Abstracts

Rationale: Traumatic brain injury (TBI) causes a robust activation of innate immune system in the brain ("priming"). We hypothesized that occurrence of peripheral infection in the brain that had previously been "primed" by TBI reactivates innate immunity cells and facilitates epileptogenesis and other post-TBI comorbidities. Methods: Adult rats were subjected to lateral fluid-percussion injury. Lesion endophenotype ("focal" or "large cavity" in the cerebral cortex) was assessed with T2-weighted magnetic resonance imaging (MRI) at 6 wk post-TBI. Then, rats were randomized into 4 groups: focal-Veh, focal-LPS, cavity-Veh, cavity-LPS. At 9 wk post-TBI, rats received a single injection of lipopolysaccharide (LPS; 5mg/kg, i.p.) or vehicle. At 3 wk post-LPS, rats underwent open-field (OF), elevated plus-maze (EPM), sucrose preference, and forced swimming tests. At 16 wk post-TBI, a 4-wk long video-EEG (v-EEG) monitoring was performed, followed by Morris water-maze (MWM) test. In the end, rats were subjected to pentylenetetrazol (PTZ) seizure-susceptibility test. The extent and progression of cortical lesion was assessed with unfolded maps prepared from MRI at 6 wk and Nissl-stained sections at 24 wk post-TBI. Results: MRI indicated that 53% of the rats developed a "focal" and 47% a "large cavity" type of lesion endophenotype. In the OF, no difference was found between the TBI-Veh and sham groups. TBI-LPS rats, however, spent less time in the middle and more in the outer zone as compared to the sham group (p < 0.01), regardless of the lesion endophenotype (cavity-LPS vs. sham, p < 0.01; focal-LPS vs. sham, p < 0.05). Moreover, TBI-LPS rats spent more time in the outer zone than TBI-Veh animals (p < 0.05). In the EPM, TBI-Veh and TBI-LPS rats spent less time in open arms than sham-controls (p < 0.05). In the MWM, the latency to find the hidden platform was prolonged both in TBI-Veh and TBI-LPS rats, and they spent less time in the target quadrant than sham-controls (p < 0.05). In the MWM probe trial, LPS treatment facilitated spatial memory impairment more in "cavity" than "focal" lesion endophenotype (p < 0.05). vEEG revealed that 2 of 7 rats in the focal-Veh group had epilepsy. No difference in occurrence of seizures was found between the TBI-LPS and TBI-Veh groups, but the percent of animals with seizures in the PTZ test was higher in focal-LPS than in focal-Veh group (p < 0.05). Duration of PTZ-induced seizures was longer in TBI-LPS than TBI-Veh rats (p < 0.05), particularly in rats with a "cavity" endophenotype (p < 0.05). Finally, in the TBI-LPS group, the lesion area in unfolded histologic maps was 111% of that in unfolded MRI maps (p < 0.05), which related to lesion progression in the "focal" endophenotype (p < 0.05). Conclusions: Exposure to peripheral infection at the chronic time point after TBI augments anxiety-like behavior, increases seizure susceptibility, and facilitates the progression of cortical lesion. Funding: Academy of Finland