Functional and microstructural biomarkers of repetitive mild head injury in a conscious momentum exchange mouse model

Repetitive mild traumatic brain injury (rmTBI) represents a significant public health concern, yet preclinical models have been limited by methodological confounds including anesthesia, restricted head motion, and skull fracture.

This study adapted the momentum exchange model, previously validated only in rats, for use in awake mice during their active circadian phase, creating the first closed-head, acceleration-driven mTBI model in conscious mice. Adult C57BL/6 mice (N = 18, 50% female) received either repetitive head impacts (0.34 J energy input at 3.7 m/s) or sham procedures across two consecutive days, followed by comprehensive multimodal assessment.

rmTBI induced significant functional and microstructural alterations observable ten days post-injury: (1) altered cerebrovascular reactivity to CO₂ challenge throughout the cortex and cerebellum, (2) global reduction in awake resting-state functional connectivity, (3) reduced fractional anisotropy in the olfactory system, midbrain dopaminergic system, and cerebellum, and (4) trends toward astrocytosis and microgliosis in the substantia nigra. Notably, single impacts produced minimal acute effects, but repetitive injuries compounded to produce lasting functional and microstructural changes that persisted through the 10-day recovery period.

These findings establish an ecologically valid mouse model of rmTBI that recapitulates key features of human mild head injury, including functional neurovascular and network disruption in the absence of overt behavioral deficits, while avoiding the confounds of anesthesia, forced head restraint, and inappropriate circadian timing that have limited translation of previous preclinical models. This model provides a critical tool for mechanistic studies and therapeutic development in rmTBI research.