Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219.
Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15213.
Proc Natl Acad Sci U S A. 2021 Jan 12;118(2). doi: 10.1073/pnas.2016150118.
The human striatum can be subdivided into the caudate, putamen, and nucleus accumbens (NAc). Each of these structures have some overlapping and some distinct functions related to motor control, cognitive processing, motivation, and reward. Previously, we used a "time-of-death" approach to identify diurnal rhythms in RNA transcripts in human cortical regions. Here, we identify molecular rhythms across the three striatal subregions collected from postmortem human brain tissue in subjects without psychiatric or neurological disorders. Core circadian clock genes are rhythmic across all three regions and show strong phase concordance across regions. However, the putamen contains a much larger number of significantly rhythmic transcripts than the other two regions. Moreover, there are many differences in pathways that are rhythmic across regions. Strikingly, the top rhythmic transcripts in NAc (but not the other regions) are predominantly small nucleolar RNAs and long noncoding RNAs, suggesting that a completely different mechanism might be used for the regulation of diurnal rhythms in translation and/or RNA processing in the NAc versus the other regions. Further, although the NAc and putamen are generally in phase with regard to timing of expression rhythms, the NAc and caudate, and caudate and putamen, have several clusters of discordant rhythmic transcripts, suggesting a temporal wave of specific cellular processes across the striatum. Taken together, these studies reveal distinct transcriptome rhythms across the human striatum and are an important step in helping to understand the normal function of diurnal rhythms in these regions and how disruption could lead to pathology.
人类纹状体可细分为尾状核、壳核和伏隔核(NAc)。这些结构中的每一个都具有一些重叠的功能,也有一些独特的功能与运动控制、认知处理、动机和奖励有关。此前,我们使用“死亡时间”方法来鉴定人类皮质区域 RNA 转录本的昼夜节律。在这里,我们鉴定了从没有精神或神经障碍的尸检人脑组织中采集的三个纹状体亚区的分子节律。核心生物钟基因在所有三个区域都呈节律性,并且在区域之间具有很强的相位一致性。然而,壳核包含的节律性转录本数量远多于其他两个区域。此外,在跨区域呈现节律性的途径中存在许多差异。引人注目的是,NAc 中(而不是其他区域)节律性最强的转录本主要是小核仁 RNA 和长非编码 RNA,这表明在 NAc 中调节昼夜节律的翻译和/或 RNA 加工可能使用了完全不同的机制,而不是其他区域。此外,尽管 NAc 和壳核通常在表达节律的时间上同步,但 NAc 和尾状核、尾状核和壳核之间存在几个不一致的节律性转录本簇,这表明在纹状体中存在特定细胞过程的时间波。总之,这些研究揭示了人类纹状体中不同的转录组节律,这是帮助理解这些区域昼夜节律正常功能以及如何中断会导致病理学的重要一步。