Abstracts

Rationale: Severe traumatic brain injury (TBI) is a leading cause of epilepsy. Post-traumatic epilepsy (PTE) affects up to 20% of patients with acquired epilepsy and has a significant impact on patients’ quality of life. Neurobehavioral comorbidities, like post-traumatic depression, may ensue; both TBI and PTE may influence their pathogenesis. The current project examines whether the development of depressive-like traits in the lateral fluid percussion injury (LFPI) model of PTE depends upon the TBI and/or associated seizures. In this study, we used the forced swim test (FST) to assess hopelessness/despair and taste preference test (TPT) for anhedonia traits to investigate whether LFPI confers increased susceptibility to and track the development of depressive symptomatology after LFPI. Methods: Male and female 9-week old Sprague-Dawley rats were used by both sites (Einstein vs UCLA). All animals underwent FST and TPT at baseline.  Two weeks later, the animals were randomized into 2 groups: shams and LFPI. A 5mm craniotomy was performed in both groups over the left parietal region; LFPI animals were subjected to a 2.91±0.33 atm fluid pulse at the craniotomy to induce severe TBI. Shams did not receive the fluid pulse. A month post-LFPI, all rats were examined again with the battery of behavioral tests. FST scores were expressed as % time in activity. Saccharin preference in TPT was expressed as a daily intake of 0.1% saccharin solution vs. total fluid intake (i.e. saccharin + regular water).  Paired t-test and repeated measures mixed model analysis were used for the statistics. Results: At baseline, there were no statistically significant sex differences in FST (53.2±13.1 vs 59.9±19) or TPT (72.42±24 vs 74.8±20; 28 females, 52 males). Einstein rats showed reduced saccharin preference (67.1±23.9%, n=49) compared to UCLA rats (84.8±9.5%, n=31) (P=0.0017, Wilcoxon/Kruskal-Wallis test). There were no site-specific differences in FST scores. Among rats that were assessed at both baseline and 1month post-induction (26 LFPI, 16 sham), there was a remarkable decrease in FST performance at one month post-induction when both sexes were combined, suggestive of more depressive-like symptomatology in the LFPI animals (P=0.0497) compared to the shams (0.2358) (Wilcoxon signed rank). Post hoc comparisons suggest that this depressive trait was more prominent in male post-LFPI male rats (P<0.05) than in females or shams (repeated measures mixed model analysis). Saccharin preference was also impaired overall in rats 1 month post-induction (P=0.0477, Wilcoxon signed rank). TPT impairment was more prominent in the UCLA rats (P=0.0173). Conclusions: We report site- and trait-specific differences in depressive symptomatology at baseline and after TBI which may be related to the source or handling of rats. Severe TBI caused a significant impairment in FST at both sites but impaired TPT only in the UCLA rats, which had higher saccharin preference at baseline. Ongoing studies are evaluating the persistence and the effect of post-TBI seizures on these depressive traits to investigate the interaction and pathogenesis of TBI, PTE and depressive symptomatology. AMK and JSMM had equal first author contribution in this study. Funding: United States Department of Defense (W81XWH-13-1-0180), NINDS RO1 NS091170, the NINDS Center without Walls U54 NS100064 (EpiBioS4Rx), S. and V. Harinarayan Endowment to UCLA Epilepsy Research Laboratories.