Immune signaling mechanisms of PTSD risk and symptom development: insights from animal models

Abstract

Post-traumatic stress disorder (PTSD) is characterized by persistent re-experiencing of a traumatic event, avoidance, and increased arousal. The approved pharmacological treatments for PTSD have limited efficacy (~60% treatment response), supporting the need for identification of biomarkers and novel pharmacological therapies. Mounting evidence suggests increased inflammatory markers and altered immune gene expression correlate with the severity of symptoms in PTSD patients. However a causal role of immune signaling in development and maintenance of PTSD symptoms is not clear, as inflammation may also be an epiphenomenon related to metabolic and behavioral effects of stress. Animal studies have been critical in understanding the potential causal role of immune signaling in PTSD. In this review we will present the most recent evidence, primarily focusing on the last 3 years, for inflammatory dysfunction both preceding and following PTSD, and how animal models of PTSD have contributed to our understanding of immune mechanisms involved in enduring anxiety after trauma. We will particularly focus on the role of peripheral vs. central immune signaling, the differences between single vs. chronic stress models of PTSD and recent utilization of these models to investigate novel anti-inflammatory treatments. We also highlight some current gaps in the literature including models of TBI/PTSD comorbidity, lack of translational peripheral markers of inflammation and the relatively incomplete understanding of the inflammatory trajectory after severe stress.

Metabolism, Metabolomics, and Inflammation in Posttraumatic Stress Disorder

“…Inflammatory responses in animal models were seen in specific brain regions and throughout the system. A predator-exposure rat study found increased proinflammatory cytokines in the hippocampus, amygdala, and prefrontal cortex, with a concomitant reduction in anti-inflammatory cytokines (58,59). Similarly, a stress-enhanced fear-learning model showed increased hippocampal IL-1b concentrations, and the learning decrement was prevented by blocking central IL-1b signaling after the stress (60).…”

Sleep disturbance at pre-deployment is a significant predictor of post-deployment re-experiencing symptoms

“…There is already considerable evidence for a significant association between inflammation and PTSD diagnosis (Breen et al, 2018;Brudluy et al, 2015;Michopoulos et al, 2015;Miller et al, 2018;Spitzer et al, 2010). Moreover, there is prospective evidence that inflammation may be a risk factor for PTSD emergence (Breen et al, 2015;Eraly et al, 2014) and that it affects fear circuits and processes (Deslauriers, Powell, & Risbrough, 2017). Taken together with findings of the present study, it is thus conceivable that pre-deployment sleep disturbance among military personnel may have resulted in an increase in inflammatory signalling which predisposed to the development of re-experiencing symptoms following trauma exposure (Besedovsky, Lange, & Haack, 2019).…”

Current Status of Animal Models of Posttraumatic Stress Disorder: Behavioral and Biological Phenotypes, and Future Challenges in Improving Translation

“…Other established biological phenotypes include increased activity/function of amygdala, reduced function and structural abnormalities in prefrontal cortex (PFC) and hippocampus (6–9). PTSD is consistently associated with increased inflammation both as a risk factor and in relation to symptom state (10). Finally, sleep disturbances, including reduced sleep duration or fragmented rapid eye movement (REM), are commonly described in PTSD (6).…”