近日，美国西奈山伊坎医学院Panos Roussos团队的研究开发出了人类前额皮质寿命单细胞转录组图谱。这一研究成果于2026年9月23日发表在国际顶尖学术期刊《自然》上。

人类大脑从早期发育到成年晚期经历深刻变化，塑造认知、行为和对疾病的易感性。理解这些变化如何在特定脑区和细胞类型中组织，对于解读正常衰老及其与精神和神经退行性疾病的关系至关重要。背外侧前额叶皮层在高级认知功能中起核心作用，并且对年龄相关衰退特别敏感，但其在人类全生命周期中的细胞和分子程序仍不明确。大多数现有研究集中于有限的年龄范围或受疾病影响的大脑，限制了区分正常发育和衰老轨迹与病理过程的能力。因此，一直缺乏人类前额叶皮层细胞状态的全面、全生命周期分辨的参考。在此，研究人员利用一个跨越人类全生命周期的单核转录组图谱，表明背外侧前额叶皮层表现出非线性的、细胞类型特异性的转录轨迹，其特征是发育过程中的动态重塑、中年时期的相对稳定以及成年晚期的选择性分子再激活。他们鉴定出不同的神经元和胶质细胞程序，包括生命早期的神经元韧性通路和晚年与免疫激活、应激反应和昼夜节律重组相关的胶质细胞程序。这些程序在皮层各层和灰白质域中具有解剖学组织，揭示了协调的空间和分子变化。总之，这些发现为理解人类皮层中细胞程序如何从韧性转变为脆弱性提供了框架，并为解读年龄相关认知衰退和疾病风险奠定了基础。

附：英文原文

Title: Lifespan single-cell transcriptomic atlas of the human prefrontal cortex

Author: Yang, Hui, Clarence, Tereza, Scott, Madeline R., Wang, Xinyi, N. M., Prashant, Pjanic, Milos, Venkatesh, Sanan, Hong, Aram, Casey, Clara, Murphy, Sarah R., Shao, Zhiping, Alvia, Marcela, Argyriou, Stathis, Yu, Alexander Kawah, Tsankova, Nadejda M., Auluck, Pavan K., Marenco, Stefano, Haroutunian, Vahram, Voloudakis, Georgios, Bendl, Jaroslav, McClung, Colleen A., Lee, Donghoon, Fullard, John F., Hoffman, Gabriel E., Girdhar, Kiran, Roussos, Panos

Issue&Volume: 2026-09-23

Abstract: The human brain undergoes profound changes from early development through late adulthood, shaping cognition, behaviour and vulnerability to disease1,2. Understanding how these changes are organized within specific brain regions and cell types is essential for interpreting normal ageing and its relationship to psychiatric and neurodegenerative disorders. The dorsolateral prefrontal cortex has a central role in higher cognitive functions and is particularly sensitive to age-related decline3, yet its cellular and molecular programs across the human lifespan remain poorly defined. Most existing studies4,5,6,7 have focused on restricted age ranges or disease-affected brains, limiting the ability to distinguish normative developmental and ageing trajectories from pathological processes. Consequently, a comprehensive, lifespan-resolved reference of cellular states in the human prefrontal cortex has been lacking. Here, using a single-nucleus transcriptomic atlas spanning the human lifespan, we show that the dorsolateral prefrontal cortex exhibits non-linear, cell-type-specific transcriptional trajectories characterized by dynamic remodelling during development, relative stability in midlife and selective molecular reactivation in late adulthood. We identify distinct neuronal and glial programs, including early-life neuronal resilience pathways and late-life glial programs associated with immune activation, stress responses and circadian reorganization. These programs are anatomically organized across cortical layers and grey–white matter domains, revealing coordinated spatial and molecular changes. Together, these findings provide a framework for understanding how cellular programs transition from resilience to vulnerability in the human cortex and establish a foundation for interpreting age-related cognitive decline and disease risk.

DOI: 10.1038/s41586-026-10271-7

Source: https://www.nature.com/articles/s41586-026-10271-7