Next-generation sequencing of cholinergic interneurons in the nucleus accumbens of cocaine-addicted and non-addicted mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE130376 | GEO | 2020/10/28
REPOSITORIES: GEO
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Project description:Despite addiction being one of the most prevalent and debilitating disorders worldwide, effective treatments are lacking. Repeated cocaine exposure induces maladaptive transcriptional regulation within the brainâ??s reward circuitry, such as the nucleus accumbens (NAc), and epigenetic mechanisms, such as histone acetylation or methylation on Lys (K) residues, have been linked to these lasting actions of cocaine. However, in contrast to K methylation, the functional role of histone Arg (R) methylation remains unexplored in addiction models and poorly understood in brain in general. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, as well as in the NAc of cocaine-addicted humans. PRMT6 downregulation occurs selectively in NAc medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we demonstrate that reduced H3R2me2a binding at gene targets in NAc after repeated cocaine is strongly correlated with increased binding of H3K4me3, and identify Src kinase signaling inhibitor 1 (Srcin1 or p140Cap) as a key gene for these chromatin modifications. Cocaine induction of Srcin1 in NAc, which is associated with reduced Src signaling, decreases cocaine reward, the motivation to self administer cocaine, and cocaine-induced changes in NAc MSN dendritic spines. These results suggest that this suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a downregulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of new treatments for cocaine addiction. H3R2me2A ChIP-seq of mouse. Cocaine vs Saline, 3 biological replicates.
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Project description:ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate that Baz1b, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression of Baz1b, along with its associated subunit Smarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to either cocaine or social stress. Together, these findings suggest important roles for BAZ1B and its associated chromatin remodeling complexes in NAc in the regulation of reward behaviors to distinct emotional stimuli and highlight the stimulus-specific nature of the actions of these regulatory proteins.
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Project description:Molecular basis of transition to addiction in vulnerable individuals is largely unknown. We hypothesized that human susceptibility genes can be identified on the basis of conserved molecular mechanisms in rodent brains. We used a short-term cocaine-dependent conditioned place preference (CPP) to identify genetic hallmarks of early steps of reward memory in basal ganglia including accumbens nucleus (NAc), globus pallidus (GP) and subthalamic nucleus (STN). Using genome-wide microarray analysis and CPP as a quantitative trait, we found that synaptic plasticity-related genes are deregulated in these three structures. A significant enrichment in bona fide transcripts involved in dendritic spine local translation was evidenced. mGluR5 is transcriptionally deregulated in Acc and GP of cocaine-treated animals. Grin3a that encodes a NMDA receptor subunit involved in Ca++ permeability is deregulated in NAc. Furthermore, Orexin/Hcrt transcript level is decreased in STN, a region known to be involved in discriminating addictive drugs and natural rewards. We also found that mGluR5 and Grin3a expression deregulation is sufficient to induce changes in synaptic plasticity-related genes. Altogether, these results suggest that a combined deregulation of mGluR5 and Grin3A pathway in NAc, mGluR5 in GP and orexin system in STN may generate an incentive memory contrasted between addictive drugs and natural rewards. Such pathways may include clusters of genes that are potential susceptibility genes for transition to addiction. Agilent Whole Mouse Genome oligomicroarrays (GEO accession no. GPL4134, Agilent Technologies, Palo Alto, CA) were used. They contain 60-mer DNA probes synthesized in situ in a 44k format. Four independent (globus pallidus from mouse treated with cocaine and having a low score of conditioned place preference compared to globus pallidus from mouse treated with saline solution) hybridizations were carried out for each group of biological conditions using exchanged dye-labeled RNA targets (i.e., Cy3 and Cy5 dyeswapping experiments).
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Project description:Molecular basis of transition to addiction in vulnerable individuals is largely unknown. We hypothesized that human susceptibility genes can be identified on the basis of conserved molecular mechanisms in rodent brains. We used a short-term cocaine-dependent conditioned place preference (CPP) to identify genetic hallmarks of early steps of reward memory in basal ganglia including accumbens nucleus (NAc), globus pallidus (GP) and subthalamic nucleus (STN). Using genome-wide microarray analysis and CPP as a quantitative trait, we found that synaptic plasticity-related genes are deregulated in these three structures. A significant enrichment in bona fide transcripts involved in dendritic spine local translation was evidenced. mGluR5 is transcriptionally deregulated in Acc and GP of cocaine-treated animals. Grin3a that encodes a NMDA receptor subunit involved in Ca++ permeability is deregulated in NAc. Furthermore, Orexin/Hcrt transcript level is decreased in STN, a region known to be involved in discriminating addictive drugs and natural rewards. We also found that mGluR5 and Grin3a expression deregulation is sufficient to induce changes in synaptic plasticity-related genes. Altogether, these results suggest that a combined deregulation of mGluR5 and Grin3A pathway in NAc, mGluR5 in GP and orexin system in STN may generate an incentive memory contrasted between addictive drugs and natural rewards. Such pathways may include clusters of genes that are potential susceptibility genes for transition to addiction. Agilent Whole Mouse Genome oligomicroarrays (GEO accession no. GPL2872, Agilent Technologies, Palo Alto, CA) were used. They contain 60-mer DNA probes synthesized in situ in a 44k format. Of 44,290 spots, 2756 are controls. The remaining 41,534 spots represent 33,661 unique transcripts which correspond to 20,202 unique human genes. Five independent (five subthalamic nuclei from mice treated with cocaine compared to five subthalamic nuclei from mice treated with saline solution) hybridizations were carried out for each group of biological conditions using exchanged dye-labeled RNA targets (i.e., Cy3 and Cy5 dyeswapping experiments). Each hybridization was numerized hybridization by a GenePix 4000B Microarray Scanner and an Agilent G6525 Microarray Scanner
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Project description:Molecular basis of transition to addiction in vulnerable individuals is largely unknown. We hypothesized that human susceptibility genes can be identified on the basis of conserved molecular mechanisms in rodent brains. We used a short-term cocaine-dependent conditioned place preference (CPP) to identify genetic hallmarks of early steps of reward memory in basal ganglia including accumbens nucleus (NAc), globus pallidus (GP) and subthalamic nucleus (STN). Using genome-wide microarray analysis and CPP as a quantitative trait, we found that synaptic plasticity-related genes are deregulated in these three structures. A significant enrichment in bona fide transcripts involved in dendritic spine local translation was evidenced. mGluR5 is transcriptionally deregulated in Acc and GP of cocaine-treated animals. Grin3a that encodes a NMDA receptor subunit involved in Ca++ permeability is deregulated in NAc. Furthermore, Orexin/Hcrt transcript level is decreased in STN, a region known to be involved in discriminating addictive drugs and natural rewards. We also found that mGluR5 and Grin3a expression deregulation is sufficient to induce changes in synaptic plasticity-related genes. Altogether, these results suggest that a combined deregulation of mGluR5 and Grin3A pathway in NAc, mGluR5 in GP and orexin system in STN may generate an incentive memory contrasted between addictive drugs and natural rewards. Such pathways may include clusters of genes that are potential susceptibility genes for transition to addiction. Agilent Whole Mouse Genome oligomicroarrays (GEO accession no. GPL2872, Agilent Technologies, Palo Alto, CA) were used. They contain 60-mer DNA probes synthesized in situ in a 44k format. Of 44,290 spots, 2756 are controls. The remaining 41,534 spots represent 33,661 unique transcripts which correspond to 20,202 unique human genes. Five independent (five accumbens nuclei from mice treated with cocaine and having a low score of conditioned place preference compared to five accumbens nuclei from mice treated with saline solution) measurements were carried out for each group of biological conditions using exchanged dye-labeled RNA targets (i.e., Cy3 and Cy5 dyeswapping experiments).
2015-05-10 | E-GEOD-28529 | biostudies-arrayexpress
Project description:Molecular basis of transition to addiction in vulnerable individuals is largely unknown. We hypothesized that human susceptibility genes can be identified on the basis of conserved molecular mechanisms in rodent brains. We used a short-term cocaine-dependent conditioned place preference (CPP) to identify genetic hallmarks of early steps of reward memory in basal ganglia including accumbens nucleus (NAc), globus pallidus (GP) and subthalamic nucleus (STN). Using genome-wide microarray analysis and CPP as a quantitative trait, we found that synaptic plasticity-related genes are deregulated in these three structures. A significant enrichment in bona fide transcripts involved in dendritic spine local translation was evidenced. mGluR5 is transcriptionally deregulated in Acc and GP of cocaine-treated animals. Grin3a that encodes a NMDA receptor subunit involved in Ca++ permeability is deregulated in NAc. Furthermore, Orexin/Hcrt transcript level is decreased in STN, a region known to be involved in discriminating addictive drugs and natural rewards. We also found that mGluR5 and Grin3a expression deregulation is sufficient to induce changes in synaptic plasticity-related genes. Altogether, these results suggest that a combined deregulation of mGluR5 and Grin3A pathway in NAc, mGluR5 in GP and orexin system in STN may generate an incentive memory contrasted between addictive drugs and natural rewards. Such pathways may include clusters of genes that are potential susceptibility genes for transition to addiction. Agilent Whole Mouse Genome oligomicroarrays (GEO accession no. GPL2872, Agilent Technologies, Palo Alto, CA) were used. They contain 60-mer DNA probes synthesized in situ in a 44k format. Of 44,290 spots, 2756 are controls. The remaining 41,534 spots represent 33,661 unique transcripts which correspond to 20,202 unique human genes. Five independent (four accumbens nuclei from mice treated with cocaine compared to four accumbens nuclei from mice treated with saline solution) measurements were carried out for each group of biological conditions using exchanged dye-labeled RNA targets (i.e., Cy3 and Cy5 dyeswapping experiments). Each hybridization was numerized hybridization by a GenePix 4000B Microarray Scanner and an Agilent G6525 Microarray Scanner.
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