Environmental enrichment during abstinence from cocaine self-administration opposes gene network expression changes associated with the incubation effect
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ABSTRACT:
PROVIDER: PRJNA604189 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10994811.fastq.gz | Fastqsanger.gz | |||
| SRR10994812.fastq.gz | Fastqsanger.gz | |||
| SRR10994813.fastq.gz | Fastqsanger.gz | |||
| SRR10994814.fastq.gz | Fastqsanger.gz | |||
| SRR10994815.fastq.gz | Fastqsanger.gz |
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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.
2020-07-15 | GSE144606 | 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.
2010-03-16 | GSE20885 | GEO
Project description:Environmental enrichment (EE) is a robust intervention for reducing cocaine-seeking behaviors in animals when given during forced abstinence. However, the mechanisms that underlie these effects are not well-established. We investigated the adult male rat transcriptome using RNA-sequencing (RNA-seq) following differential housing during forced abstinence from cocaine self-administration for either 1 or 21 days. Enriched, 21-day forced abstinence rats 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 forced 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 forced abstinence length including RELN, the Eif2 signaling pathway, synaptogenesis and neurogenesis pathways. Numerous pathways showed upregulation with incubation, but downregulation with EE, suggesting that EE may prevent or reverse changes in gene expression associated with protracted forced abstinence. The findings reveal novel candidate mechanisms involved in the protective effects of EE against cocaine seeking, which may inform efforts to develop pharmacological and gene therapies for treating cocaine use disorders. Furthermore, the finding that EE opposes multiple pathway changes associated with incubation of cocaine seeking strongly supports EE as a therapeutic intervention and suggests EE is capable of preventing or reversing the widespread dysregulation of signaling pathways that occurs during cocaine forced abstinence.
| S-EPMC7347882 | biostudies-literature
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:Childhood maltreatment is associated with increased severity of substance use disorder and frequency of relapse to drug use following abstinence. However, the molecular and neurobiological substrates engaged during early traumatic events and mediating the relapse risk are poorly understood. Here, we show that the exposure to an adverse/hostile social experience in juvenile mice (social stressed mice, SS) influences the propensity to reinstate cocaine seeking after withdrawal periods. This effect is associated with an increased blood coagulation and a pauperization of brain vasculature. Moreover, a treatment with an anticoagulant agent during withdrawal abolishes the susceptibility to reinstate cocaine seeking in SS mice. These findings for the first time propose a molecular mechanism contributing to the increased susceptibility to relapse into cocaine abuse observed in individuals who had experienced childhood maltreatment. To analyze global gene expression differences between mice experiencing an hostile/adverse social environment during the third postnatal week and juvenile social isolated (SI) mice during cocaine abstinence. Peripheral Blood Mononuclear Cells were measured with Agilent mouse gene expression microarray during cocaine abstince after undergoing cocaine-seeking behavior studies by conditioned place preference test, extinction and withdrawal. Blood was collected 24 hours after the extinction test and genome-wide
2015-11-15 | GSE69019 | GEO
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.
2023-06-14 | GSE221177 | GEO
Project description: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.
2019-12-05 | GSE141520 | GEO
Project description:MicroRNAs are “master regulators” of gene expression. To investigate microRNAs involved in the incentive motivation for cocaine elicited by exposure to cocaine-associated cues, we conducted NanoString nCounter analyses of microRNA expression in the nucleus accumbens shell of male rats that had been tested for cue reactivity in a previous study. These rats had been trained to self-administer cocaine while living in isolate housing, then during a subsequent 21-day forced abstinence period they either stayed under isolate housing or switched to environmental enrichment (EE), as this EE intervention is known to decrease cocaine seeking. This allowed us to create groups of “high” and “low” cocaine seekers using a median split of cocaine-seeking behavior. We conducted a differential expression analysis across these two groups that identified 33 miRNAs that were differentially altered in the nucleus accumbens shell. Predicted mRNA targets of these microRNAs are implicated in synaptic plasticity and neuronal signaling. Some of these microRNAs have previously been implicated in substance use disorders, while others are predicted to target large numbers of cocaine-related genes. Of the 33 differentially expressed microRNAs, 8 were specifically downregulated in the low-seeking group and another set of 8 had expression levels that were significantly correlated with cocaine-seeking. These findings suggest that processes involved in cocaine-seeking behavior may alter, or be altered by, multiple microRNAs. Further research examining the mechanisms involved in these microRNA changes and their effects on signaling may reveal novel therapeutic targets for attenuating drug craving.
2020-12-25 | GSE153524 | GEO
Project description:Abstract Background Psychostimulant use disorder is a major public health issue, and despite the scope of the problem there are currently no FDA approved treatments. There would be tremendous utility in development of a treatment that could help patients both achieve and maintain abstinence. Previous work from our group has identified granulocyte-colony stimulating factor (G-CSF) as a neuroactive cytokine that alters behavioral response to cocaine, increases synaptic dopamine release, and enhances cognitive flexibility. Here, we investigate the role of G-CSF in affecting extinction and reinstatement of cocaine-seeking and perform detailed characterization of its proteomic effects in multiple limbic substructures. Methods Sprague-Dawley rats were injected with PBS or G-CSF during (1) extinction or (2) abstinence from cocaine self-administration, and drug seeking behavior was measured. Quantitative assessment of changes in the proteomic landscape in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were performed via data-independent acquisition (DIA) mass spectrometry analysis. Results Administration of G-CSF during extinction accelerated the rate of extinction, and administration during abstinence attenuated cue-induced cocaine-seeking. Analysis of global protein expression demonstrated that G-CSF regulated proteins primarily in mPFC that are critical to glutamate signaling and synapse maintenance. Conclusion Taken together, these findings support G-CSF as a viable translational research target with the potential to reduce drug craving or seeking behaviors. Importantly, recombinant G-CSF exists as an FDA-approved medication which may facilitate rapid clinical translation. Additionally, using cutting-edge multi-region discovery proteomics analyses, these studies identify a novel mechanism underlying G-CSF effects on behavioral plasticity.
2021-01-28 | PXD019485 | 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. 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