0279 SLEEP AND BEHAVIORAL PHENOTYPE OF A COMBINED MOUSE MODEL OF TBI AND PTSD

Abstract

Introduction: Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are commonly comorbid, especially in the Veteran population. We have recently shown sleep-wake disturbances in rodent models of TBI. PTSD is also associated with significant sleep-wake and behavioral disturbances. Little is known about the phenomenology and pathophysiology underlying the combined disorder (TBI+PTSD). We created a novel mouse model of TBI+PTSD, and analyzed sleep staging, behavior, and neural activation patterns. Methods: Mice were randomized to one of four conditions: Naïve, TBI (using controlled-cortical impact), PTSD (using Single Prolonged Stress, or SPS), or TBI+PTSD. The first cohort of mice (n=8-9/group) was instrumented with EEG/EMG for chronic sleep-wake recordings and then underwent fear extinction and digital gait assessment testing. The second cohort of mice (n=20/group) underwent prepulse inhibition (PPI) testing, followed by brain immunohistochemistry for c-Fos neural activation patterns after exposure to a novel environment compared to a sleep condition. Results: Baseline sleep staging did not differ between groups. When placed into a novel environment, both PTSD and TBI+PTSD mice in showed a shorter latency to fall asleep (p=0.035) and more sleepwake transitions (p=0.066) compared to naïve mice. Both PTSD and TBI+PTSD mice showed less exploration during the fear extinction task (p<0.001). Mice in the TBI, PTSD, and TBI+PTSD groups showed decreased tau propulsion (a gait metric affected by muscle strength) in Digigait testing compared to controls (p=0.015). Mice in the TBI+PTSD group showed decreased startle response in PPI (p=0.031) compared to controls. Conclusion: Similar to what we have observed with in-lab polysomnography studies in Veteran subjects with TBI and PTSD, the mouse model of combined TBI+PTSD shows only subtle differences in objective baseline sleep staging. However, trauma-exposed mice showed profound behavioral deficits, including inability to maintain wakefulness in a novel environment, inability to extinguish fearful memories, and enhanced PPI. Ongoing studies will examine patterns of neural activation across sleep and stress circuits, and relationships between EEG and behavior.