Zeppilli Sara, Gurrola Alonso O, Demetci Pinar, Brann David H, Pham Tuan M, Attey Robin, Zilkha Noga, Kimchi Tali, Datta Sandeep R, Singh Ritambhara, Tosches Maria A, Crombach Anton, Fleischmann Alexander
Department of Neuroscience and Carney Institute for Brain Science, Brown University, Providence, RI, USA.
Department of Biological Sciences, Columbia University, New York, NY, USA.
Nat Neurosci. 2025 May;28(5):937-948. doi: 10.1038/s41593-025-01924-3. Epub 2025 Apr 8.
Understanding the molecular logic of cortical cell-type diversity can illuminate cortical circuit function and evolution. Here, we performed single-nucleus transcriptome and chromatin accessibility analyses to compare neurons across three- to six-layered cortical areas of adult mice and across tetrapod species. We found that, in contrast to the six-layered neocortex, glutamatergic neurons of the three-layered mouse olfactory (piriform) cortex displayed continuous rather than discrete variation in transcriptomic profiles. Subsets of piriform and neocortical glutamatergic cells with conserved transcriptomic profiles were distinguished by distinct, area-specific epigenetic states. Furthermore, we identified a prominent population of immature neurons in piriform cortex and observed that, in contrast to the neocortex, piriform cortex exhibited divergence between glutamatergic cells in laboratory versus wild-derived mice. Finally, we showed that piriform neurons displayed greater transcriptomic similarity to cortical neurons of turtles, lizards and salamanders than to those of the neocortex. In summary, despite over 200 million years of coevolution alongside the neocortex, olfactory cortex neurons retain molecular signatures of ancestral cortical identity.
了解皮质细胞类型多样性的分子逻辑有助于阐明皮质回路的功能和进化。在此，我们进行了单核转录组和染色质可及性分析，以比较成年小鼠三至六层皮质区域以及四足动物物种之间的神经元。我们发现，与六层新皮质不同，三层小鼠嗅觉（梨状）皮质的谷氨酸能神经元在转录组图谱上表现出连续而非离散的变化。具有保守转录组图谱的梨状皮质和新皮质谷氨酸能细胞亚群通过不同的、区域特异性的表观遗传状态得以区分。此外，我们在梨状皮质中鉴定出大量未成熟神经元，并观察到，与新皮质不同，梨状皮质在实验室小鼠和野生来源小鼠的谷氨酸能细胞之间表现出差异。最后，我们表明，梨状皮质神经元与海龟、蜥蜴和蝾螈的皮质神经元在转录组上的相似性高于与新皮质神经元的相似性。总之，尽管与新皮质共同进化了超过2亿年，但嗅觉皮质神经元仍保留着原始皮质身份的分子特征。
