Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder.
Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder.
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DOI：
10.1038/s41398-022-01894-1
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发表时间：
2022-03-26
影响因子：
6.8
通讯作者：
Logan RW
中科院分区：
文献类型：
--
作者：
Xue X;Zong W;Glausier JR;Kim SM;Shelton MA;Phan BN;Srinivasan C;Pfenning AR;Tseng GC;Lewis DA;Seney ML;Logan RW
严重和持续的睡眠和昼夜节律中断在阿片类药物使用障碍（OUD）患者中很常见。临床前证据表明，大脑中改变的分子节律调节阿片类药物的奖励和复发。然而，OUD患者大脑中的分子节律是否被破坏仍然是一个悬而未决的问题，这对于理解昼夜节律在阿片类药物成瘾中的作用至关重要。使用受试者的死亡时间作为一天中时间的标记，我们研究了OUD受试者与未受影响的对照受试者大脑中的转录节律。我们发现，在背外侧前额叶皮层（DLPFC）和背外侧核（NAc），参与OUD的关键脑区，这在很大程度上是不同的OUD和未受影响的受试者之间的节奏转录。与未受影响的受试者相比，在OUD受试者的DLPFC中发现了较少的节律性转录本，而在NAc中，OUD受试者中发现了近两倍的节律性转录本。在OUD受试者的NAc中，节律性转录物在晚上或接近日出时达到峰值，并与阿片类药物、多巴胺和GABA能神经传递相关。与NAc中神经传递改变的关联得到了共表达网络分析的进一步支持，该分析确定了OUD特异性模块，其富含参与多巴胺、GABA和多巴胺能突触功能的转录物。此外，OUD受试者的DLPFC和NAc中的节律性转录物富含与睡眠相关的GWAS特征（包括睡眠持续时间和失眠）相关的基因组位点。总的来说，我们的研究结果将人脑中阿片类、多巴胺、GABA能信号的转录节律变化与阿片类成瘾的睡眠相关特征联系起来。
Severe and persistent disruptions to sleep and circadian rhythms are common in people with opioid use disorder (OUD). Preclinical evidence suggests altered molecular rhythms in the brain modulate opioid reward and relapse. However, whether molecular rhythms are disrupted in the brains of people with OUD remained an open question, critical to understanding the role of circadian rhythms in opioid addiction. Using subjects’ times of death as a marker of time of day, we investigated transcriptional rhythms in the brains of subjects with OUD compared to unaffected comparison subjects. We discovered rhythmic transcripts in both the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), key brain areas involved in OUD, that were largely distinct between OUD and unaffected subjects. Fewer rhythmic transcripts were identified in DLPFC of subjects with OUD compared to unaffected subjects, whereas in the NAc, nearly double the number of rhythmic transcripts was identified in subjects with OUD. In NAc of subjects with OUD, rhythmic transcripts peaked either in the evening or near sunrise, and were associated with an opioid, dopamine, and GABAergic neurotransmission. Associations with altered neurotransmission in NAc were further supported by co-expression network analysis which identified OUD-specific modules enriched for transcripts involved in dopamine, GABA, and glutamatergic synaptic functions. Additionally, rhythmic transcripts in DLPFC and NAc of subjects with OUD were enriched for genomic loci associated with sleep-related GWAS traits, including sleep duration and insomnia. Collectively, our findings connect transcriptional rhythm changes in opioidergic, dopaminergic, GABAergic signaling in the human brain to sleep-related traits in opioid addiction.
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通讯作者：
Snyder SH
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Price AL
影响因子：
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作者：
Cahill KM;Huo Z;Tseng GC;Logan RW;Seney ML
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