Principles for developing animal models of military PTSD

Figures & data

Table 1 Lists of behavioral outcomes associated with deployment conditions and responses

Behavioral domain	Example of behavioral paradigm
Addiction liability	Place conditioning
Aggression	Territorial behavior, urine marking
Anhedonia	Preference for sucrose–fat, sexual activity
Anxiety	Open field, elevated plus maze
Avoidance of trauma cues	Cat odor, auditory cues
Fear extinction deficits	Fear conditioning and extinction
Food intake	Weight, food consumption
Hyperarousal	Acoustic startle response
Memory deficits	Spatial memory
Social avoidance	Interaction test, partition test, social preference
Sustained fear	Cue and contextual fear

Fig. 1 Proportional diagrams of the number of studies from a PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) literature search (all references until December 2013) for: (A) (stress disorder or depressive disorder or anxiety disorder) AND animal AND predator; (B) (stress disorder or depressive disorder or anxiety disorder) AND animal AND social defeat; (C) (stress disorder or depressive disorder or anxiety disorder) AND animal AND single prolonged stress; (D) (stress disorder or depressive disorder or anxiety disorder) AND animal AND chronic unpredictable stress. The review articles were filtered out. The remaining studies were divided into studies not addressing individual differences or studies addressing individual differences (genetic, sex-related, epigenetic, or related to prior experiences).

Table 2 Exposure characteristics of the reviewed animal models of PTSD

Animal model	Exposure	Reference
Predator stress	1 day: 10-min inescapable exposure to a cat	1993
Predator-scent stress	1 day: 10-min inescapable exposure to cat litter	2003
Predator-based psychosocial stress	31 days: - Days 1/11: inescapable 1 h immobilization & exposure to a novel cat - Daily unstable housing conditions	2008
Social defeat stress (resident-intruder paradigm)	5–10 days: - Daily inescapable contact with a novel aggressive—resident for 5–10 min (social defeat). - Subsequent housing with sensory (not physical) contact with the intruder for the remainder of the day.	Golden et al., 2011; Koolhaas et al., 2013
Witnessed social defeat stress	5–10 days: - Daily inescapable sensory (not physical) contact with the social defeat of a novel intruder by a novel resident for 5–10 min. - Subsequent housing with sensory (not physical) contact with the intruder for the remainder of the day	Warren et al., 2013
Cage-within-cage resident–intruder paradigm	5–10 days: - Daily inescapable sensory (not physical) contact with a novel resident for 6 h - One to three random times within the 6-h sessions, physical contact with the resident for 1 min.	Hammamieh et al., 2012
Fear conditioning	1–2 days: Daily trials of unconditioned stimulus (e.g., foot-shock) paired with conditioned stimulus (e.g., tone)	1992; Phillips & LeDoux, 1992
Immobilization stress and fear conditioning	7 days: 2-h immobilization stress followed by fear conditioning trials in a novel room 6 days after	Andero et al., 2011

Fig. 2 Theoretical longitudinal experimental design using an animal model of PTSD. On the left part, three predisposing factors (gender, genotype, and early environment) are depicted on a gray discontinued line which could be examined or controlled for in an animal experiment. In the right black continuous bar, the experimental design includes sampling, stress-exposure, behavioral testing and re-sampling. The time windows for primary/secondary prevention and treatment are also depicted. Pre-stress sampling is important for the discovery of a priori differences that could have predictive value on post-stress phenotypes. Yet, the possible tissue-types for sampling are limited. Stress-exposure depending on the animal model may include a single, repeated or multiple stressors. Behavioral testing should be repeated (phenotyping, re-phenotyping) to evaluate persistence of phenotypes or to detect phenotypes with delayed onset. According to phenotyping/re-phenotyping outcome (–, +) exposed animals can be classified in “Vulnerable/Not-recovered,” “Delayed onset vulnerable,” “Vulnerable/Recovered,” and “Resistant.” Often in literature the terms “Vulnerable/Not-Recovered” and “Delayed onset vulnerable” are merged into the term “Vulnerability” and “Vulnerable/Recovered” and “Resistant” are merged into “Resilience.” Phenotyping/re-phenotyping can differentiate between the overlapping groups. Post-stress re-sampling can be performed after behavioral testing with the advantage of more extensive tissue collection and the disadvantage of the numerous factors (e.g., behavioral testing) that can influence the biological material apart from stress-exposure and group differences.

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