Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214267 | GEO | 2022/12/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Genome-wide DNA methylation profile in the peripheral blood of cocaine and crack dependents

Project description:Objective: Cocaine use disorders (CUD) represent a major public health problem in many countries. To better understand the interaction between the environmental modulations and phenotype, the aim of the present study was to investigate the DNA methylation pattern of CUD patients, which were concomitant dependents of cocaine and crack, and healthy controls. Methods: We studied DNA methylation profiles in the peripheral blood of 23 CUD patients and 24 healthy control subjects using the Illumina Infinium HumanMethylation450 BeadChip arrays. Results: Comparison between CUD patients and controls revealed 186 differentially methylated positions (DMPs, adjP<10-5) related to 152 genes, with a subset of CpGs confirmed by pyrosequencing. DNA methylation patterns discriminated CUD patients and control groups. A gene network approach showed that EHMT1, EHMT2, MAPK1, MAPK3, MAP2K1 and HDAC5 genes, which are involved in transcription and chromatin regulation cellular signaling pathways, were also associated with cocaine dependence. Conclusion: The investigation of DNA methylation patterns in CUD patients may contribute to a better understanding of the biological mechanisms involved in cocaine use disorders.

2019-06-30 | GSE77056 | GEO

Heightened Cocaine-Seeking in Male Rats Associates with a Distinct Transcriptomic Profile in the Medial Prefrontal Cortex

Project description:Drug overdose deaths involving cocaine have skyrocketed, an outcome attributable in part to the lack of FDA-approved medications for the treatment of cocaine use disorder (CUD), highlighting the need to identify new pharmacotherapeutic targets. Vulnerability to cocaine-associated environmental contexts and stimuli serves as a risk factor for relapse in CUD recovery, with individual differences evident in the motivational aspects of these cues. The medial prefrontal cortex (mPFC) provides top-down control of striatal circuitry to regulate the incentive-motivational properties of cocaine-associated stimuli. Clinical and preclinical studies have identified genetic variations that impact the degree of executive restraint over drug-motivated behaviors, and we designed the present study to employ next-generation sequencing to identify specific genes associated with heightened cue-evoked cocaine-seeking in the mPFC of male, outbred rats. Rats were trained to stably self-administer cocaine, and baseline cue-reinforced cocaine-seeking was established. Rats were phenotyped as either high cue (HC) or low cue (LC) responders based upon lever pressing for previously associated cocaine cues and allowed 10 days of abstinence in their home cages prior to mPFC collection for RNA-sequencing. The expression of 309 genes in the mPFC was significantly different in HC vs. LC rats. Functional gene enrichment analyses identified ten biological processes that were overrepresented in the mPFC of HC vs. LC rats. The present study identifies distinctions in mPFC mRNA transcripts that characterizes individual differences in relapse-like behavior and provides prioritized candidates (i.e., Htr2c, Adora2a, Drd2) for future pharmacotherapeutics aimed to help maintain abstinence in CUD.

2022-12-09 | GSE196374 | GEO

Peripheral gene expression in cocaine use disorders with low and high anhedonia

Project description:Treatments for Cocaine Use Disorder (CUD) are variably effective, and there are no FDA-approved medications. One approach to developing new treatments for CUD may be to investigate and target poor prognostic signs. One such sign is anhedonia (i.e. a loss of pleasure or interest in non-drug rewards), which predicts worse outcomes in existing CUD treatments. Inflammation is thought to underlie anhedonia in many other disorders, but the relationship between anhedonia and inflammation has not been investigated in CUD. Therefore, we assessed peripheral genome-wide gene expression in n = 48 individuals with CUD with high (n=24) vs. low (n = 24) levels of anhedonia, defined by a median split of self-reported anhedonia. Our hypothesis was that individuals with high anhedonia would show differential gene expression in inflammatory pathways. No individual genes were significantly different between the low and high anhedonia groups when using t-tests with a stringent false discovery rate correction. However, an exploratory analysis identified 166 loci where t-tests suggested group differences at a nominal p < 0.05. We used DAVID, a bioinformatics tool that provides functional interpretations of complex lists of genes, to examine representation of this gene list in known pathways. It confirmed that mechanisms related to immunity were the top significant associations with anhedonia in the sample. Further, the two top differentially expressed genes in our sample, IRF1 and GBP5, both have primary inflammation and immune functions, and were significantly negatively correlated with total scores on our self-report of anhedonia across all 48 subjects. These results suggest that prioritizing development of anti-inflammatory medications for CUD may pay dividends, particularly in combination with treatment-matching strategies using either phenotypic measures of anhedonia or biomarkers of inflammatory gene expression to individualize treatment.

2018-11-02 | GSE116833 | GEO

Epigenome-wide association study of cocaine use disorder in postmortem human brain tissue

Project description:Analysis of cocaine use disorder (CUD) associated epigenome-wide DNA methylation (DNAm) alterations in human postmortem brain tissue of Brodmann Area 9. Tissue samples from N=21 CUD cases and N=21 individuals without CUD originating from the Douglas Bell Canada Brain Bank (DBCBB) were included. Epigenome-wide DNAm was investigated using the Illumina Infinium MethylationEPIC array.

| EGAD00010002396 | EGA

Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models

Project description:Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models

| PRJNA884679 | ENA

Cocaine self-administration induces divergent protein expression in the nucleus accumbens of male and female mice to eliminate basal sex differences

Project description:Substance use disorder (SUD) is a chronic neuropsychiatric condition characterized by long-lasting alterations in the neural circuitry regulating reward and motivation. Substantial work has focused on characterizing the molecular substrates which underlie these persistent changes in neural function and behavior; however, this work has overwhelmingly focused on male subjects, despite mounting clinical and preclinical evidence that females demonstrate dissimilar progression to SUD and responsivity to drugs of abuse, such as cocaine. Here, we show that sex is a critical biological variable that defines drug-induced plasticity in the NAc. Using quantitative mass spectrometry, we assessed the protein expression patterns altered by cocaine self-administration and demonstrate unique molecular profiles between males and females. We show that 1. Cocaine self-administration induces non-overlapping protein expression patterns in males and females and 2. Cocaine specifically acts on baseline sexual dimorphisms to exert these effects. Critically, we find that cocaine administration blunts not only basal sex-differences in the accumbens proteome, but also the pre-existing sex differences in behavior for natural rewards. Together, these data suggest that chronic cocaine is capable of rewriting baseline proteomic function to maintain cocaine-specific behaviors.

2021-09-09 | PXD022832 | Pride

Circuit-wide gene network analysis reveals sex-specific roles for phosphodiesterase enzymes in cocaine addiction

Project description:Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms in the brain that underly long-lasting maladaptive plasticity and addiction-like behaviors. In this study, we leverage a large RNA-sequencing dataset to generate gene co-expression networks across 6 interconnected regions of the brain’s reward circuitry from mice that underwent saline or cocaine self-administration, followed by a 24-hour or 30-day withdrawal period and a saline or cocaine challenge. We identify phosphodiesterase 1b (Pde1b), a Ca2+/calmodulin-dependent enzyme that catalyzes the hydrolysis of cAMP and cGMP, as one of the top hub genes within a nucleus accumbens (NAc) gene module that was bioinformatically associated with addiction-like behavior. Within Drd1- and Drd2-expressing medium spiny neurons (D1 and D2 MSNs) in the NAc, we found that chronic cocaine selectively upregulates Pde1b expression in D2 MSNs. Using a virus-mediated overexpression approach, we demonstrate that Pde1b in the NAc influences cocaine self-administration behavior, locomotor responses, electrophysiological properties of MSNs, and cocaine-induced transcriptomic adaptations in a cell-type- and sex-dependent manner. Together, we identify novel gene modules across the brain’s reward circuitry associated with addiction-like behavior and explore the role of Pde1b in regulating the molecular, cellular, and behavioral response to cocaine.

2024-04-19 | GSE244767 | GEO

Cocaine-regulated expression of striatal microRNAs

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

Microbial short-chain fatty acids regulate drug seeking and transcriptional control in a model of cocaine seeking.

Project description:Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an FR1 schedule. However, microbiome-depleted subjects exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.

2024-05-01 | GSE227980 | 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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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