Histological comparison of repeated mild weight drop and lateral fluid percussion injury models of traumatic brain injury (TBI) in female and male rats.

Abstract

In preclinical traumatic brain injury (TBI) research, the animal model should be selected based on the research question and outcome measures of interest. Direct side by side comparisons of different injury models are essential for informing such decisions. Here, we used immunohistochemistry to compare the outcomes from two common models of TBI, lateral fluid percussion (LFP) and repeated mild weight drop (rmWD) in adult female and male Wistar rats. Specifically, we measured the effects of LFP and rmWD on markers of cerebrovascular and tight junction disruption, neuroinflammation, mature neurons, and perineuronal nets in the cortical site of injury, cortex adjacent to injury, dentate gyrus, and the CA2/3 area of the hippocampus. Animals were randomized into LFP or rmWD groups. On day 1, the LFP group received a craniotomy and on day 4, injury (or sham procedure; randomly assigned). The rmWD animals underwent either injury or isoflurane-only (randomly assigned) on each of those 4 days. Seven days after injury, brains were harvested for analysis. Overall, our observations revealed that the most significant disruptions were evident in response to LFP, followed by craniotomy-only, while rmWD animals showed the least residual changes compared to isoflurane-only controls, supporting consideration of rmWD as a mild injury. LFP led to longer-lasting disruptions, perhaps more representative of moderate TBI. We also report that craniotomy and LFP produced greater disruptions in females relative to males. These findings will assist the field in the selection of animal models based on target severity of post-injury outcomes, and support the inclusion of both sexes and appropriate control groups.