School of Life Sciences, Arizona State University, PO Box 874501, Tempe, AZ, 85287-4501, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sci Rep. 2020 Jul 9;10(1):11291. doi: 10.1038/s41598-020-67966-8.
Environmental enrichment (EE) is a robust intervention for reducing cocaine-seeking behaviors in animals when given during forced abstinence. However, the mechanisms that underlie these effects are not well-established. We investigated the adult male rat transcriptome using RNA-sequencing (RNA-seq) following differential housing during forced abstinence from cocaine self-administration for either 1 or 21 days. Enriched, 21-day forced abstinence rats displayed a significant reduction in cocaine-seeking behavior compared to rats housed in isolation. RNA-seq of the nucleus accumbens shell revealed hundreds of differentially regulated transcripts between rats of different forced abstinence length and housing environment, as well as within specific contrasts such as enrichment (isolated 21 days vs. enriched 21 days) or incubation (isolated 1 day vs. isolated 21 days). Ingenuity Pathway Analysis affirmed several pathways as differentially enriched based on housing condition and forced abstinence length including RELN, the Eif2 signaling pathway, synaptogenesis and neurogenesis pathways. Numerous pathways showed upregulation with incubation, but downregulation with EE, suggesting that EE may prevent or reverse changes in gene expression associated with protracted forced abstinence. The findings reveal novel candidate mechanisms involved in the protective effects of EE against cocaine seeking, which may inform efforts to develop pharmacological and gene therapies for treating cocaine use disorders. Furthermore, the finding that EE opposes multiple pathway changes associated with incubation of cocaine seeking strongly supports EE as a therapeutic intervention and suggests EE is capable of preventing or reversing the widespread dysregulation of signaling pathways that occurs during cocaine forced abstinence.
环境丰富（EE）是一种强大的干预措施，可以减少动物在强制戒断期间可卡因寻求行为。然而，这些效果的机制尚未得到很好的确立。我们使用 RNA 测序（RNA-seq）在雄性大鼠进行差异环境暴露后，研究了可卡因自我给药的强制戒断 1 或 21 天后的成年雄性大鼠转录组。与单独饲养的大鼠相比，在 21 天强制戒断期间接受丰富环境的大鼠，可卡因寻求行为明显减少。来自不同强制戒断时长和饲养环境的大鼠之间，以及特定对比（例如，丰富环境（单独饲养 21 天与丰富饲养 21 天）或孵育（单独饲养 1 天与单独饲养 21 天）之间的核壳伏隔核中，有数百个差异调节的转录本。基于不同的饲养条件和强制戒断时长，包括 RELN、Eif2 信号通路、突触发生和神经发生途径，对 IPA 进行了确认，证实了几种途径存在差异富集。许多途径随着孵育而上调，但随着 EE 而下调，这表明 EE 可能预防或逆转与长期强制戒断相关的基因表达变化。研究结果揭示了 EE 对可卡因寻求的保护作用所涉及的新候选机制，这可能为开发治疗可卡因使用障碍的药理学和基因治疗方法提供信息。此外，EE 对抗与孵育可卡因寻求相关的多种途径变化的发现强烈支持 EE 作为一种治疗干预措施，并表明 EE 能够预防或逆转可卡因强制戒断期间发生的广泛信号通路失调。
