Behavioral responses following repeated bilateral frontal region closed head impacts and fear conditioning in male and female mice.

The frontal lobes are among the most vulnerable sites in traumatic brain injuries (TBIs). In the current study, a balanced 2 x 2 x 2 design (n = 18 mice/group), female and male C57Bl/6J mice received repeated bilateral frontal concussive brain injury (frCBI) and underwent fear conditioning (FC) to assess how injured mice respond to adverse conditions. Shocks received during FC impacted behavior on all subsequent tests except the tail suspension test. FC resulted in more freezing behavior in all mice that received foot shocks when evaluated in subsequent context and cue tests and induced hypoactivity in the open field (OF) and elevated zero maze (EZM). Mice that sustained frCBI learned the FC association between tone and shock. Injured mice froze less than sham controls during context and cue tests, which could indicate memory impairment, but could also suggest that frCBI resulted in hyperactivity that overrode the rodent's natural freezing response to threat, as injured mice were also more active in the OF and EZM. There were notable sex differences, where female mice exhibited more freezing behavior than male mice during FC context and cue tests. The findings suggest frCBI impaired, but did not eliminate, FC retention and resulted in an overall increase in general activity. The injury was characterized pathologically by increased inflammation (CD11b staining) in cortical regions underlying the injury site and in the optic tracts. The performance of male and female mice after injury suggested the complexity of possible sex differences for neuropsychiatric symptoms.