Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models . Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models

Cocaine use disorder (CUD) is an intractable syndrome, and rising overdose death rates represent a significant public health crisis that exacts tremendous personal and financial costs on patients and society. Sharp increases in cocaine use drive the urgent need for better mechanistic insight into this chronic relapsing brain disorder that currently lacks effective treatment options. To investigate the transcriptomic changes involved, we conducted RNA sequencing on two striatal brain regions that are heavily implicated in CUD, the nucleus accumbens and caudate nucleus, from postmortem brains of subjects with CUD and matched control subjects. Weighted gene co-expression analyses identified CUD-specific gene networks enriched in ionotropic receptors and associated with lowered neuroinflammation, contrasting the proinflammatory responses found in opioid use disorder. Integration of comprehensive transcriptomic datasets from mouse cocaine self-administration models revealed evolutionarily conserved gene networks in CUD that implicate especially D1 medium spiny neurons as drivers of cocaine-induced plasticity. Overall design: We performed RNA sequencing (RNAseq) on both the ventral (NAc) and dorsal (CN) striatum from postmortem tissue of persons with CUD and matched control subjects. We combined differential gene expression and network-based approaches to provide an integrative and unbiased characterization of transcriptional signatures triggered by chronic cocaine use across the striatum. Our analyses revealed a profound overlap between CUD-specific transcriptome changes in the NAc and CN, introducing the downregulation of neuroinflammatory processes, and upregulation of synaptic transmembrane transporters and ionotropic receptors.

可卡因使用障碍（Cocaine Use Disorder, CUD）是一种难治性综合征，不断攀升的过量致死率构成了严峻的公共卫生危机，给患者与社会带来了沉重的个人与经济负担。可卡因使用人群的大幅增长，迫切需要我们对这种目前缺乏有效治疗方案的慢性复发性脑疾病展开更深入的机制研究。为探究相关转录组变化，我们对可卡因使用障碍患者及匹配对照者的死后脑组织中，与CUD密切相关的两个纹状体脑区——伏隔核（nucleus accumbens, NAc）和尾状核（caudate nucleus, CN）——进行了RNA测序（RNA sequencing, RNAseq）。加权基因共表达分析鉴定出了CUD特异性基因网络，该网络富集于离子型受体相关通路，并与神经炎症水平降低相关，这与阿片类物质使用障碍中观察到的促炎症反应形成鲜明对比。整合小鼠可卡因自身给药模型的全面转录组数据集后发现，CUD中存在进化保守的基因网络，尤其提示D1型中型多棘神经元（medium spiny neurons）是可卡因诱导的神经可塑性的驱动因素。总体实验设计：我们对可卡因使用障碍患者及匹配对照者的死后脑组织的腹侧纹状体（伏隔核，NAc）与背侧纹状体（尾状核，CN）均进行了RNA测序。我们结合差异基因表达分析与基于网络的分析方法，对慢性可卡因使用引发的全纹状体转录特征进行了整合且无偏倚的表征。分析结果显示，伏隔核与尾状核中的CUD特异性转录组变化存在显著重叠，其中包括神经炎症过程的下调，以及突触跨膜转运蛋白与离子型受体的上调。