A spatiotemporal map of the mouse brain reveals white matter tracts as vulnerable foci of aging

Aging is a key driver of cognitive decline and the predominant risk factor for several neurodegenerative diseases. Recent behavioral studies as well as structural and functional MRI data suggest that aging does not impact the brain in a uniform manner but follows region- and age-specific trajectories. Yet so far, quantitative analyses of the molecular dynamics in the aging brain have been limited to few regions at low temporal resolution. Here we performed spatiotemporal RNA-seq of the brain across the adult mouse lifespan, encompassing 847 samples dissected from 15 regions spanning 7 age groups. We reveal that aging impacts gene expression in a region-dependent manner, varying in timing, magnitude and biological function. mRNA-seq data of 15 distinct brain regions sampled from 59 C57BL/6JN mice ( n = 3-6 males per age; aged 3, 12, 15, 18, 21, 26 and 28 months; n = 5 females per age; aged 3, 12, 15, 18 and 21 months; all C57BL/6JN strain) were generated by deep sequencing using Illumina sequencing.衰老是认知衰退的核心驱动因素，亦是多种神经退行性疾病的首要危险因素。现有行为学研究结合结构与功能磁共振成像（MRI）数据表明，衰老对大脑的影响并非均匀一致，而是呈现脑区特异性与年龄特异性的动态变化轨迹。然而迄今为止，针对衰老大脑分子动态变化的定量分析仅局限于少数脑区，且时间分辨率较低。本研究对成年小鼠整个生命周期的大脑开展了时空RNA测序（spatiotemporal RNA-seq），共获取覆盖7个年龄组、15个脑区的847份解剖样本。研究揭示，衰老对基因表达的影响具有脑区依赖性，其发生时序、调控幅度及关联生物学功能均存在显著差异。本研究从59只C57BL/6JN品系小鼠的15个独立脑区中采集样本：各年龄组雄性小鼠样本量为3~6份，对应年龄为3、12、15、18、21、26及28月龄；各年龄组雌性小鼠样本量为5份，对应年龄为3、12、15、18及21月龄。所有样本均采用Illumina测序平台开展深度测序，最终生成mRNA测序（mRNA-seq）数据。