Abstinence from Escalation of Cocaine Intake Changes the microRNA Landscape in the Cortico-Accumbal Pathway
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ABSTRACT:
PROVIDER: PRJNA876564 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21412200.fastq.gz | Fastqsanger.gz | |||
| SRR21412300.fastq.gz | Fastqsanger.gz | |||
| SRR21412201.fastq.gz | Fastqsanger.gz | |||
| SRR21412301.fastq.gz | Fastqsanger.gz | |||
| SRR21412202.fastq.gz | Fastqsanger.gz |
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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: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.
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Project description:Environmental enrichment (EE) is a robust intervention for reducing cocaine-seeking behaviors in animals when given during abstinence. However, the mechanisms that underlie these effects have not been well-established. We investigated the adult male rat transcriptome using RNA-sequencing (RNA-seq) following differential housing during abstinence from cocaine self-administration for either 1 or 21 days. Rats housed for 21 days of abstinence in EE displayed a significant reduction in cocaine-seeking behavior compared to rats housed in isolation. RNA-seq of the nucleus accumbens shell revealed hundreds of differentially regulated transcripts between rats of different abstinence length and housing environment, as well as within specific contrasts such as enrichment (isolated 21 days vs. enriched 21 days) or incubation (isolated 1 day vs. isolated 21 days). Ingenuity Pathway Analysis affirmed several pathways as differentially enriched based on housing condition and abstinence length including RELN, the Eif2 signaling pathway, synaptogenesis and neurogenesis pathways. Additionally, multiple pathways reversed their directionality between enrichment and incubation contrasts, potentially indicating oppositional roles across housing and abstinence length. Together, these findings reveal novel mechanisms potentially involved in the protective effects of EE against cocaine seeking, which may inform efforts to develop new pharmacological and gene therapies for treating cocaine use disorders.
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Project description:Striatal microRNA controls cocaine intake through CREB signalling
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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:By using high-density oligonucleotide arrays, we profiled gene expression in reward-related brain regions of rats that developed escalated cocaine intake after extended access to cocaine (6 h per day). Rats allowed restricted daily access to cocaine (only 1 h) that displayed a stable level of cocaine intake and cocaine naive rats were used for controls. Four analysis methods were compared: Affymetrix microarray suite 4 and microarray suite 5, which use perfect-match-minus-mismatch models, and dchip and rma, which use perfect-match-only models to generate expression values. Results were validated by RT-PCR in individual animals from an independent replication of the experiment. A small number of genes was associated with escalated cocaine intake (ESC genes). Unexpectedly, of the brain regions examined [prefrontal cortex, nucleus accumbens, septum, lateral hypothalamus (LH), amygdala, and ventral tegmental area], the LH was the most transcriptionally responsive in escalation of cocaine intake. Most of the ESC genes identified are also expressed during synaptogenesis and synaptic plasticity and include genes that code for several presynaptic and postsynaptic proteins involved in neurotransmission. These results suggest that LH intrinsic circuitry undergoes a structural reorganization during escalation of cocaine use. This remodeling of LH circuitry could contribute to the chronic deficit in reward function that has been hypothesized to drive the transition to drug addiction. Results also support the value of using multiple analysis strategies to identify the most robust changes in gene expression and to compensate for the biases that affect each strategy. Keywords: cocaine addiction
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Project description:Enduring patterns of epigenomic and transcriptional plasticity within the mesolimbic dopamine system contribute importantly to persistent behavioral adaptations that characterize substance use disorders (SUD). While drug addiction has long been thought of as a disorder of dopamine (DA) neurotransmission, therapeutic interventions targeting receptor mediated DA-signaling have not yet resulted in efficacious treatments. Our laboratory recently identified a non-canonical, neurotransmission-independent signaling moiety for DA in brain, termed dopaminylation, whereby DA itself acts as a donor source for the establishment of post-translational modifications (PTM) on substrate proteins (e.g., histone H3 at glutamine 5; H3Q5dop). In our previous studies, we demonstrated that H3Q5dop plays a critical role in the regulation of neuronal transcription and, when perturbed within monoaminergic neurons of the ventral tegmental area (VTA), critically contribute to pathological states, including relapse vulnerability to both psychostimulants (e.g., cocaine) and opiates (e.g., heroin). Importantly, H3Q5dop is also observed throughout the mesolimbic DA reward pathway (e.g., in nucleus accumbens/NAc and medial prefrontal cortex/mPFC, which receive DA input from VTA). As such, we investigated whether H3Q5dop may similarly be altered in its expression in response to drugs of abuse in these non-dopamine-producing regions. In rats undergoing extended abstinence from cocaine self-administration (SA), we observed both acute and prolonged accumulation of H3Q5dop in NAc, but not mPFC. Attenuation of H3Q5dop in NAc during drug abstinence reduced cocaine-seeking and affected cocaine-induced gene expression programs associated with altered dopamine signaling and neuronal function. These findings thus establish H3Q5dop in NAc, but not mPFC, as an important mediator of cocaine-induced behavioral and transcriptional plasticity during extended cocaine abstinence.
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Project description:By using high-density oligonucleotide arrays, we profiled gene expression in reward-related brain regions of rats that developed escalated cocaine intake after extended access to cocaine (6 h per day). Rats allowed restricted daily access to cocaine (only 1 h) that displayed a stable level of cocaine intake and cocaine naive rats were used for controls. Four analysis methods were compared: Affymetrix microarray suite 4 and microarray suite 5, which use perfect-match-minus-mismatch models, and dchip and rma, which use perfect-match-only models to generate expression values. Results were validated by RT-PCR in individual animals from an independent replication of the experiment. A small number of genes was associated with escalated cocaine intake (ESC genes). Unexpectedly, of the brain regions examined [prefrontal cortex, nucleus accumbens, septum, lateral hypothalamus (LH), amygdala, and ventral tegmental area], the LH was the most transcriptionally responsive in escalation of cocaine intake. Most of the ESC genes identified are also expressed during synaptogenesis and synaptic plasticity and include genes that code for several presynaptic and postsynaptic proteins involved in neurotransmission. These results suggest that LH intrinsic circuitry undergoes a structural reorganization during escalation of cocaine use. This remodeling of LH circuitry could contribute to the chronic deficit in reward function that has been hypothesized to drive the transition to drug addiction. Results also support the value of using multiple analysis strategies to identify the most robust changes in gene expression and to compensate for the biases that affect each strategy. Experiment Overall Design: The experimental design for this study comprised three groups of rats (n = 8) with different daily access to a continuous schedule of i.v. cocaine self-administration (0.25 mg per injection): 0 h access per day (drug-naive control rats), 1 h access per day (ShA rats), or 6 h access per day (LgA rats). Experiment Overall Design: Gene expression profiling was then performed for each dissected brain region by using Affymetrix rat neurobiology arrays.
2007-10-10 | E-GEOD-3016 | biostudies-arrayexpress
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