Individual variability in behavior and functional networks predicts vulnerability using a predator scent model of PTSD

Abstract

30Only a minority of individuals who experience traumatic event(s) subsequently 31 develop post-traumatic stress disorder (PTSD). However, whether differences in 32 vulnerability to PTSD result from predisposition or a consequence of trauma exposure 33 remains unclear. A major challenge in differentiating these possibilities is that clinical 34 studies focus on individuals already exposed to traumatic experiences, and do not take 35 into account pre-trauma conditions. Here using the predator scent model of PTSD in rats 36 and a longitudinal design, we measured pre-trauma brain-wide neural circuit functional 37 connectivity (FC), behavioral and corticosterone responses to trauma exposure, and post-38 trauma anxiety. Individual differences in freezing responses to predator scent exposure 39 correlated with differences in pre-trauma FC in a set of neural circuits, especially in 40 olfactory and stress-related systems, indicating that pre-existing function in these circuits 41 could predispose animals to differential fearful responses to threats. Counterintuitively, 42 rats with the lowest freezing showed more avoidance of the predator scent, a prolonged 43 corticosterone response, and higher anxiety long after exposure. This study provides a 44 comprehensive framework of pre-existing circuit function that determines threat response 45 strategy, which might be directly related to the development of PTSD-like behaviors. 46 47 91 awake rat rsfMRI approach established in our lab [17][18][19][20] . Awake rat rsfMRI avoids 92 confounding factors from anesthetics and permits correlation with behavior 21-23 . We 93 5 found that individual differences in behavior and neural circuit function prior to trauma 94 exposure predicted animals' susceptibility to developing PTSD-like behaviors. This 95 suggests that pre-existing traits such as anterior olfactory nucleus (AON)-amygdala 96 connectivity may be critical for determining individual resilience/susceptibility to 97 developing PTSD. 98 99 Results 100The experimental schedule was summarized in Fig. 1a. Rats were first scanned 101 using rsfMRI, then exposed to fox urine, and then given an anxiety test approximately 102 one week after exposure. 103Freezing responses to fox urine were highly variable across animals 104 A total of 87 Long-Evans (LE) rats were exposed to a predator scent stressor in 105 the form of a compressed cotton pad sprayed with fox urine in an inescapable cage for 106 10 min. Freezing and location within the cage were quantified with behavioral tracking 107 software (ANY-maze, Stoelting Co., Reston, VA). Compared to control animals that were 108 exposed to a clean cotton pad, the group exposed to predator scent showed increased 109 freezing (t-test, t87 = 3.660, p = 0.00044, Fig. 1b, left), and maintained a significantly 110 greater distance from the cotton pad (t-test, t87 = 3.568, p = 0.00060, Fig. 1b, right). These 111 data confirm that predator scent exposed animals displayed a significantly greater stress 112 response compared to controls. 113Clos...

Increased alcohol self-administration following exposure to the predator odor TMT in active coping female rats

“…Additionally, exposure to 2,3,5-trimethyl-3thiazoline (TMT; an extract of fox feces) has been shown to produce alcohol reinstatement (e.g., relapse-like behavior) in mice [18]. Animal models can also be used to examine relevant individual variability in responses to stress [19][20][21][22][23][24], including stress resilience. Previous studies have utilized a variety of methods to classify animals into specific phenotype groups to examine individual variability following the stress exposure.…”

Increased alcohol self-administration following exposure to the predator odor TMT in high stress-reactive female rats

“…Additionally, exposure to 2,3,5-trimethyl-3thiazoline (TMT; an extract of fox feces) has been shown to produce alcohol reinstatement (e.g., relapse-like behavior) in mice [18]. Animal models can also be used to examine relevant individual variability in responses to stress [19][20][21][22][23][24], including stress resilience. Previous studies have utilized a variety of methods to classify animals into specific phenotype groups to examine individual variability following the stress exposure.…”