Unknown,Transcriptomics,Genomics,Proteomics

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RGS9-2-controlled adaptations in the striatum determine the onset of action and eficacy of antidepressants in neuropathic pain states

ABSTRACT: The striatal protein Regulator of G protein signaling-2 (RGS9-2) plays a key modulatory role in opioid, monoamine and other GPCR responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood reward and motivation, modulates the actions of tricyclic antidepressants (TCAs). Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein a and bg subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5 (HDAC5), that are important for TCA responsiveness. Furthermore, information from RNA-seq analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states. The RNAseq study was designed in order to reveal the impact of RGS9-2 on gene regulation in the Nucleus Accumbens under neuropathic pain and antidepressant treatment conditions. A total of 18 samples was used, coprising 6 different groups , and each group consisted of three different biological replicates.

ORGANISM(S): Mus musculus

SUBMITTER: Venetia Zachariou

PROVIDER: E-GEOD-71527 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Many of the long-term effects of cocaine on the brain's reward circuitry have been shown to be mediated by alterations in gene expression. Several chromatin modifications, including histone acetylation and methylation, have been implicated in this regulation, but the effect of other histone modifications remains poorly understood. Poly(ADP-ribose) polymerase-1 (PARP-1), a ubiquitous and abundant nuclear protein, catalyzes the synthesis of a negatively charged polymer called poly(ADP-ribose) or PAR on histones and other substrate proteins and forms transcriptional regulatory complexes with several other chromatin proteins. Here, we identify an essential role for PARP-1 in cocaine-induced molecular, neural, and behavioral plasticity. Repeated cocaine administration, including self-administration, increased global levels of PARP-1 and its mark PAR in mouse nucleus accumbens (NAc), a key brain reward region. Using PARP-1 inhibitors and viral-mediated gene transfer, we established that PARP-1induction in NAc mediates enhanced behavioral responses to cocaine, including increased self-administration of the drug. Using chromatin immunoprecipitation sequencing, we demonstrated a global, genome-wide enrichment of PARP-1 in NAc of cocaine-exposed mice and identified several PARP-1 target genes that could contribute to the lasting effects of cocaine. Specifically, we identified sidekick-1-important for synaptic connections during development-as a critical PARP-1 target gene involved in cocaine's behavioral effects as well as in its ability to induce dendritic spines on NAc neurons. These findings establish the involvement of PARP-1 and PARylation in the long-term actions of cocaine. c57bl/6 mice were given IP injections of chronic cocaine 20mg/kg once per day for 7 days and sacrificed 30 minutes after the final dose of cocaine. Control animals were given saline for 7 days and sacrificed 30 minutes after the final dose of saline. Nucleus accumbens (NAc) tissue was collected and then PARP-1 ChIP-seq was performed. Three sequencing replicates were performed on each group.

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RGS9-2-controlled adaptations in the striatum determine the onset of action and eficacy of antidepressants in neuropathic pain states

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