An experimental protocol for mimicking pathomechanisms of traumatic brain injury in mice

Traumatic brain injury (TBI) is a result of an outside force causing immediate mechanical disruption of brain tissue and delayed pathogenic events that can exacerbate the injury (reviewed by [1]). It represents a leading cause of death and disability in the industrialized countries [2,3] and a growing health problem in the developing countries [4-7]. To better understand the pathological mechanisms underlying TBI and to develop strategies and interventions to limit the secondary damage, the use of rodent models is essential. A number of rodent models to induce brain trauma have been described; however, none of them covers the entire spectrum of events that might occur in TBI [8]. As an example, the cortical cryolesion model is particularly suited for investigating TBI-associated focal lesions with blood-brain barrier leakage and vasogenic brain edema [9-13] but contre coup and diffuse axonal injuries that typically complicate human head injuries [1] are missing. This pathophysiology is present in the weight drop models of TBI which use the gravitational forces of a free falling weight to produce a mix of focal and diffuse brain injury [14-16]. One main characteristic of TBI associated diffuse axonal injury is the axonal disruption caused by shearing forces. Typical pathological changes include axonal swelling, axoplasmic ovoid retraction balls and expression of amyloid beta peptides [17]. The original weight drop model in rats by Feeney [18,19] was optimimized to produce an open-head brain injury whereas the model developed by Shohami [20-22] produces a closed-head brain injury with both focal and diffuse injury and enables its adaptation for mice. We provide here a methodological description of our modification of the Shohami model [14,21] to induce closed head weight drop injury in mice.All experiments require an appropriate animal experimentation facility and need to be conducted in accordance with the laws and regulations of the regulatory authorities for animal