Impact of predatory threat on fear extinction in Lewis rats

Abstract

Humans with post-traumatic stress disorder (PTSD) are deficient at extinguishing conditioned fear responses. A study of identical twins concluded that this extinction deficit does not predate trauma but develops as a result of trauma. The present study tested whether the Lewis rat model of PTSD reproduces these features of the human syndrome. Lewis rats were subjected to classical auditory fear conditioning before or after exposure to a predatory threat that mimics a type of traumatic stress that leads to PTSD in humans. Exploratory behavior on the elevated plus maze 1 wk after predatory threat exposure was used to distinguish resilient vs. PTSD-like rats. Properties of extinction varied depending on whether fear conditioning and extinction occurred before or after predatory threat. When fear conditioning was carried out after predatory threat, PTSD-like rats showed a marked extinction deficit compared with resilient rats. In contrast, no differences were seen between resilient and PTSD-like rats when fear conditioning and extinction occurred prior to predatory threat. These findings in Lewis rats closely match the results seen in humans with PTSD, thereby suggesting that studies comparing neuronal interactions in resilient vs. at-risk Lewis rats might shed light on the causes and pathophysiology of human PTSD.

Figure 1.

Impact of predatory threat and fear conditioning on the incidence of extreme behavioral manifestations of anxiety (EBMA). (A) Experimental groups. (B) Graph plotting the proportion of subjects that spent zero time exploring the open arms of the EPM during a 5-min test period.

Figure 2.

Impact of predatory threat on the acquisition and extinction of conditioned fear responses. Lewis rats were subjected to a fear-conditioning protocol either after (A1,A2) or before (B1,B2) predatory threat as detailed in A1 and B1, respectively. Panels A2 and B2 plot the percentage of time spent freezing (y-axis) during the various phases of the fear-conditioning protocol (x-axis). In A2 and B2, rats are sorted as a function of their behavior on the EPM with rats exploring the open arms in black (resilient) and rats that avoided the open arms entirely in red (PTSD-like).

Figure 3.

Matching of fear levels to analyze the mechanisms underlying the within- and between-session extinction deficit of PTSD-like rats. (A1,A2) Higher levels of conditioned fear do not explain within-session extinction deficit seen in PTSD-like rats. Freezing levels at the beginning of the extinction training session (arrow) were matched by dropping subjects at opposite poles of the distributions in the two rat groups. Two samples of six rats remained. (A1) Time spent freezing (y-axis) during the various phases of the fear-conditioning protocol (x-axis). (A2) Bar graph plots freezing levels in these subsets of PTSD-like (red) and resilient (black) rats during the last six CSs of the extinction training session (left) and first four CSs of the extinction testing session (right). (B1,B2) Higher freezing levels of PTSD-like rats during extinction recall are not due to a within-session extinction deficit. Freezing levels at the end of extinction training (last two CSs, arrow) were matched between the resilient and PTSD-like rats. To achieve this, we dropped subjects at the opposite ends of the distributions in the PTSD-like and resilient rats. We remained with samples of six PTSD-like and five resilient rats. (B1) Graph plotting percentage of time spent freezing (y-axis) during the various phases of the fear-conditioning protocol (x-axis) in these two subsets of rats. (B2) Bar graph plots freezing levels in these subsets of PTSD-like (red) and resilient (black) rats during the last two CSs of the extinction training session (left) and first two CSs of the extinction testing session (right). Even after matching freezing levels at the end of extinction training, we still observed significantly higher freezing at the beginning of the extinction test, suggesting that PTSD-like rats are deficient in the overnight consolidation of extinction.

Figure 4.

Behavior of PTSD-like and resilient rats depending on timing of predatory threat. Bar graphs plot freezing levels in PTSD-like (red) and resilient (black) rats when fear conditioning was performed before (empty bars) vs. after (filled bars) predatory threat. Four phases are considered: (A) end of fear-conditioning session, (B) beginning of extinction training session, (C) end of extinction training session, and (D) beginning of extinction testing session.