Blast-induced "PTSD": Evidence from an animal model

Abstract

A striking observation among veterans returning from the recent conflicts in Iraq and Afghanistan has been the co-occurrence of blast-related mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). PTSD and mTBI might coexist due to additive effects of independent psychological and physical traumas experienced in a war zone. Alternatively blast injury might induce PTSD-related traits or damage brain structures that mediate responses to psychological stressors, increasing the likelihood that PTSD will develop following a subsequent psychological stressor. Rats exposed to repetitive low-level blasts consisting of three 74.5 kPa exposures delivered once daily for three consecutive days develop a variety of anxiety and PTSD-related behavioral traits that are present for at least 9 months after blast exposure. A single predator scent challenge delivered 8 months after the last blast exposure induces additional anxiety-related changes that are still present 45 days later. Because the blast injuries occur under general anesthesia, it appears that blast exposure in the absence of a psychological stressor can induce chronic PTSD-related traits. The reaction to a predator scent challenge delivered many months after blast exposure suggests that blast exposure in addition sensitizes the brain to react abnormally to subsequent psychological stressors. The development of PTSD-related behavioral traits in the absence of a psychological stressor suggests the existence of blast-induced "PTSD". Findings that PTSD-related behavioral traits can be reversed by BCI-838, a group II metabotropic glutamate receptor antagonist offers insight into pathogenesis and possible treatment options for blast-related brain injury. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".

Keywords: Animal models; Anxiety; BCI-838; Blast; Metabotropic glutamate receptor; Post-traumatic stress disorder; Postconcussion syndrome; Rat; Traumatic brain injury.

Fig. 1.

Anxiety in blast-exposed rats revealed by a light/dark emergence task performed 12 weeks after blast exposure. Graphs show that latency to reach the light center (A) was increased in blast-exposed rats, which also made fewer entries to the light center (B) as well as spent less total time spent on the light side (C) compared with the controls. Error bars indicate ± SEM. Values significantly different from controls are indicated by asterisks (*p < 0.05, **p < 0.01, unpaired t-tests). Bottom figures show the design of the light/dark arena and the measured parameters. Also shown are the brain areas supporting the task in rodents (Steimer, 2011). Original data was reported in Perez-Garcia et al. (2018a).

Fig. 2.

Blast-exposed rats exhibit anxiety in an elevated zero maze when tested 12 weeks after blast exposure. Blast-exposed and control rats were tested for 5 min in an elevated zero maze. Graphs show latency to reach the open arm (A), entries to the open arm (B), time spent in open arms (C) as well as the latency to cross between two open arms (D, cross latency) compared with the controls. Error bars indicate ± SEM. Values significantly different from controls are indicated by asterisks (**p < 0.01, ****p < 0.0001 unpaired t-tests). Bottom figures show the design of the elevated zero maze arena and the measured parameters. Also shown are the brain areas supporting the task in rodents (Shepherd et al., 1994). Original data was reported in Perez-Garcia et al. (2018a).

Fig. 3.

Altered startle magnitude and sensory gating in blast-exposed rats 24 weeks after blast exposure. Acoustic startle (Pulse) and Pulse-Prepulse readings are increased in the blast exposed. Error bars indicate ± SEM. Asterisk(s) indicate statistically significant differences between blast and control (*p < 0.05, unpaired t-tests). Panel on the right shows the brain areas supporting the task in rodents (Winer et al., 2002). Original data was reported in Elder et al. (2012).

Fig. 4.

Altered cued fear responses in blast-exposed rats 35 weeks after blast exposure. Cued fear memory was tested 48 h after training. Each subject was placed in a novel context for 2 min, and baseline freezing was measured followed by exposure to the conditioned stimulus (20 s tone) at 120 and 290 s. Error bars indicate ± SEM. Asterisk(s) indicate statistically significant differences between blast and control (**p < 0.01, unpaired t-tests). Panels on the right show the fear conditioning chamber and the brain areas supporting the task in rodents (Tronson et al., 2012). Original data was reported in Perez-Garcia et al. (2018b).

Fig. 5.

Blast-exposed rats exhibit an altered novel object localization response 33 weeks after blast exposure. Novel object recognition (NOR) and novel object localization (NOL) responses were determined 1 h (short-term memory, STM) after training. Upper graph shows that blast-exposed subjects displayed a preference for the novel object compared with the familiar object when tested 1 h after training, suggesting that blast does not affect STM. Bottom graph shows results for subjects allowed to investigate two unfamiliar objects followed by presentation of the same objects 1 h after training with the location of one of the previously presented objects altered. Error bars indicate ± SEM. Values significantly different from controls are indicated by asterisks (**p < 0.01, ****p < 0.0001, unpaired t-tests). Right panels show brain regions that appear critical for NOR, including neocortex, ventromedial prefrontal cortex, insular cortex, perirhinal cortex and hippocampus. The importance of regions appears to vary based on the experimental timing. NOL requires the hippocampus for encoding, consolidation and retrieval and is particularly sensitive to manipulations in dorsal CA1 (Vogel-Ciernia and Wood, 2014). Original data was reported in Perez-Garcia et al. (2018b).

Fig. 6.

Delayed behavioral changes in blast-exposed rats at 3 and 45 days following a single predator scent exposure. Upper graph shows center time plotted before and immediately following the predator scent exposure (pre and postexposure). No acute changes were found. However, blast-exposed rats showed delayed changes that were present 3 and 45 days after a predator scent exposure. Error bars indicate ± SEM. Asterisk(s) indicate statistically significant differences between blast-exposed and control (*p < 0.05, **p < 0.01, ***p < 0.001, all comparisons unpaired t-tests). Bottom panels show the brain areas involved in the predator scent exposure (Takahashi, 2014), and the graphs show summary plots of total center time at 3 and 45 days following the predator scent exposure. Original data was reported in Perez-Garcia et al. (2016).

Fig. 7.

Brain areas implicated in blast effects on the nervous system based on behavioral testing.