Neuropsychiatric Symptom Modeling in Male and Female C57BL/6J Mice after Experimental Traumatic Brain Injury

Abstract

Psychiatric symptoms such as anxiety and depression are frequent and persistent complaints following traumatic brain injury (TBI). Modeling these symptoms in animal models of TBI affords the opportunity to determine mechanisms underlying behavioral pathologies and to test potential therapeutic agents. However, testing these symptoms in animal models of TBI has yielded inconsistent results. The goal of the current study was to employ a battery of tests to measure multiple anxiety- and depressive-like symptoms following TBI in C57BL/6J mice, and to determine if male and female mice are differentially affected by the injury. Following controlled cortical impact (CCI) at a parietal location, neither male nor female mice showed depressive-like symptoms as measured by the Porsolt forced-swim test and sucrose preference test. Conclusions regarding anxiety-like behaviors were dependent upon the assay employed; CCI-induced thigmotaxis in the open field suggested an anxiogenic effect of the injury; however, results from the elevated zero maze, light-dark box, and marble-burying tests indicated that CCI reduced anxiety-like behaviors. Fewer anxiety-like behaviors were also associated with the female sex. Increased levels of activity were also measured in female mice and injured mice in these tests, and conclusions regarding anxiety should be taken with caution when experimental manipulations induce changes in baseline activity. These results underscore the irreconcilability of results from studies attempting to model TBI-induced neuropsychiatric symptoms. Changes in injury models or better attempts to replicate the clinical syndrome may improve the translational applicability of rodent models of TBI-induced anxiety and depression.

Sexual dimorphism in the inflammatory response to traumatic brain injury

“…Other groups have used in-depth behavioral studies to study sex-differences after preclinical TBI. Similar to our findings, Tucker et al demonstrated that female mice had a similar lesion volume to male mice 30 d after CCI, and presented with similar behavioral deficits in the Morris Water maze and rotarod test, although female mice display fewer anxiety-like behaviors after CCI (Tucker et al 2017; Tucker et al 2016). Other studies have found that female rates have better motor ability following TBI compared to males (Roof et al 1993; Wagner et al 2004).…”

“…Previous studies have revealed that the estrous cycle stage at the time of the injury has no effect on post-injury neuroprotection of female mice and rats (Bramlett and Dietrich 2001; Monaco et al 2013). In addition, when TBI was induced at random stages of the estrous cycle the performance variability was similar to that reported in male mice (Tucker et al 2017; Tucker et al 2016). …”

“…Multiple reports have noted that females rodents appear protected against the effects of CNS injury compared with males (Dang, Mitkari, Kipp, & Beyer, 2011;Fleiss, Nilsson, Blomgren, & Mallard, 2012;Igarashi, Huang, & Noble, 2001) but conversely a study examining the effect of sex on TBI outcome in mice report no effect on lesion volume (Bruce-Keller et al, 2007;Tucker, Burke, Fu, & McCabe, 2017;Tucker, Fu, & McCabe, 2016;Xiong et al, 2007). Most of these studies have examined a single time-point postinjury, but in the current study, we found that female mice had a faster resolution of TUNEL staining compared with male mice, which correlated with smaller lesion volume at 3 and 7 dpi.…”

Progression of histopathological and behavioral abnormalities following mild traumatic brain injury in the male ferret

“…In addition, anxiety measurements in mice/rats after TBI using the open field test are to date inconclusive (Malkesman et al, 2013). Mice decrease their traverse of the center distance traveled in severe, but not mild, injury (Tucker et al, 2017); our animals more likely fall into the mild injury category.…”

“…Depressed animals can exhibit futility (e.g., Crawley, 1999;Porsolt, Anton, Blavet, & Jalfre, 1978). Results regarding behavioral despair in mice/rats after TBI using the more aversive swim test or tail suspension test, however, are inconclusive or negative (Malkesman, Tucker, Oz, & McCabe, 2013;Tucker, Burke, Fu, & McCabe, 2017). The open field test would not be called aversive, so the reduction in rearing may be related to something else.…”