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Review
. 2020 Jan 14;13:85.
doi: 10.3389/fnsys.2019.00085. eCollection 2019.

Investigating Individual Pre-trauma Susceptibility to a PTSD-Like Phenotype in Animals

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Free PMC article
Review

Investigating Individual Pre-trauma Susceptibility to a PTSD-Like Phenotype in Animals

Khadijah S Alexander et al. Front Syst Neurosci. .
Free PMC article

Abstract

Post-Traumatic Stress Disorder (PTSD) is a complex condition that develops after experiencing a severe emotional trauma, with or without physical trauma. There is no known cure and evidence-based treatments, which are effective in reducing symptoms, have low retention rates. It is therefore important, in addition to seeking new therapeutics, to identify ways to reduce the likelihood of developing PTSD. The fact that some, but not all, individuals exposed to the same traumatic event develop PTSD suggests that there is individual susceptibility. Investigating susceptibility and underlying factors will be better guided if there is a coherent framework for such investigations. In this review, we propose that susceptibility is a dynamic state that is comprised of susceptibility factors (before trauma) and sequalae factors (during or after trauma, but before PTSD diagnosis). We define key features of susceptibility and sequalae factors as: (1) they are detectable before trauma (susceptibility factors) or during/shortly after trauma (sequalae factors), (2) they can be manipulated, and (3) manipulation of these factors alters the likelihood of developing PTSD, thus affecting resilience. In this review we stress the importance of investigating susceptibility to PTSD with appropriate animal models, because prospective human studies are expensive and manipulation of susceptibility and sequalae factors for study purposes may not always be feasible. This review also provides a brief overview of a subset of animal models that study PTSD-related behaviors and related alterations in endocrine and brain systems that focus on individual differences, peri- and post-trauma. Attention is drawn to the RISP model (Revealing Individual Susceptibility to a PTSD-like Phenotype) which assesses susceptibility before trauma. Using the RISP model and expression of plasticity-associated immediate early genes, Arc and Homer1a, we have identified impaired hippocampal function as a potential susceptibility factor. We further discuss other putative susceptibility factors and approaches to mitigate them. We assert that this knowledge will guide successful strategies for interventions before, during or shortly after trauma that can decrease the probability of developing PTSD.

Keywords: PTSD; RISP model; hippocampus; immediate early genes; medial prefrontal cortex; rats; risk factors; susceptibility.

Figures

FIGURE 1
FIGURE 1
Theoretical framework of the relationship between risk, susceptibility, and sequalae factors. Susceptibility is a state that can be altered by manipulating susceptibility and/or sequalae factors.
FIGURE 2
FIGURE 2
RISP model: Stage 1 (Pre-trauma classification): Rats are briefly stressed with a mild stressor (a ball of cat hair). Four days later, they are classified as Resilient (RES), Susceptible (SUS), or Intermediate (Int) based on their acoustic startle response (ASR1) and anxiety-like behavior in the Elevated Plus Maze (EPM); Stage 2 (Psychogenic trauma): Rats experience foot shock-motivated contextual fear conditioning (CFC) as a psychogenic trauma; Stage 3 (Post-trauma phenotype): Fear extinction and post-trauma startle (ASR2) are assessed. The original presentation of the model does not include other tests aligned with a complex PTSD-like phenotype, but these can be performed to evaluate cognitive and anxiety-like behavior after trauma. D = day; W = week.
FIGURE 3
FIGURE 3
(A) Freezing during daily extinction sessions of Resilient (gray circles) and Susceptible (black squares) rats. (B) Magnitude of extinction on day 4 (ED4) in Resilient (RES) and Susceptible (SUS) rats which is the percent reduction in freezing from ED1 to ED4; p < 0.01. (C) Acoustic startle response at classification (ASR 1) and 3 weeks post trauma (ASR 2); p < 0.001. From “Predicting impaired extinction of traumatic memory and elevated startle,” by Nalloor et al. (2011). Copyright 2011 by the PLoS One. Adapted with permission.
FIGURE 4
FIGURE 4
(A) Experimental design for spatial exploration (A-A). (B,C) Representative images of neuronal Arc (red) and Homer1a (green) expression in dCA1 of Resilient (RES) and Susceptible (SUS) rats using FISH. Nuclei are counterstained with DAPI (blue). (D) Exploring a novel context twice (box A), leads to a significant decrease in the size of IEG-expressing neuronal ensembles during the second exploration in RES and SUS rats. [Event effect F(1,13) = 111.68, p < 0.0001, no significant group effect and no significant group × event interaction]. (E) In SUS rats, qualitatively different dorsal/septal CA1 neuronal ensembles express plasticity-related IEGs during the second exploration (E2) compared to RES rats, as revealed by the significantly lower overlap score. [F(1,13) = 4.84, p < 0.05]. RES rats have significantly higher overlap. (F) There were no significant differences in the percentage of IEG-expressing ventral CA3 neurons during the initial exploration (E1): %E1 (SUS) was similar to %E1 (RES). During the second exploration, SUS rats activated smaller vCA3 neuronal ensembles: %E2 (SUS) < %E2 (RES) [F(1,13) = 6.37, p = 0.025]. (G) There was no significant difference in vCA3 overlap scores between RES and SUS rats. From “Predicting impaired extinction of traumatic memory and elevated startle,” by Nalloor et al. (2011). Copyright 2011 by the PLoS One. Adapted with permission. = SUS vs RES; # = E1 vs E2 within a group.

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