Sensory sensitivity as a link between concussive traumatic brain injury and PTSD

Abstract

Traumatic brain injury (TBI) is one of the most common injuries to military personnel, a population often exposed to stressful stimuli and emotional trauma. Changes in sensory processing after TBI might contribute to TBI-post traumatic stress disorder (PTSD) comorbidity. Combining an animal model of TBI with an animal model of emotional trauma, we reveal an interaction between auditory sensitivity after TBI and fear conditioning where 75 dB white noise alone evokes a phonophobia-like phenotype and when paired with footshocks, fear is robustly enhanced. TBI reduced neuronal activity in the hippocampus but increased activity in the ipsilateral lateral amygdala (LA) when exposed to white noise. The white noise effect in LA was driven by increased activity in neurons projecting from ipsilateral auditory thalamus (medial geniculate nucleus). These data suggest that altered sensory processing within subcortical sensory-emotional circuitry after TBI results in neutral stimuli adopting aversive properties with a corresponding impact on facilitating trauma memories and may contribute to TBI-PTSD comorbidity.

Figure 1

White noise promotes defensive behavior after fluid percussion injury and contributes to enhanced contextual fear learning when paired with footshocks. (A) Experimental design. (B) During noise pre-exposure with presentations of white noise cues in the absence of footshocks, FPI (fluid percussion injury) groups froze significantly more than shams and (C) to an even greater degree at the offset and during the intervals between trials. (D) When white noise was paired with footshocks, both groups increased freezing across trials indicating learning, however the FPI group was not different than sham. (E) Freezing in the conditioning context was robustly increased in the FPI groups across three days of testing. Both groups decreased freezing across days, indicating contextual fear extinction. (F) When tested in a novel context there were no group differences in freezing to the white noise cue. ***p < 0.001 vs. Sham; data are represented as mean ± SEM.

Figure 2

Lateral fluid percussion injury reduces tone fear memory. (A) Experimental design. (B,C) FPI (fluid percussion injury) rats displayed slightly elevated levels of freezing behavior during pre-exposure to pure tone (2800 Hz/75 dB) trials (B) and during inter stimuli intervals (C). (D) FPI had no effect on baseline freezing prior to the first tone-shock conditioning trial. Although both groups learned, FPI had no effect on freezing across acquisition trials when pure tones were paired with mild footshocks. (E) While both groups decreased freezing across context extinction sessions, FPI had no effect on fear to the conditioning context. (F) FPI rats froze less during tone CS trials when presented in a novel context. *p < 0.05 vs. Sham. Data are represented as mean ± SEM.

Figure 3

Arc protein induction in response to white noise after FPI. (A) Lateral amygdala, (LA) White noise exposure in FPI (fluid percussion injury) rats caused robust Arc induction within the ipsilateral LA relative to contralateral and all other groups, ***p < 0.001 vs. contra and all other groups. (C) Dorsal dentate gyrus, (DG) FPI caused a significant overall reduction in Arc protein in response to novel context exploration alone or in the presence of white noise exposure in the ipsilateral DG (*p < 0.05). White noise exposure led to greater Arc induction within the dorsal DG in uninjured sham controls (^##p < 0.01), but not FPI groups. Data are represented as mean ± SEM. (B,D) Photomicrographs are representative images of Arc immunohistochemistry (IHC) within the ipsilateral LA (B) and DG (D) in groups exposed to white noise.

Figure 4

Increased activity in ipsilateral thalamo-amygdala projecting neurons during white noise exposure after lateral FPI. (A) Experimental design. (B) Increased Arc activity in MGN-LA (medial geniculate nucleus-lateral amygdala) projection neurons (*p < 0.05), but not Te3-LA (secondary auditory cortex-lateral amygdala; C) during white noise exposure after FPI. *p < 0.05; Data are represented as mean ± SEM. (B) Representative Arc activity (red) in retrolabeled CTB (cholera toxin subunit B) in LA afferents (green) in ipsilateral MGN. Scale bar 200 µm.