Striatal microRNA controls cocaine intake through CREB signalling
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PROVIDER: PRJNA126865 | ENA |
REPOSITORIES: ENA
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Project description:MicroRNAs (miRNAs) regulate many basic aspects of cell biology including neuronal plasticity, but little is known of their roles in drug addiction. Extended access to cocaine can trigger the emergence of compulsive drug-seeking behaviors, but molecular mechanisms regulating this process remain unclear. Here we report that microRNA-212 (miR-212) is upregulated in the dorsal striatum of rats with extended access to cocaine. Striatal overexpression of miR-212 decreases, whereas its inhibition increases cocaine intake in rats with extended but not restricted drug access, suggesting that miR-212 serves as a protective factor against the development of compulsive drug seeking. The transcription factor CREB (cAMP response element-binding protein) is considered a core regulator of cocaine reward. We show that miR-212 controls responsiveness to cocaine by dramatically amplifying striatal CREB signaling. This action occurs through miR-212-enhanced Raf-1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential CREB co-activator TORC (Transducer of Regulated CREB; also known as CRTC). Our findings suggest that striatal miR-212 signaling plays a key role in vulnerability to addiction, and that noncoding RNAs such as the miRNAs may serve as novel targets for the development of anti-addiction therapeutics. To identify potential targets for miR-212, we transfected cells with a vector to overexpress miR-212 or an empty vector. We then analyzed profiled gene expression using Affymetrix arrays.
2010-07-08 | GSE21901 | GEO
Project description:MicroRNAs (miRNAs) regulate many basic aspects of cell biology including neuronal plasticity, but little is known of their roles in drug addiction. Extended access to cocaine can trigger the emergence of compulsive drug-seeking behaviors, but molecular mechanisms regulating this process remain unclear. Here we report that microRNA-212 (miR-212) is upregulated in the dorsal striatum of rats with extended access to cocaine. Striatal overexpression of miR-212 decreases, whereas its inhibition increases cocaine intake in rats with extended but not restricted drug access, suggesting that miR-212 serves as a protective factor against the development of compulsive drug seeking. The transcription factor CREB (cAMP response element-binding protein) is considered a core regulator of cocaine reward. We show that miR-212 controls responsiveness to cocaine by dramatically amplifying striatal CREB signaling. This action occurs through miR-212-enhanced Raf-1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential CREB co-activator TORC (Transducer of Regulated CREB; also known as CRTC). Our findings suggest that striatal miR-212 signaling plays a key role in vulnerability to addiction, and that noncoding RNAs such as the miRNAs may serve as novel targets for the development of anti-addiction therapeutics. To identify potential targets for miR-212, we transfected cells with a vector to overexpress miR-212 or an empty vector. We then analyzed profiled gene expression using Affymetrix arrays. Human Affymetrix Study: Cells were transfected with a vector to overexpress miR-212 or an empty vector. We then analyzed profiled gene expression using Affymetrix arrays. The complete, unfiltered set of signal intensity data for Samples miR-212 and pMIF, including miR-212/pMIF ratios, are in the supplementary file at the foot of the record. Probes excluded from analysis (pMIF intensity <100) are indicated in the supplementary file by a no in the far-right column, 'Passed data filtering and included in analysis: no/yes'. Probes that were included in the analyses (pMIF intensity >100) are indicated in the supplementary file by a yes in the 'Passed data filtering and included in analysis: no/yes' column. Rat miRNA Study: Rats were permitted access to intravenous cocaine self-administration (0.5 mg/kg/infusion) for 7 consecutive days during restricted (1-h) or extended (6-h) daily sessions. Control rats remained coaine-naïve throughout. 24-h after the last session the dorsal striatum from each rats was removed, and RNA extracted for microarray profiling. There was a total of n=6 rats per access condition. RNA from 2 rats per access condition were pooled on to arrays, for a total of 3 arrays per access condition, and 9 arrays in total.
2010-07-08 | E-GEOD-21901 | biostudies-arrayexpress
Project description: Not available
| S-EPMC2916751 | biostudies-literature
Project description:We cataloged miRNA expression in the nucleus accumbens and at striatal synapses in control and chronically cocaine-treated mice. We identified cocaine-responsive miRNAs, synaptically-enriched and depleted miRNA families, and confirmed cocaine-induced changes in protein expression for several predicted synaptic target genes. Analysis of small RNA from Mus musculus nucleus accumbens (NAc) and postsynaptic densities (PSD) with and without chronic cocaine treatment.
2011-05-13 | E-GEOD-29261 | biostudies-arrayexpress
Project description:We cataloged miRNA expression in the nucleus accumbens and at striatal synapses in control and chronically cocaine-treated mice. We identified cocaine-responsive miRNAs, synaptically-enriched and depleted miRNA families, and confirmed cocaine-induced changes in protein expression for several predicted synaptic target genes.
2011-05-13 | GSE29261 | GEO
Project description:Cocaine use disorder (CUD) is an intractable syndrome, and rising overdose death rates represent a significant public health crisis that exacts tremendous personal and financial costs on patients and society. Sharp increases in cocaine use drive the urgent need for better mechanistic insight into this chronic relapsing brain disorder that currently lacks effective treatment options. To investigate the transcriptomic changes involved, we conducted RNA sequencing on two striatal brain regions that are heavily implicated in CUD, the nucleus accumbens and caudate nucleus, from postmortem brains of subjects with CUD and matched control subjects. Weighted gene co-expression analyses identified CUD-specific gene networks enriched in ionotropic receptors and associated with lowered neuroinflammation, contrasting the proinflammatory responses found in opioid use disorder. Integration of comprehensive transcriptomic datasets from mouse cocaine self-administration models revealed evolutionarily conserved gene networks in CUD that implicate especially D1 medium spiny neurons as drivers of cocaine-induced plasticity.
2022-12-19 | GSE214267 | GEO
Project description:Ablation of the Creb1 gene in forebrain neurons was performed using the Cre/loxP system, with the recombinase expressed from the Camk2alfa promoter. Mice were crossed into the Crem KO background to prevent compensation of CREB loss by CREM overexpression. Our goal was to analyze how loss of CREB will affect acitivity-regulated transcription induced by strong stimulation, i.e. cocaine. Keywords: Treatment x Genotype
2008-04-03 | GSE8948 | GEO
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
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:Changes in gene expression contribute to the long-lasting regulation of the brain's reward circuitry seen in drug addiction, however, the specific genes regulated and the transcriptional mechanisms underlying such regulation remain poorly understood. Here, we used chromatin immunoprecipitation coupled with promoter microarray analysis to characterize genome-wide epigenetic changes in the mouse nucleus accumbens, a crucial brain reward region, after repeated cocaine administration. Our findings reveal several interesting principles of gene regulation by cocaine and of the role of Î?FosB and CREB, two prominent cocaine-induced transcription factors, in this brain region. Mice were treated with cocaine or saline. Chromatin immunoprecipitation was performed for methylated histone H3 lysine 9 and 27, â??FosB, and phospho-CREB as described previously (Kumar et al., 2005) with minor modifications. Immunoprecipitated DNA was amplified via ligation-mediated PCR and hybridized to Nimblgen mouse MM8 promoter arrays. 2-3 biological replicates per condition.
2010-05-18 | E-GEOD-16184 | biostudies-arrayexpress