Animal Models of Post‐Traumatic Stress Disorder
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Abstract
Animal behavioral studies have commonly regarded the entire group of animals subjected to the study conditions as homogeneous, disregarding individual differences in response patterns. The following discussion will focus on a method of analyzing data that aims to model clinical diagnostic criteria applied to individual patterns of response using data from behavioral measures, and employing cut?off scores to distinguish between extremes of response versus non?response and the sizeable proportion of study subjects in?between them. This protocol unit will present the concept of the model and its background, provide detailed protocols for each of its components, and present a selection of studies employing and examining the model, alongside the underlying translational rationale of each. Curr. Protoc. Neurosci. 64:9.45.1?9.45.18. © 2013 by John Wiley & Sons, Inc.
Keywords: post?traumatic stress disorder; animal model; cut?off behavioral criteria; anxiety; resilience; vulnerability; elevated plus?maze; acoustic startle response; freezing
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- Introduction
- Basic Protocol 1: The Predator‐Scent Stress (PSS) Paradigm
- Basic Protocol 2: Assessment of Overall Exploratory Behavior Using the Elevated Plus Maze (EPM) and Quantification of Hyper‐Alertness Using the Acoustic Startle Response (ASR)
- Basic Protocol 3: Classification According to Cut‐Off Behavioral Criteria (CBC)
- Basic Protocol 4: Exposure to Trauma Cues
- Commentary
- Literature Cited
- Figures
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Basic Protocol 1: The Predator‐Scent Stress (PSS) Paradigm
Materials
Basic Protocol 2: Assessment of Overall Exploratory Behavior Using the Elevated Plus Maze (EPM) and Quantification of Hyper‐Alertness Using the Acoustic Startle Response (ASR)
Materials
Basic Protocol 3: Classification According to Cut‐Off Behavioral Criteria (CBC)
Materials
Basic Protocol 4: Exposure to Trauma Cues
Materials
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Figure 9.45.1 Predator scent stress (PSS) test apparatus. The apparatus consists of a 40 × 40 × 40–cm chamber of transparent Plexiglas with transparent roof. The floor is covered with a 5‐ to 6‐cm layer of well soiled cat litter (in use by the cat for 2 days, sifted for stools). The apparatus is placed on a yard paving stone. View Image -
Figure 9.45.2 The elevated plus‐maze apparatus. The maze is made of black Plexiglas, consists of four arms in form of a maze: two open arms (for rats: 50 × 10 cm; for mice: 30 × 6 cm) and two arms of the same size, that are enclosed by walls (for rats: 40 cm high; for mice: 30 cm). The open arms are opposite each other and converge into a central platform (for rats: 10 × 10 cm; for mice: 6 × 6 cm). A video camera mounted above the maze is used to observe the animal's behavior and record the trails for automatic computer analysis, for later additional scoring or both. View Image -
Figure 9.45.3 The acoustic startle response apparatus. (A ) The cabinet contains a complete sound generation system for white noise production, separately adjustable background noise levels, and accessory connections for optional stimuli. The audio source module is used to provide acoustic stimuli. For tone stimuli (B ), amplitude, frequency, and duration are computer controlled. Amplitude and duration of noise bursts are computer controlled. Specialized amplifier circuitry, contained in the cabinet, permits the use of a dynamic standardization system that emulates actual startle response movements. The dynamic response sensor design ignores static animal weights enabling the full range of the transducer capacity to be available for response recording. (D ) Animal enclosures are designed to locate the subject without using restraint so the animals do not suffer from restraint stress and confound the results of the startle testing. View Image -
Figure 9.45.4 The cut‐off behavioral criteria (CBC) algorithm. Behavioral models can be more closely matched with contemporary clinical conceptions of PTSD by using an approach that enables the classification of study animals into groups according to degree of response to the stressor, i.e., the degree to which individual behavior is altered or disrupted. This was achieved by defining both the behavioral criteria and the cut‐off criteria that reflect response severity, a design that parallels the inclusion and exclusion criteria applied in clinical research. (A ) The data must demonstrate that the stressor had a significant effect on the overall behavior of exposed versus non‐exposed populations at the time of assessment. (B ) To maximize the resolution and minimize false positives, extreme responses to both of these paradigms performed in sequence are required for “inclusion” in the EBR group, whereas a negligible degree of response to both is required for inclusion in the MBR group. View Image -
Figure 9.45.5 The effect of the predator scent stress (PSS) paradigm on overall anxiety‐like behavior and acoustic startle response. A single ten‐minute exposure to PSS significantly increased anxiety‐like behavior/avoidance of open spaces as compared to unexposed controls. Time spent in the open arms (A ) and entries into open arms (B ) were significantly decreased after a single exposure to the stressor, as compared to control conditions [F(1,298) = 126.4, p < 0.0001 and F(1,298) = 68.25, p < 0.0001, respectively]. There were no differences in total exploration (C ) of the maze between groups. This result suggests overall anxiety and avoidance of exploration in the open arms, as opposed to an impairment of locomotion/exploration. PSS exposure significantly increased the mean startle amplitude (D ) and caused a significant deficit in the startle habituation of ASR (E ) in exposed rats as compared to controls [F(1,298) = 51.04, p < 0.0001 and F(1, 298) = 45.25, p < 0.0001, respectively]. All data represent group mean ± S.E.M. View Image -
Figure 9.45.6 The distributions of the exposed groups and the control group. The distributions of the exposed groups and the control group (time spent in the closed arms, startle response and startle habituation) were compared by a Kolmogorov‐Smirnov statistic. The results showed that there are differences in the general shapes of the distributions curve in the two populations ( p < 0.001). The distribution curve for exposed animals has a distinct shifts (in the parameter of time spent in the open arms: shift to the left; startle response: a discontinuous nature, tending towards a bimodal distribution; Startle habituation: shift to the left). View Image -
Figure 9.45.7 The effect of the predator scent stress (PSS) paradigm on anxiety‐like behavior and acoustic startle response. The figures represent time spent in the open arms (A ,B ) of the elevated plus maze and in the mean acoustic startle amplitude (C ,D ) in rats exposed to a cat‐scent, as compared to controls. Exposed rats spent less time in the open arms (center) and exhibited higher mean startle amplitude (circumference) as compared to controls. Overall, a wide distribution in results was observed within the exposed rats with a broad range of variation in behavioral response. We thus hypothesized that the group is not homogeneous, and we may be dealing with several subgroups in this population. Based on the results of this phase of the study the animals were subdivided into groups reflecting magnitude of response according to the CBC's, focusing selectively on EBR, PBR, and MBR. In E , representation of the data from both the elevated plus maze (EPM) and ASR paradigms reveals two distinct features. First, PSS exposure alters the response of the majority of individuals to at least some degree. Second, the cluster of individuals that forms in the upper left hand corner of the graph (i.e., more extreme responses to exposure) is distinct from the majority of individuals. View Image -
Figure 9.45.8 Relative prevalence rates according to CBCs. Re‐analysis of data applying Cut‐off Behavioral Criteria: (A ) Prevalence of extreme behavioral response (EBR) rats. (B ) Prevalence of minimal behavioral response (MBR) rats. (C ) Prevalence of partial behavioral response (PBR) rats. There were significant differences in the prevalence rates of individuals displaying EBR among groups (Pearson χ2 = 296.11, df = 3, p < 0.0001). PSS exposure increased the prevalence of PTSD‐like behavioral responses (EBR) ( x 2 = 29.85, p < 0.0001) and concomitantly reduced prevalence rates of minimal behavioral response (MBR) (x2 = 11.54, p < 0.0008), relative to unexposed controls. View Image
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