Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):2005-10. doi: 10.1073/pnas.1319703111. Epub 2014 Jan 21.
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-1 induction 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.
可卡因对大脑奖励回路的许多长期影响已被证明是通过基因表达的改变来介导的。几种染色质修饰，包括组蛋白乙酰化和甲基化，已被牵连到这种调节中，但其他组蛋白修饰的影响仍知之甚少。多聚（ADP-核糖）聚合酶-1（PARP-1）是一种普遍存在且丰富的核蛋白，可催化在组蛋白和其他底物蛋白上合成一种称为聚（ADP-核糖）或 PAR 的带负电荷的聚合物，并与其他几种染色质蛋白形成转录调节复合物。在这里，我们确定了 PARP-1 在可卡因诱导的分子、神经和行为可塑性中的重要作用。重复给予可卡因，包括自我给药，会增加小鼠伏隔核（NAc）中 PARP-1 及其标记 PAR 的整体水平，NAc 是大脑奖励区域的关键部位。使用 PARP-1 抑制剂和病毒介导的基因转移，我们确定了 NAc 中 PARP-1 的诱导介导了对可卡因的增强的行为反应，包括增加药物的自我给药。通过染色质免疫沉淀测序，我们在可卡因暴露的小鼠的 NAc 中证明了 PARP-1 的全基因组广泛富集，并鉴定了几个可能有助于可卡因持久作用的 PARP-1 靶基因。具体来说，我们确定了 sidekick-1--在发育过程中对突触连接很重要--作为一个关键的 PARP-1 靶基因，参与可卡因的行为效应以及诱导 NAc 神经元树突棘的能力。这些发现确立了 PARP-1 和 PAR 化在可卡因的长期作用中的参与。
