Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area.
Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area.
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Coconut诱导腹侧被盖区内转录组的范式特异性变化。
DOI：
10.1038/s41386-021-01031-4
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Wood MA
中科院分区：
文献类型：
--
作者：
Campbell RR;Chen S;Beardwood JH;López AJ;Pham LV;Keiser AM;Childs JE;Matheos DP;Swarup V;Baldi P;Wood MA
在药物使用的初始阶段，可卡因诱导的腹侧被盖区（VTA）内的神经适应对于药物相关线索学习和药物强化过程至关重要。这些神经适应性改变部分来自转录组的改变。虽然可卡因诱导的VTA内的转录机制已被检查，各种方案和范例已被用来检查候选靶基因。为了确定调节可卡因诱导过程的关键基因和生物学过程，我们采用全基因组RNA测序来分析雄性小鼠VTA内的转录谱，这些小鼠经历了四种常用范式之一：急性家庭笼注射可卡因，慢性家庭笼注射可卡因，可卡因调节或静脉内自我注射可卡因。我们发现，可卡因改变不同套的VTA基因内的每个曝光范例。使用可卡因自我给药小鼠的行为测量，我们还发现了几个基因的表达模式与可卡因摄入量相关。除了总体基因表达水平外，我们还确定了几种在所有范式中共享的可卡因诱导转录的预测上游调节因子。虽然不同的基因集改变可卡因暴露范式，我们发现，从基因本体论（GO）术语分析，重要的能量调节和突触可塑性的生物过程中受到影响的所有可卡因范式。共表达分析还确定了被可卡因改变的基因网络。这些数据表明，可卡因改变富含参与基因调控和突触过程的腹侧被盖区神经胶质细胞标志物的网络。我们的分析表明，VTA内的转录变化取决于可卡因暴露的途径，剂量和背景，并强调了可卡因影响的几个生物过程。总的来说，这些发现为未来研究调节药物相关行为的新型可卡因基因靶点提供了独特的基因表达数据资源。
During the initial stages of drug use, cocaine-induced neuroadaptations within the ventral tegmental area (VTA) are critical for drug-associated cue learning and drug reinforcement processes. These neuroadaptations occur, in part, from alterations to the transcriptome. Although cocaine-induced transcriptional mechanisms within the VTA have been examined, various regimens and paradigms have been employed to examine candidate target genes. In order to identify key genes and biological processes regulating cocaine-induced processes, we employed genome-wide RNA-sequencing to analyze transcriptional profiles within the VTA from male mice that underwent one of four commonly used paradigms: acute home cage injections of cocaine, chronic home cage injections of cocaine, cocaine-conditioning, or intravenous-self administration of cocaine. 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. Coexpression analysis also identified gene networks that are altered by cocaine. These data indicate that cocaine alters networks enriched with glial cell markers of the VTA that are involved in gene regulation and synaptic processes. Our analyses demonstrate that transcriptional changes within the VTA depend on the route, dose and context of cocaine exposure, and highlight several biological processes affected 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.
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