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MiR-218 regulates heroin seeking behavior by targeting Mecp2

ABSTRACT: Noncoding RNAs, especially microRNAs (miRNAs) have been implicated in the regulation of neuronal functions, such as learning, cognition and memory formation. However, the particular miRNAs involved in drug-induced behavioral plasticity are largely unknown. Here we report a novel regulator, miR-218, that inhibits heroin-induced behavioral plasticity. Network propagation-based method revealed several miRNAs that play key roles in drug-addiction, among which, miR-218 was decreased in nucleus accumbens (NAc) after chronic exposure to heroin. Lentiviral overexpression of miR-218 in NAc could inhibit heroin-induced reinforcement in both conditioning place preference (CPP) test and heroin self-administration (SA) experiment. Luciferase activity assay indicated miR-218 could regulate neuroplasticity related genes and directly target Mecp2 3’UTR. Consistently, Mecp2-/y mice exhibited reduced heroin seeking behavior in CPP test. These data reveal a functional role of miR-218 and its target, Mecp2, in the regulation of heroin-induced behavioral plasticity.

ORGANISM(S): synthetic construct Rattus norvegicus

PROVIDER: GSE89202 | GEO | 2017/03/08

SECONDARY ACCESSION(S): PRJNA350673

REPOSITORIES: GEO

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Rattus norvegicus

Project description:MiR-218 regulates heroin seeking behavior by targeting Mecp2

| PRJNA350673 | ENA

Chromatin accessibility underlies cell-type specific programs of amphetamine-regulated gene expression in Nucleus Accumbens interneurons [ATAC-Seq]

Project description:Parvalbumin-expressing (PV+) interneurons of the nucleus accumbens (NAc) play an essential role in the addictive-like behaviors induced by psychostimulant exposure. To identify molecular mechanisms of PV+ neuron plasticity, we isolated interneuron nuclei from the NAc of male and female mice following acute or repeated exposure to amphetamine (AMPH) and sequenced for cell type-specific RNA expression and chromatin accessibility. AMPH regulated the transcription of hundreds of genes in PV+ interneurons, and this program was largely distinct from that regulated in other NAc GABAergic neurons. Chromatin accessibility at enhancers predicted cell-type specific gene regulation, identifying transcriptional mechanisms of differential AMPH responses. Finally, we observed dysregulation of multiple PV-specific, AMPH-regulated genes in an Mecp2 mutant mouse strain that shows heightened behavioral sensitivity to psychostimulants, suggesting the functional importance of this transcriptional program. Together these data provide novel insight into the cell-type specific programs of transcriptional plasticity in NAc neurons that underlie addictive-like behaviors.

2021-08-06 | GSE181420 | GEO

Chromatin accessibility underlies cell-type specific programs of amphetamine-regulated gene expression in Nucleus Accumbens interneurons [Nuclear and Ribo-tag RNA-seq]

2021-08-06 | GSE181419 | GEO

Chromatin accessibility underlies cell-type specific programs of amphetamine-regulated gene expression in Nucleus Accumbens interneurons [SingleNucleus-RNA-seq]

2021-08-06 | GSE181399 | GEO

L-methionine counteracts cocaine-conditioned place preference in mice through Glutamatergic plasticity pathways

Project description:Drug-induced alterations in gene expression play an important role in the development of addictive behavior. Methionine has been proven to inhibit addictive behaviors of cocaine dependence. However, the mechanisms underlying how methionine use corresponds to drug-induced behaviors still remain unclear. We performed mRNA and miRNA high-throughput sequencing of the prefrontal cortex in a mouse model of cocaine CPP combined with L-methionine in order to identify L-methionine target miRNAs and genes that participate in the cocaine conditioned place preference (CPP). We found that the L-methionine inhibits cocaine CPP. Sequencing data analysis showed that L-methionine down-regulates genes enriched in the Glutamatergic Synapse pathways and significantly reversed the cocaine-induced expression changes of the substance dependence pathways (Morphine addiction and Nicotine addiction) and the neurotransmitter synapse pathways (Glutamatergic Synapse, Cholinergic Synapse and GABAergic Synapse). Furthermore, the Glutamatergic synapse was either overlapped between DEGs with DEGs-miRNA induced by cocaine CPP, or with the MET effects on cocaine CPP. Nineteen targeted genes were investigated and five were identified (Gria4, Grid1, Grik4, Grik5 and Grin3a) to belong to iGluR family. Interestingly, there were several miRNAs that had the same sequence which targets the iGluR family: Mmu-miR-30e-50p and mmu-miR-380-5p share UUGAC motif and targets Grik4; mmu-miR-6940-3p and mmu-miR-212-5p both share UGGCU motif which targets Gria4 and Grid1 respectively. Thus, we demonstrated the efficacy of L-methionine in counteracting the effects of cocaine CPP and identified specific genes of synaptic plasticity pathways, especially the Glutamatergic synapse pathway, which is modulated by L-methionine in response to cocaine dependence.

2020-03-10 | GSE146631 | GEO

Morphine incubation craving-NAc_small RNA sequencing

Project description:The current study aimed at addressing two questions: 1) How the expression of key miRNAs is altered in the NAc during the cue-induced incubation of morphine craving? 2) Which is/are the target gene(s) and what is/are the regulatory mechanism(s) of gene(s) in response to the candidate miRNAs? To answer these two questions, the cue-induced incubation of the morphine craving model was first established by using the conditioned place preference (CPP) paradigm. Then, the aberrant expression of miRNAs was identified in the NAc tissue by RNA-sequencing.

2022-06-08 | GSE192888 | GEO

MicroRNA-218 instructs proper assembly of hippocampal networks

Project description:The assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression. Post-transcriptional regulation of gene expression by microRNAs (miRNAs) is a key aspect of this program. Indeed, deletion of neuron-enriched miRNAs induces strong developmental phenotypes, and miRNA levels are altered in patients with neurodevelopmental disorders. However, the mechanisms used by miRNAs to instruct brain development remain largely unexplored. Here, we identified miR-218 as a critical regulator of hippocampal assembly. MiR-218 is highly expressed in the hippocampus and enriched in both excitatory principal neurons (PNs) and GABAergic inhibitory interneurons (INs). Early life inhibition of miR-218 results in an adult brain with a predisposition to seizures. Changes in gene expression in the absence of miR-218 suggest that network assembly is impaired. Indeed, we find that miR-218 inhibition results in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. Conditional knockout of miR-218 in INs, but not PNs, is sufficient to recapitulate long-term instability. Finally, de-repressing Kif21b and Syt13, two miR-218 targets, phenocopies the effects on early synchronous network activity induced by miR-218 inhibition. Taken together, the data suggest that miR-218 orchestrates formative events in PNs and INs to produce stable networks.

2023-10-15 | GSE241245 | GEO

Morphine addiction-NAc_small RNA sequencing

Project description:The current study aimed at addressing two questions: 1) How the expression of key miRNAs is altered in the NAc during the morphine-induced addiction? 2) Which is/are the target gene(s) and what is/are the regulatory mechanism(s) of gene(s) in response to the candidate miRNAs? To answer these two questions, the morphine addiction model was first established by using the conditioned place preference (CPP) paradigm. Then, the aberrant expression of miRNAs was identified in the NAc tissue by RNA-sequencing.

2022-04-04 | GSE199917 | GEO

Chromatin remodeler INO80 is essential for cocaine craving during prolonged withdrawal

Project description:Neuroadaptations in the nucleus accumbens (NAc) underlie cue-induced cocaine craving that intensifies (“incubates”) during withdrawal and contributes to persistent relapse vulnerability. Long-lasting gene changes govern perpetual behavioral abnormalities but the role of epigenetic plasticity in cocaine craving during prolonged withdrawal is poorly understood. Here we show that chromatin remodeler INO80 in the NAc mediates cocaine-induced, withdrawal-dependent plasticity and incubated cocaine craving.

2019-10-29 | GSE119627 | GEO

Comparison of gene expression in the nucleus accumbens of rats expressing or not the conditioned place preference to cocaine [CPPE, nCPPE, Saline after cocaine reinstatement]

Project description:Substance use disorder emerges in a small proportion of drug users and has the characteristics of a chronic relapsing pathology. The objective of our study was to demonstrate and characterize the variability in the expression of the reinforcing effects of cocaine in the conditioned place preference (CPP) paradigm. An unbiased cocaine-CPP paradigm in Sprague-Dawley rats with an extinction period of 12 days and reinstatement was conducted. We developed a statistical model to distinguish rats that express or do not express cocaine-induced place preference. Two groups of rats were identified: rats that did express reinforcing effects (CPP expression (CPPE), score > 102 s) and rats that did not (no CPP expression (nCPPE), score between −85 and 59 s). These two groups did not show significant differences in a battery of behavioral tests. To identify differentially expressed genes in the CPPE and nCPPE groups, we performed a whole-transcriptome RNA-sequencing analysis in the nucleus accumbens (Nac) 24 h after the CPP test. Four immediate early genes (Fos, Egr2, Nr4a1 and Zbtb37) were differentially expressed in the Nac of CPPE rats after CPP memory retrieval. Variability in cocaine-induced place preference persisted in the CPPE and nCPPE groups after the extinction and reinstatement phases. Transcriptomic differences observed after reinstatement were distinct from those observed immediately after CPP memory retrieval. These new findings provide insights into the identification of mechanisms underlying interindividual variability in the response to cocaine's reinforcing effects.

2024-03-11 | GSE169666 | GEO

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