Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes.

ABSTRACT: Endogenous homeostatic mechanisms can restore normal neuronal function following cocaine-induced neuroadaptations. Such mechanisms may be exploited to develop novel therapies for cocaine addiction, but a molecular target has not yet been identified. Here we profiled mouse gene expression during early and late cocaine abstinence to identify putative regulators of neural homeostasis. Cocaine activated the transcription factor, Nr4a1, and its target gene, Cartpt, a key molecule involved in dopamine metabolism. Sustained activation of Cartpt at late abstinence was coupled with depletion of the repressive histone modification, H3K27me3, and enrichment of activating marks, H3K27ac and H3K4me3. Using both CRISPR-mediated and small molecule Nr4a1 activation, we demonstrate the direct causal role of Nr4a1 in sustained activation of Cartpt and in attenuation of cocaine-evoked behavior. Our findings provide evidence that targeting abstinence-induced homeostatic gene expression is a potential therapeutic target in cocaine addiction.

ORGANISM(S): Mus musculus

PROVIDER: GSE141520 | GEO | 2019/12/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Abstinence from Escalation of Cocaine Intake Changes the microRNA Landscape in the Cortico-Accumbal Pathway

Project description:Cocaine administration alters the microRNA (miRNA) landscape in the cortico-accumbal pathway. These changes in miRNA can play a major role in the posttranscriptional regulation of gene expression during withdrawal. This study aimed to investigate the changes in microRNA expression in the cortico-accumbal pathway during acute withdrawal and protracted abstinence following escalated cocaine intake. Small RNA sequencing (sRNA-seq) was used to profile miRNA transcriptomic changes in the cortico-accumbal pathway [infralimbic- and prelimbic-prefrontal cortex (IL and PL) and nucleus accumbens (NAc)] of rats with extended access to cocaine self-administration followed by an 18-h withdrawal or a 4-week abstinence. An 18-h withdrawal led to differential expression (fold-change > 1.5 and p < 0.05) of 21 miRNAs in the IL, 18 miRNAs in the PL, and two miRNAs in the NAc. The mRNAs potentially targeted by these miRNAs were enriched in the following pathways: gap junctions, neurotrophin signaling, MAPK signaling, and cocaine addiction. Moreover, a 4-week abstinence led to differential expression (fold-change > 1.5 and p < 0.05) of 23 miRNAs in the IL, seven in the PL, and five miRNAs in the NAc. The mRNAs potentially targeted by these miRNAs were enriched in pathways including gap junctions, cocaine addiction, MAPK signaling, glutamatergic synapse, morphine addiction, and amphetamine addiction. Additionally, the expression levels of several miRNAs differentially expressed in either the IL or the NAc were significantly correlated with addiction behaviors. Our findings highlight the impact of acute and protracted abstinence from escalated cocaine intake on miRNA expression in the cortico-accumbal pathway, a key circuit in addiction, and suggest developing novel biomarkers and therapeutic approaches to prevent relapse by targeting abstinence-associated miRNAs and their regulated mRNAs.

2023-08-30 | GSE212651 | GEO

Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes.

Project description:Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes.

| PRJNA593775 | ENA

A single-cell atlas of gene expression and chromatin accessibility changes associated with cocaine addiction in the rat amygdala (snATAC-Seq Multiome)

Project description:The amygdala plays a key role in the negative emotional states associated with the relapse to drug seeking behavior. Neuroanatomical and functional observations have uncovered the role of discrete amygdala subregions in different aspects of these negative affective states. However, the underlying transcriptional regulatory programs driving the function of distinct amygdala cell types remains unknown. We generated an atlas of single nucleus gene expression and chromatin accessibility in the amygdala of rats with low and high cocaine addiction-like behaviors after prolonged abstinence from extended access to cocaine intravenous self-administration. We identified thousands of cell type-specific differentially expressed genes, suggesting that negative affective states are associated with cell type-specific mechanisms which are enriched for molecular pathways, including energy metabolism and GABAergic synapses in excitatory and somatostatin neurons. We demonstrate that higher addiction severity is linked to excessive GABAergic inhibition and, using pharmacological inhibition, we find that addiction-like phenotypes are regulated by the metabolite methylglyoxal which is an agonist at GABA-A receptors. By analyzing differences in chromatin accessibility, we predict upstream transcriptional regulators associated with addiction-like behavior and find discordant regulation of key transcription factors among distinct cell populations. Overall, we provide a comprehensive characterization of cell type-specific transcriptional changes in the amygdala during protracted abstinence and use these insights to identify a novel target for pharmacological intervention.

2023-08-09 | GSE235317 | GEO

A single-cell atlas of gene expression and chromatin accessibility changes associated with cocaine addiction in the rat amygdala [snRNA-seq]

2023-08-09 | GSE212415 | GEO

A single-cell atlas of gene expression and chromatin accessibility changes associated with cocaine addiction in the rat amygdala (snRNA-Seq Multiome)

2023-08-09 | GSE235314 | GEO

A single-cell atlas of gene expression and chromatin accessibility changes associated with cocaine addiction in the rat amygdala [snATAC-seq]

2023-08-09 | GSE212416 | GEO

Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration

Project description:Many studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence. Persistent changes in gene expression, as well as alterations induced during abstinence may underlie long-lasting drug craving and relapse liability. Results: Whole-genome expression analysis was conducted on a rat cocaine binge-abstinence model that has previously been demonstrated to engender increased drug seeking and taking with abstinence. Gene expression changes in two mesolimbic terminal fields (mPFC and NAc) were identified in a comparison of cocaine-naïve rats with rats after 10 days of cocaine selfadministration followed by 1, 10, or 100 days of enforced abstinence (n=6-11 per group). A total of 1,461 genes in the mPFC and 414 genes in the NAc were altered between at least two time points (ANOVA, p<0.05; ±1.4 fold-change). These genes can be subdivided into: 1) changes with cocaine self-administration that do not persist into periods of abstinence, 2) changes with cocaine self-administration that persist with abstinence, 3) and those not changed with cocaine self-administration, but changed during enforced abstinence. qPCR analysis was conducted to confirm gene expression changes observed in the microarray analysis.

2010-03-16 | GSE20885 | GEO

Dopaminylation of Histone H3 in Ventral Tegmental Area Regulates Cocaine-seeking

Project description:Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in VTA. By reducing H3Q5dop in VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated cue-induced dopamine release in nucleus accumbens and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in VTA.

2020-05-19 | GSE124055 | GEO

Histone Arginine Methylation in Cocaine Action: Essential Role of Src Signaling in the Nucleus Accumbens

Project description:Despite addiction being one of the most prevalent and debilitating disorders worldwide, effective treatments are lacking. Repeated cocaine exposure induces maladaptive transcriptional regulation within the brainâ??s reward circuitry, such as the nucleus accumbens (NAc), and epigenetic mechanisms, such as histone acetylation or methylation on Lys (K) residues, have been linked to these lasting actions of cocaine. However, in contrast to K methylation, the functional role of histone Arg (R) methylation remains unexplored in addiction models and poorly understood in brain in general. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, as well as in the NAc of cocaine-addicted humans. PRMT6 downregulation occurs selectively in NAc medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we demonstrate that reduced H3R2me2a binding at gene targets in NAc after repeated cocaine is strongly correlated with increased binding of H3K4me3, and identify Src kinase signaling inhibitor 1 (Srcin1 or p140Cap) as a key gene for these chromatin modifications. Cocaine induction of Srcin1 in NAc, which is associated with reduced Src signaling, decreases cocaine reward, the motivation to self administer cocaine, and cocaine-induced changes in NAc MSN dendritic spines. These results suggest that this suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a downregulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of new treatments for cocaine addiction. H3R2me2A ChIP-seq of mouse. Cocaine vs Saline, 3 biological replicates.

2016-08-08 | E-GEOD-85310 | biostudies-arrayexpress

3’ RNA-seq of five brain structures after repeated exposure to cocaine

Project description:At the core of addiction, drug experiences induce circuit-specific transcriptional adaptations to hijack the native mechanisms of neuroplasticity and promote maladaptive behaviors. In the present study, we utilized 3’-RNA-sequencing to define the transcriptional landscapes of five brain nuclei within the reward circuit following distinct cocaine experiences. We exposed mice to cocaine (20 mg/kg, IP), acutely (single exposure), repeatedly (5 daily exposures) as well as to a challenge cocaine (acute exposure after 21 days of abstinence following repeated cocaine). We then profiled transcription (applying 3’-RNAseq) within key brain structures of the reward circuitry: limbic cortex- medial prefrontal and cingulate together (LCtx), nucleus accumbens (NAc), dorsal striatum (DS), amygdala (Amy), and lateral hypothalamus (LH) at 0, 1, 2, 4 hrs following cocaine exposure.

2021-04-14 | GSE158588 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data