Predicting Impaired Extinction of Traumatic Memory and Elevated Startle

Abstract

BackgroundEmotionally traumatic experiences can lead to debilitating anxiety disorders, such as phobias and Post-Traumatic Stress Disorder (PTSD). Exposure to such experiences, however, is not sufficient to induce pathology, as only up to one quarter of people exposed to such events develop PTSD. These statistics, combined with findings that smaller hippocampal size prior to the trauma is associated with higher risk of developing PTSD, suggest that there are pre-disposing factors for such pathology. Because prospective studies in humans are limited and costly, investigating such pre-dispositions, and thus advancing understanding of the genesis of such pathologies, requires the use of animal models where predispositions are identified before the emotional trauma. Most existing animal models are retrospective: they classify subjects as those with or without a PTSD-like phenotype long after experiencing a traumatic event. Attempts to create prospective animal models have been largely unsuccessful.Methodology/Principal FindingsHere we report that individual predispositions to a PTSD-like phenotype, consisting of impaired rate and magnitude of extinction of an emotionally traumatic event coupled with long-lasting elevation of acoustic startle responses, can be revealed following exposure to a mild stressor, but before experiencing emotional trauma. We compare, in rats, the utility of several classification criteria and report that a combination of criteria based on acoustic startle responses and behavior in an anxiogenic environment is a reliable predictor of a PTSD-like phenotype.Conclusions/SignificanceThere are individual predispositions to developing impaired extinction and elevated acoustic startle that can be identified after exposure to a mildly stressful event, which by itself does not induce such a behavioral phenotype. The model presented here is a valuable tool for studying the etiology and pathophysiology of anxiety disorders and provides a platform for testing behavioral and pharmacological interventions that can reduce the probability of developing pathologic behaviors associated with such disorders.

Altered hippocampal function before emotional trauma in rats susceptible to PTSD-like behaviors

“…The findings, however, did not support this hypothesis (Figures 6 and 7). They are, however, consistent with previous findings showing that Sus rats and Res rats have similar levels of fear expression and by inference, similar levels of memory for fear conditioning (Nalloor et al, 2011). Sus rats differed from Res rats in their rate of fear extinction, which may be influenced by the observed impairment of hippocampal function when fear is not externally elicited.…”

“…We observed impaired hippocampal expression of plasticity-related IEGs ( Arc and Homer 1a ) and impaired fidelity of network activation during repeated spatial exploration prior to emotional trauma in rats that were pre-classified as susceptible (Sus) to developing a PTSD-like phenotype (Nalloor et al, 2011). Surprisingly, we did not find support for the hypothesis that there is altered hippocampal or basolateral amygdala (BLA) Arc/H1a expression as a result of a traumatic event (Experiment II).…”

“…Using a priori set criteria, they were classified as Susceptible (Sus), Resistant (Res), or Intermediate as described in detail in (Nalloor et al, 2011). Only Res and Sus rats were used for Experiments I and II.…”

“…We addressed this fundamental question by assessing the integrity of hippocampal function with a cellular imaging method ( Arc/Homer1a catFISH) both before (Experiment I) and during (Experiment II) a traumatic event in a rat model of susceptibility for PTSD-like behaviors (Nalloor et al, 2011). The Arc/Homer1a catFISH (cellular compartmental analysis of temporal activity using fluorescence in situ hybridization) method (Vazdarjanova et al, 2002) is a sensitive technique that utilizes the expression of two plasticity-associated immediate-early genes, Arc and Homer1a ( H1a ), to identify and dissociate large neuronal ensembles activated during either of two events (Nalloor et al, 2012; Ramírez-Amaya et al, 2005; Rosi et al, 2009; Vazdarjanova & Guzowski, 2004; Vazdarjanova et al, 2006).…”

Exposure to variable prenatal stress in rats: Effects on anxiety-related behaviors, innate and contextual fear, and fear extinction

“…A predatory odor avoidance task was used to determine if prenatal stress results in alterations of innate defensive behaviors towards predatory odors [38]. Cat hair (compressed into a ball, 10 cm in diameter) was obtained from a domestic male cat prior to the day of testing and kept in airtight (Zip-Lock) plastic bag until use.…”