Quantitatively controlled and measured-traumatic brain injury impairs adult neurogenesis and alters neuropathological signatures in mice.

Rationale: Traumatic brain injury (TBI) poses a significant global health concern, necessitating a comprehensive understanding of its pathophysiology to devise effective treatments. The correlation between the intensity of head impact during injury and resultant neuropathology and behavioral changes in TBI remains unclear. Methods: The Quantitatively Controlled and Measured-TBI (QCM-TBI) system, a novel closed-head injury model, enables precise control and measurement of impact during collision. The QCM-TBI system is designed with a unique gravity-compensating animal support system that replicates natural head motion in human TBI. Using QCM-TBI in conjunction with a multimodal sensor fusion technique, we measured instantaneous force over the time of collision, while compensating distortion led by extreme acceleration of the force sensor. To address whether TBI affects neuropathology and behaviors of mice in a force-dependent manner, we conducted transcriptome analysis, electron microscopy, and confocal microscopy in QCM-TBI model. We further compared molecular and pathological features of QCM-TBI mice with chronic traumatic encephalopathy (CTE) patients. Results: Transcriptome analysis of QCM-TBI mice showed a significant downregulation of neuronal genes associated with synaptic function and neurogenesis, particularly in the hippocampus, which correlated with the severity of neuropathological features. Molecular and neuropathological characteristics of QCM-TBI mice partially resemble those of chronic traumatic encephalopathy (CTE) patients. Levels of phosphorylated Tau (p-Tau) and amyloid precursor protein (APP) correlate with impact magnitude, while neurofilament levels diminish in QCM-TBI mice. Neurons exhibit ultrastructural axonal damage in an impact-dependent manner. Conclusions: Overall, this study suggests head impact intensity leads to decreased adult hippocampal neurogenesis, increased levels of phosphorylated Tau (p-Tau), and axonal damage, reflecting key neuropathological signatures of traumatic brain injury. Consequently, therapeutic strategies for TBI should account for the impact's severity in determining neuropathological outcomes.