Lateral Fluid Percussion Injury Causes Sex-Specific Deficits in Anterograde but Not Retrograde Memory

Abstract

Cognitive impairment is a common symptom after traumatic brain injury (TBI). Memory, in particular, is often disrupted during chronic post-injury recovery. To understand the sex-specific effects of brain injury on retrograde and anterograde memory, we examined paired associate learning (PAL), spatial learning and memory, and fear memory after lateral fluid percussion TBI. We hypothesized that male and female mice would display unique memory deficits after TBI. PAL task acquisition was initiated via touchscreen operant conditioning 22 weeks before sham injury or TBI. Post-injury PAL testing occurred 7 weeks post-injury. Barnes maze and fear conditioning were completed at 14- and 15-weeks post-injury, respectively. Contrary to our expectations, behavioral outcomes were not primarily influenced by TBI. Instead, sex-specific differences were observed in all tasks which exposed task-specific trends in male TBI mice. Male mice took longer to complete the PAL task, but this was not affected by TBI and did not compromise the ability to make a correct choice. Latency to reach the goal box decreased across testing days in Barnes maze, but male TBI mice lagged in improvement compared to all other groups. Use of two learning indices revealed that male TBI mice were deficient in transferring information from 1 day to the next. Finally, acquisition and contextual retention of fear memory were similar between all groups. Cued retention of the tone-shock pairing was influenced by both injury and sex. Male sham mice displayed the strongest cued retention of fear memory, evidenced by increased freezing behavior across the test trial. In contrast, male TBI mice displayed reduced freezing behavior with repetitive tone exposure. An inverse relationship in freezing behavior to tone exposure was detected between female sham and TBI mice, although the difference was not as striking. Together, these studies show that retrograde memory is intact after lateral TBI. However, male mice are more vulnerable to post-injury anterograde memory deficits. These behaviors were not associated with gross pathological change near the site injury or in subcortical brain regions associated with memory formation. Future studies that incorporate pre- and post-injury behavioral analysis will be integral in defining sex-specific memory impairment after TBI.

Sleep fragmentation after traumatic brain injury impairs behavior and conveys long-lasting impacts on neuroinflammation

“…The sex-specific effect of post-TBI SF on MWM performance is of particular interest. These findings are in line with previous work showing that moderate LFPI produces sex-specific deficits in anterograde memory ( Fitzgerald et al, 2022 ). Therefore, in our post-TBI stress model, the male mouse brain may be vulnerable to memory impairment.…”

“…Surgical preparations were completed as previously described ( Fitzgerald et al, 2022 ; Tapp et al, 2020 , 2022 , 2023 ). Briefly, mice were anesthetized with 4% isoflurane gas for 4 min.…”

IDO-1 inhibition improves outcome after fluid percussion injury in adult male rats

“…While FPI did not impact rat learning ability on the Barnes maze at 14-17 DPI, it did cause memory disruption. The lack of learning deficits after FPI is in keeping with previous reports (Fitzgerald et al, 2022; Krishna et al, 2017; Lima, Camila Nayane de Carvalho et al, 2019) and not unexpected. FPI-induced memory deficits were not as marked on the short-term probe trial as they were on the long-term probe.…”

IDO‐1 inhibition improves outcome after fluid percussion injury in adult male rats

“…While FPI did not impact rat learning ability on the Barnes maze at 14-17 DPI, it did cause memory disruption. The lack of learning deficits after FPI is in keeping with previous reports (de Carvalho Lima et al, 2019;Fitzgerald et al, 2022;Krishna et al, 2017) and not unexpected. FPI-induced memory deficits were not as marked on the shortterm probe trial as they were on the long-term probe.…”

“…While our results show promise for IDO1 manipulation as a target to improve memory after TBI, the mechanisms remain to be elucidated. (Himanshu et al, 2020;Knight et al, 2021) and is consistent with reports of increased anxiety-like behaviors in rats after FPI demonstrated in a variety of tests (Almeida-Suhett et al, 2014;Bao et al, 2012;Fucich et al, 2019). Increased IDO1 activity has been linked with anxious behaviors in response to environmental stress (de Carvalho Lima et al, 2019), and IDO1 inhibition following an inflammatory challenge significantly reduced previously present anxious behaviors (Salazar et al, 2012).…”