Transcriptome profiling of the ventral pallidum reveals a role for pallido-thalamic neurons in cocaine reward
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE199725 | GEO | 2022/06/13
REPOSITORIES: GEO
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Project description:Transcriptome profiling of the ventral pallidum reveals a role for pallido-thalamic neurons in cocaine reward
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Project description:The ventral pallidum (VP) is critical for motivated behaviors. While contemporary work has begun to elucidate the functional diversity of VP neurons, the molecular heterogeneity underlying this functional diversity remains incompletely understood. We used snRNA-seq and in situ hybridization to define the transcriptional taxonomy of VP cell types in mice, macaques, and baboons. We found transcriptional conservation between all three species, within the broader neurochemical cell types. Unique dopaminoceptive and cholinergic subclusters were identified and conserved across both primate species but had no homolog in mice. This harmonized consensus VP cellular atlas will pave the way for understanding the structure and function of the VP and identified key neuropeptides, neurotransmitters, and neuro receptors that could be targeted within specific VP cell types for functional investigations.
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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
Project description:We describe the effects of cocaine and methamphetamine treatment on astrocytic expression of the corticotropin releasing factor 2 receptor and the excitatory amino acid transporter 1 in the ventral midbrain. The RNA-sequencing data confirms the expression of CRF2R on astrocytes using the Aldh1l1-NuTRAP model. This allowed for astrocyte mRNA isolation and characterization, confirming CRF2R expression on ventral midbrain astrocytes.
2021-10-15 | GSE184497 | GEO
Project description:Global changes in gene expression that underlie the circuit and behavioral dysregulation associated with cocaine addiction remain incompletely understood. Here, we determined how a history of cocaine self-administration (SA) “re-programs” transcriptome-wide responses at baseline and in response to cocaine re-exposure after prolonged withdrawal (WD). We assigned male mice to one of six groups: saline or cocaine SA + 24 hr WD; or saline/cocaine SA + 30 d WD + an acute saline/cocaine challenge within the previous drug-paired context. RNA-seq was then conducted on six interconnected brain reward regions. We focused on patterns of gene expression that were altered by cocaine SA, in particular, molecular targets that show priming or desensitization upon re-exposure to cocaine. Genes that were affected uniquely by acute cocaine after cocaine SA+WD displayed region-specific regulation. The greatest number of regulated genes were seen in nucleus accumbens, dorsal striatum, and basolateral amygdala. Further analysis revealed several transcription factors as key upstream regulators in these three regions, including several not previously implicated in cocaine action. Regulation of subsets of these primed and desensitized genes correlated robustly with SA behavior displayed by individual mice. For example, analysis of transcriptome-wide expression changes revealed that genes associated with cocaine intake respond to contextual information in a region-specific manner. This comprehensive picture of transcriptome-wide regulation by cocaine SA and WD throughout the brain’s reward circuitry provides new insight into the molecular basis of cocaine addiction, which will guide future studies of the key molecular pathways involved.
2018-08-22 | GSE110344 | GEO
Project description:Neuronal alternative splicing is a key gene regulatory mechanism in brain. Yet the spliceosome machinery is insufficient to fully specify splicing complexity. In considering the role of the epigenome in activity-dependent alternative splicing, we and others find the histone modification, H3K36me3, to be a putative splicing regulator. In the current study, we found that mouse cocaine self-administration caused widespread differential alternative splicing, concomitant with enrichment of H3K36me3 at differentially spliced junctions. Importantly, only targeted epigenetic editing can distinguish between a direct role of H3K36me3 in splicing and an indirect role via regulation of splice factor expression elsewhere on the genome. We targeted Srsf11, which was both alternatively spliced and H3K36me3 enriched in brain following cocaine self-administration. Results: Epigenetic editing of H3K36me3 at Srsf11 was sufficient to drive its alternative splicing and enhanced cocaine self-administration, establishing the direct causal relevance of H3K36me3 to alternative splicing of Srsf11 and to reward behavior.
2021-07-31 | GSE180988 | GEO
Project description:The 10 samples below represent a study where gene expression levels were measured in 5 different parts of the rat brain under cocaine-treated (GSM4696, GSM4698 - GSM4701) and saline-treated control (GSM4702 - GSM4706) conditions. The regions studied were amygdala (amy), caudate putamen (cpu), nucleus acumbens (na), prefrontal cortex (cpu), and the ventral tegmental area (vta). The data were analyzed using two different computational techniques, viz. singular value decomposition (SVD) and self-organizing maps (SOM), to identify a common set of genes that were regulated by cocaine administration. Keywords = cocaine Keywords = oligonucleotide microarrays Keywords = svd Keywords = som Keywords: repeat sample
2003-03-13 | GSE340 | GEO
Project description:We found that cocaine alters distinct sets of VTA genes within each exposure paradigm. Using behavioral measures from cocaine self-administering mice, we also found several genes whose expression patterns corelate with cocaine intake. In addition to overall gene expression levels, we identified several predicted upstream regulators of cocaine-induced transcription shared across all paradigms. Although distinct gene sets were altered across cocaine exposure paradigms, we found, from Gene Ontology (GO) term analysis, that biological processes important for energy regulation and synaptic plasticity were affected across all cocaine paradigms. Our analyses demonstrate that transcriptional changes within the VTA depend on the route and context of cocaine exposure, and highlight several affected biological processes by cocaine. Overall, these findings provide a unique resource of gene expression data for future studies examining novel cocaine gene targets that regulate drug-associated behaviors.
2020-07-29 | GSE155313 | GEO
Project description:Dopaminylation of Histone H3 in Ventral Tegmental Area Regulates Cocaine-seeking
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Project description:All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance use disorders. Another recently appreciated mechanism of neural circuit plasticity is mediated through activity-regulated changes in myelin that can tune circuit function and influence cognitive behavior1. Here, we explored the role of myelin plasticity in dopaminergic circuity and reward learning. We demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by either optogenetic stimulation of dopaminergic neurons, optogenetic inhibition of GABAergic neurons, or administration of morphine or cocaine. These oligodendroglial changes are evident selectively within the ventral tegmental area (VTA), but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens (NAc). Genetic blockade of oligodendrogenesis dampens dopamine release dynamics in nucleus accumbens and impairs behavioral conditioning to morphine. Taken together, these findings underscore a critical role for oligodendrogenesis in reward learning and identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.
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