic landscape altered in the NAc by cocaine and provide a comprehensive dataset for future research toward potential therapeutics.
2025-05-06 | PXD050162 | Pride
Project description:Genetic association studies, pharmacological investigations and analysis of mice-lacking individual genes have made it clear that Cocaine administration and Withdrawal have a profound impact on multiple neurotransmitter systems. The GABAergic medium spiny neurons of the nucleus accumbens (NAc) exhibit changes in the expression of genes encoding receptors for glutamate and in the signaling pathways triggered by dopamine binding to G-protein-coupled dopamine receptors. Deep sequence analysis provides a sensitive, quantitative and global analysis of the effects of Cocaine on the NAc transcriptome. RNA prepared from the NAc of adult male mice receiving daily injections of Saline or Cocaine, or Cocaine followed by a period of Withdrawal, was used for high-throughput sequence analysis. Changes were validated by quantitative polymerase chain reaction or Western blot. On the basis of pathway analysis, a preponderance of the genes affected by Cocaine and Withdrawal was involved in the cadherin, heterotrimeric G-protein and Wnt signaling pathways. Distinct subsets of cadherins and protocadherins exhibited a sustained increase or decrease in expression. Sustained down-regulation of several heterotrimeric G-protein β- and γ-subunits was observed. In addition to altered expression of receptors for small molecule neurotransmitters, neuropeptides and endocannabinoids, changes in the expression of plasma membrane transporters and vesicular neurotransmitter transporters were also observed. The effects of chronic Cocaine and Withdrawal on the expression of genes essential to cholinergic, glutamatergic, GABAergic, peptidergic and endocannabinoid signaling are as profound as their effects on dopaminergic transmission. Simultaneous targeting of multiple Withdrawal-specific changes in gene expression may facilitate development of new therapeutic approaches that are better able to prevent relapse. High-throughput sequence analysis of RNA prepared from the nucleus accumbens of adult male mice receiving daily injections of Saline or Cocaine, or Cocaine followed by a period of Withdrawal. Nucleus accumbens libraries were sequenced in nine lanes (three technical replicates per sample) on an Illumina GAIIx using a 37-cycle paired-end sequencing protocol. Replicates were analyzed for intra-sample disparity and read data from all three lanes were then merged into one composite data file per sample; intra-sample coefficient of determination, R2 ≥ 0.98. The composite file was used for subsequent analyses.
2013-01-10 | E-GEOD-43410 | biostudies-arrayexpress
Project description:Prior research demonstrated that environmental enrichment creates individual differences in behavior leading to a protective addiction phenotype in rats. Understanding the mechanisms underlying this phenotype will guide selection of targets for much-needed novel pharmacotherapeutics. The current study investigates basal differences in proteome expression in the nucleus accumbens of enriched and isolated rats and the proteomic response to cocaine self-administration using a liquid chromatography mass spectrometry (LCMS) technique to quantify 1917 proteins. Results of complementary Ingenuity Pathways Analyses (IPA) and gene set enrichment analyses (GSEA) demonstrate that cocaine increases vesicular transporters for dopamine and glutamate, as well as increasing proteins in the RhoA pathway. Further, cocaine regulates proteins related to ERK, CREB and AKT signaling. Environmental enrichment altered expression of a large number of proteins with diverse functions, including mood disorders, energy production, ubiquitination, splicing, transport, kinases and neurodegenerative diseases. Most of the biological functions and pathways listed above were also identified in the Cocaine X Enrichment interaction analysis, providing clear evidence that enriched and isolated rats respond quite differently to cocaine exposure. The overall impression of the current results is that enriched saline-administering rats have a unique proteomic complement compared to enriched cocaine-administering rats as well as saline and cocaine-taking isolated rats. These results identify possible mechanisms of the protective phenotype and provide fertile soil for developing novel pharmacotherapeutics.
2014-07-22 | PXD000990 | Pride
Project description:Gene expression profiling of nucleus Accumbens of rats that self administered cocaine and were subjected to 1 or 30 withdrawal days with or without extinction tests.
2015-02-27 | GSE66349 | GEO
Project description:DNA methylation profiling of nucleus Accumbens of rats that self administered cocaine and were subjected to 1 or 30 withdrawal days with or without extinction tests.
2015-02-27 | GSE66348 | GEO
Project description:Gene expression profiling of nucleus Accumbens of rats that self administered cocaine and were subjected to 1 or 30 withdrawal days with or without extinction tests. The groups consist of 1. Saline rats (Sal.) 2. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 1 day (1W) 3. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 1 day and to an extinction test for assessment of cue-induced cocaine-seeking behavior (1C) 4. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 30 days (30W) 5. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 30 days and to an extinction test for assessment of cue-induced cocaine-seeking behavior (30C)
2015-02-27 | E-GEOD-66349 | biostudies-arrayexpress