Swaro Aditya, Bristow Brianna N, Anwer Mehwish, Zhang Angela A, Kraus Larissa, Gandhi Riya K, Erwin Sarah R, Stach Tara R, Sullivan Kaitlin E, Fan Jianjia, Cheng Wai Hang, Wellington Cheryl L, Cembrowski Mark S
Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Cell Rep. 2025 Jun 24;44(6):115795. doi: 10.1016/j.celrep.2025.115795. Epub 2025 Jun 5.
Knowledge of how traumatic brain injury (TBI) alters the brain is urgently needed. A major challenge to this understanding is that TBI is a multiscale problem capable of evoking a host of perturbations across the brain and often presents large subject-to-subject variability. To circumvent these challenges, here, we employ the murine closed-head impact model of engineered rotational acceleration (CHIMERA) TBI model to produce mild, diffuse TBI reproducibly across mice in the subacute phase and apply spatial transcriptomics to study the multiscale effects of TBI. In doing so, we identify generalizable signatures of TBI that are present across brain regions, as well as a variety of brain-region- and cell-type-specific dysregulation. This dysregulation includes unexpected susceptibility of astrocytes in the molecular layer of the dentate gyrus, as well as dramatic gene expression changes in neurons of the thalamus. Ultimately, our work here helps to distill the multiscale complexity of TBI into interpretable brain regions, cell types, and molecular sequelae.
迫切需要了解创伤性脑损伤（TBI）如何改变大脑。理解这一问题的一个主要挑战在于，TBI是一个多尺度问题，能够引发大脑中的一系列扰动，并且常常在个体之间呈现出很大的变异性。为了规避这些挑战，在此我们采用工程化旋转加速度的小鼠闭合性颅脑撞击模型（CHIMERA）TBI模型，在亚急性期在小鼠中可重复地产生轻度、弥漫性TBI，并应用空间转录组学来研究TBI的多尺度效应。通过这样做，我们识别出了在整个脑区都存在的TBI的可概括特征，以及各种脑区和细胞类型特异性的失调。这种失调包括齿状回分子层中星形胶质细胞出人意料的易感性，以及丘脑神经元中显著的基因表达变化。最终，我们在此所做的工作有助于将TBI的多尺度复杂性提炼为可解释的脑区、细胞类型和分子后遗症。
