Conceptualization and standardization of a non-invasive closed head injury model using directed shockwave to mice

Abstract

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with closed head injury (CHI) being one of the most common forms of TBI. Preclinical modeling of TBI is challenging due to confounding factors like craniectomy and poorly controlled injury severity. This study proposes a non-invasive CHI model using directed shockwaves. The mice heads were exposed to the shockwave and accommodated together following the implantation of RFID tags for automated neurocognitive assessment. Following a 13-days paradigm, mice underwent a digital gait analysis and subsequent classical behavioral test paradigms for affective, cognitive, and locomotor functions. Qualitative and quantitative histopathological assessment was carried out for shockwave pulses-dependent changes in terms of lesion volume, neuronal death, dendritic complexity, and spine density. Studies showed shockwave pulses-dependent differences in survivability, righting reflex, neural damage, and death. Shockwave-exposed mice showed significantly impaired learning and cognitive flexibility. Interestingly, exposed mice showed locomotor hyperactivity and risk-taking behavior (lack of anxiety) along with depression-like phenotypes. Our result suggests that the shockwave-based CHI models result in the clinically relevant phenotype and are precisely controlled for reproducibility.