A Repetitive Weight-Drop Procedure for Establishing a Mouse Model of Chronic Traumatic Brain Injury

Traumatic brain injury (TBI) can lead to persistent neuropathological changes and long-term neuropsychiatric sequelae. During recovery, a substantial proportion of patients develop affective disturbances, including depressive symptoms and sleep-related complaints, even when routine computed tomography or magnetic resonance imaging reveals no obvious structural abnormalities. Experimental models that reproduce these features are needed to investigate the mechanisms underlying chronic post-traumatic neuropsychiatric symptoms. Here, we present a protocol to establish a repetitive closed-head mild traumatic brain injury mouse model for studying the mechanisms underlying chronic depressive-like behavior in the absence of overt gross structural brain lesions detectable by macroscopic examination and T2-weighted MRI. In this method, the intact skull is exposed and subjected to repeated impacts using defined weight-drop parameters over five consecutive days. Under the conditions described here, the procedure produces a closed-head injury without gross skull fracture or macroscopic focal contusion. After a post-injury interval, mice exhibit depressive-like behaviors while showing no obvious focal structural abnormalities on gross examination or T2-weighted magnetic resonance imaging under the conditions used in this study. This protocol provides an experimental approach for studying chronic depressive-like behavior after repetitive mild traumatic brain injury and for evaluating potential therapeutic interventions.