2025年6月30日出版的《自然—神经科学》杂志发表了美国科学家的一项最新研究成果。来自神经科学系的Genevieve Konopka研究组报道了人体时钟增强新皮层功能。

该团队建立了一个motheme模型（HU）来概括人类皮层中CLOCK的表达。HU小鼠表现出增强的认知灵活性，这可能与CLOCK时空表达的改变有关。细胞类型特异性基因组图谱鉴定了HU小鼠兴奋性神经元中与树突生长和脊柱形成相关的上调基因。研究组还发现，HU小鼠的兴奋性神经元树突复杂性和脊柱密度增加，兴奋性突触后电流频率更高，表明神经连通性更丰富。相比之下，在人类诱导的多能干细胞来源的神经元中，CLOCK敲除显示树突复杂性降低，突触前点密度降低。总之，他们的数据表明，CLOCK可能通过改变时空基因表达而进化出与大脑相关的功能增益，这些功能可能是人类大脑特化的基础。

研究人员表示，转录因子CLOCK普遍表达，对昼夜节律至关重要，而其在人类新皮层中的特异性表达表明其具有其他功能。

附：英文原文

Title: Human CLOCK enhances neocortical function

Author: Liu, Yuxiang, Fontenot, Miles R., Kulkarni, Ashwinikumar, Khandelwal, Nitin, Voth Park, Seon Hye E., Criswell, Connor, Harper, Matthew, Xu, Pin, Gupta, Nisha, Gibson, Jay R., Takahashi, Joseph S., Konopka, Genevieve

Issue&Volume: 2025-06-30

Abstract: The transcription factor CLOCK is ubiquitously expressed and important for circadian rhythms, while its human-specific expression in neocortex suggests additional functions. Here, we generated a mouse model (HU) that recapitulates human cortical expression of CLOCK. The HU mice show enhanced cognitive flexibility, which might be associated with alteration in spatiotemporal expression of CLOCK. Cell-type-specific genomic profiling identified upregulated genes related to dendritic growth and spine formation in excitatory neurons of HU mice. We also found that excitatory neurons in HU mice have increased dendritic complexity and spine density, and a greater frequency of excitatory postsynaptic currents, suggesting a greater abundance of neural connectivity. In contrast, CLOCK knockout in human induced pluripotent stem cell-derived neurons showed reduced complexity of dendrites and lower density of presynaptic puncta. Together, our data demonstrate that CLOCK might have evolved brain-relevant gains of function via altered spatiotemporal gene expression and that these functions may underlie human brain specializations.

DOI: 10.1038/s41593-025-01993-4

Source: https://www.nature.com/articles/s41593-025-01993-4