QUANTITATIVELY CONTROLLED TRAUMATIC BRAIN INJURY IMPAIRS ADULT HIPPOCAMPAL NEUROGENESIS AND INDUCES CHRONIC TRAUMATIC ENCEPHALOPATHY-LIKE NEUROPATHOLOGY IN A FORCE-DEPENDENT MANNER

Traumatic brain injury (TBI) poses significant health risks, yet the correlation between impact intensity and neuropathological outcomes remains unclear due to limitations in existing animal models. We aimed to elucidate impact-dependent changes in adult neurogenesis and Chronic Traumatic Encephalopathy (CTE)-like signatures using a novel Quantitatively Controlled and Measured-TBI (QCM-TBI) system. We subjected male C57BL/6 mice to precise closed-head injuries at two force levels (F20: 21.7 mNs; F40: 41.1 mNs) and performed transcriptomic analysis, immunohistochemistry, electron microscopy, and behavioral assessments, comparing findings with human CTE post-mortem tissues. Results demonstrated that QCM-TBI induced a force-dependent downregulation of hippocampal neuronal genes, particularly those related to synaptic function and neurogenesis (Dcx, NeuroD1, Syn1), which significantly overlapped with gene signatures downregulated in CTE patients. Neuropathologically, mice exhibited impact-dependent increases in phosphorylated Tau (p-Tau) and amyloid precursor protein (APP), alongside axonal damage and myelin disruption, mirroring key CTE features. Behavioral tests revealed that higher impact forces led to delayed recovery, increased anxiety-like behavior, and memory deficits. We conclude that mechanical impact intensity directly correlates with impaired neurogenesis and the onset of CTE-like pathology. The QCM-TBI system provides a validated, force-responsive model for dissecting the biomechanical mechanisms of TBI and identifying therapeutic targets for trauma-induced neurodegeneration.