Transcriptome profiling of the ventral pallidum reveals a role for pallido-thalamic neurons in cocaine reward
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PROVIDER: PRJNA821246 | ENA |
REPOSITORIES: ENA
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Project description:Using RNAseq, we evaluated transcriptomic changes in the ventral pallidum (VP) of mice 24h following 10 days of cocaine self-administration.
2022-06-13 | GSE199725 | GEO
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: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.
2024-02-10 | GSE255072 | 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:Chromatin-mediated alternative splicing regulates cocaine reward behavior
| PRJNA750320 | ENA
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:Maladaptive reward seeking is a hallmark of cocaine use disorder. To develop therapeutic targets, it is critical to understand the neurobiological changes specific to cocaine-seeking without altering the seeking of natural rewards, e.g., sucrose. The prefrontal cortex (PFC) and the nucleus accumbens core (NAcore) are known regions associated with cocaine- and sucrose-seeking ensembles, i.e., a sparse population of co-activated neurons. Within ensembles, transcriptomic alterations in the PFC and NAcore underlie the learning and persistence of cocaine- and sucrose-seeking behavior. However, transcriptomes exclusively driving cocaine seeking independent from sucrose seeking have not yet been defined using a within-subject approach. Using Ai14:cFos-TRAP2 transgenic mice in a dual cocaine and sucrose self-administration model, we fluorescently sorted (FACS) and characterized (RNAseq) the transcriptomes defining cocaine- and sucrose-seeking ensembles. We found reward- and region-specific transcriptomic changes that will help develop clinically relevant genetic approaches to decrease cocaine-seeking behavior without altering non-drug reward-based positive reinforcement.
2023-11-08 | GSE247029 | GEO
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. BAZ1B (WSTF) ChIP-seq of mouse. Cocaine vs Saline, 3 biological replicates. In social defeat model: Normal control vs Susceptible vs Resilient, 3 biological replicates.
2016-07-30 | E-GEOD-85005 | biostudies-arrayexpress
Project description:By using high-density oligonucleotide arrays, we profiled gene expression in reward-related brain regions of rats that developed escalated cocaine intake after extended access to cocaine (6 h per day). Rats allowed restricted daily access to cocaine (only 1 h) that displayed a stable level of cocaine intake and cocaine naive rats were used for controls. Four analysis methods were compared: Affymetrix microarray suite 4 and microarray suite 5, which use perfect-match-minus-mismatch models, and dchip and rma, which use perfect-match-only models to generate expression values. Results were validated by RT-PCR in individual animals from an independent replication of the experiment. A small number of genes was associated with escalated cocaine intake (ESC genes). Unexpectedly, of the brain regions examined [prefrontal cortex, nucleus accumbens, septum, lateral hypothalamus (LH), amygdala, and ventral tegmental area], the LH was the most transcriptionally responsive in escalation of cocaine intake. Most of the ESC genes identified are also expressed during synaptogenesis and synaptic plasticity and include genes that code for several presynaptic and postsynaptic proteins involved in neurotransmission. These results suggest that LH intrinsic circuitry undergoes a structural reorganization during escalation of cocaine use. This remodeling of LH circuitry could contribute to the chronic deficit in reward function that has been hypothesized to drive the transition to drug addiction. Results also support the value of using multiple analysis strategies to identify the most robust changes in gene expression and to compensate for the biases that affect each strategy. Experiment Overall Design: The experimental design for this study comprised three groups of rats (n = 8) with different daily access to a continuous schedule of i.v. cocaine self-administration (0.25 mg per injection): 0 h access per day (drug-naive control rats), 1 h access per day (ShA rats), or 6 h access per day (LgA rats). Experiment Overall Design: Gene expression profiling was then performed for each dissected brain region by using Affymetrix rat neurobiology arrays.
2007-10-10 | E-GEOD-3016 | biostudies-arrayexpress
Project description:By using high-density oligonucleotide arrays, we profiled gene expression in reward-related brain regions of rats that developed escalated cocaine intake after extended access to cocaine (6 h per day). Rats allowed restricted daily access to cocaine (only 1 h) that displayed a stable level of cocaine intake and cocaine naive rats were used for controls. Four analysis methods were compared: Affymetrix microarray suite 4 and microarray suite 5, which use perfect-match-minus-mismatch models, and dchip and rma, which use perfect-match-only models to generate expression values. Results were validated by RT-PCR in individual animals from an independent replication of the experiment. A small number of genes was associated with escalated cocaine intake (ESC genes). Unexpectedly, of the brain regions examined [prefrontal cortex, nucleus accumbens, septum, lateral hypothalamus (LH), amygdala, and ventral tegmental area], the LH was the most transcriptionally responsive in escalation of cocaine intake. Most of the ESC genes identified are also expressed during synaptogenesis and synaptic plasticity and include genes that code for several presynaptic and postsynaptic proteins involved in neurotransmission. These results suggest that LH intrinsic circuitry undergoes a structural reorganization during escalation of cocaine use. This remodeling of LH circuitry could contribute to the chronic deficit in reward function that has been hypothesized to drive the transition to drug addiction. Results also support the value of using multiple analysis strategies to identify the most robust changes in gene expression and to compensate for the biases that affect each strategy. Keywords: cocaine addiction
2006-01-26 | GSE3016 | GEO