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

Abstract

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. 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. 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 sleep-wake 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. 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. VA CDA # IK2 BX002712, OR Medical Research Foundation, Portland VA Research Foundation.