ACNP 57th Annual Meeting: Poster Session II

<span title="">2018</span> <i title="Springer Science and Business Media LLC"> <a target="_blank" rel="noopener" href="" style="color: black;">Neuropsychopharmacology</a> </i> &nbsp;
Post-traumatic stress disorder (PTSD) remains a growing and often debilitating psychiatric disorder resulting from severe trauma. Increasing evidence suggests a role for systemic and neurological inflammation in the pathophysiology of fear and trauma exposure based psychiatric disorders (Micholpoulos et al., 2017; Haroon et al., 2012). Several large case-control and prospective studies have shown associations with PTSD diagnosis and elevated serum peripheral inflammatory markers, including the
more &raquo; ... cute phase reactant C-reactive protein (CRP) (Spitzer et al., 2010; Passos et al., 2014). Moreover, one prospective study demonstrated that marines who were diagnosed with post-deployment PTSD previously had a twofold higher baseline serum CRP levels prior to deployment (Eraly et al., 2014). CRP genetic mutations have also been positively correlated with increased PTSD symptoms, further suggesting CRP may confer risk for PTSD pathogenesis (Michopoulos et al., 2015). We tested the hypothesis that increased CRP after gene transfer using an adeno-associated virus (AAV8) encoding murine CRP may confer a higher risk for PTSD-like behaviors after predator stress. Methods: Male C57BL6J mice received a single intrajugular injection of 1011 genome copies (gc) of either AAV8.CRP or AAV8. Null. Four weeks after infection, mice were exposed to either predator stress (10 minutes roomed with a laboratory cat) or handled (stress control). After one week, mice were tested for avoidance behaviors by open field and light-dark box testing. Two weeks post predator stress, we assessed avoidance of trauma cues by measuring exploration of a cue scented with dirty cat litter. Mice where cheek-bled one day after the trauma reminder to measure differential peripheral CRP protein expression post trauma reminder. We further assessed fear conditioning by pairing five separate twenty-second tones (75 dB, 4 kHz) with terminal shocks (0.7 mAmps, 1 second) and forty second inter-trial intervals (ITI). Twenty-four hours later, contextual fear was assessed by exposing mice to the chambers for 16 minutes without tones or shocks. After a final twenty-four hours, mice were exposed again to thirty-two tones (20 seconds, 5 second ITI) within chambers containing altered visual, tactile, and odor dimensions to minimize contextual fear. Following fear conditioning, mice were sacrificed for further brain and peripheral tissue analysis. Results: 6 weeks post AAV8.CRP infection, and subsequent to predator stress and trauma reminder behavioral testing, levels of plasma CRP were almost three-fold higher in animals who had received AAV8.CRP (~18,300 ng/mL, n = 29) compared to AAV8. Null (~6,500 ng/mL, n = 32, p < 0.0001). Predator stress did not significantly alter CRP levels in either group (n = 17-19). A composite avoidance score (average of Z-scores across open field, light-dark box, and trauma reminder) demonstrated a main effect of increased avoidance behaviors by two-way ANOVA (Fstress = 9.10, p = 0.0036), though CRP overexpression had no effect either in baseline avoidance or in response to predator stress. Predator stress also increased conditioned fear acquisition as evidence by increased freezing (Fstress = 4.21, n = 11-13, p = 0.006), overall there was no effect of either predator stress or CRP on either contextual freezing or in freezing with altered context. CRP expression across peripheral organs and brain will also be discussed. Conclusions: This preliminary study indicated that CRP overexpression exposure did not induce increase risk for avoidance behaviors or conditioned fear after trauma exposure through predator stress, despite high levels of protein. Further investigation is still required to determine if there are sex-specific differences. These data indicate that when limited to adulthood, high CRP loads representing physiological levels in humans do not appear to be sufficient to alter susceptibility to trauma. These results suggest that either CRP gene mutations are required to increase risk or that CRP may only be a marker of immune pathology but is not itself directly contributing to PTSD pathogenesis.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="">doi:10.1038/s41386-018-0267-6</a> <a target="_blank" rel="external noopener" href="">fatcat:febeq6uwefgdzm65ccmzrmjwjy</a> </span>
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