P.2.020 - Blunted basal corticosterone pulsatility predicts post-exposure susceptibility to post-traumatic stress disorder phenotype in rats

Abstract

Introduction Glucocorticoid (GC) hormones play a major role in orchestrating the physiological and behavioral reactions essential for homeostasis. As such, these hormones enable the organism to prepare for, respond to, and cope with the acute demands of physical and emotional stressors [1]. The secretion of GC hormones is a dynamic process which displays, in addition to a circadian pattern of release, an ultradian rhythmicity in the blood and in target tissues [2] Inadequate GC release following stress not only delays recovery but can also interfere with the processing or interpretation of stressful information, resulting in long-term disruptions of memory integration processes [3]. An example of such an impaired process is post-traumatic stress disorder (PTSD) [4]. In the rat, corticosterone ultradian pulses have a near-hourly frequency and changes in the amplitude of these pulses throughout the 24 h cycle determine the circadian variation in hormone secretion [2]. Aims We used an animal model of PTSD [5] in order to assess whether stress-induced impairment of behavioral responses is mediated by an aberrant secretion of corticosterone. Methods Serial blood samples were collected manually via the jugular vein cannula during the inactive phase in conscious male rats at 20-min intervals for a period of 5 h before and 6.5 h after exposure to predator scent stress (PSS). The outcome measures included behavior in an elevated plus-maze and acoustic startle response 7 days after exposure. Individual animals were retrospectively classified as having extreme, partial, and minimal behavioral responses according to pre-set cut-off criteria for behavioral response patterns [5] and blood samples were analyzed retrospectively for corticosterone secretion patterns. For the behavioral results and for serum corticosterone levels, the statistical analyses were performed using one-way analysis of variance (ANOVA), bonferroni tests were used to examine differences between individual groups. To gain additional understanding about the relationship between behavioral measures and corticosterone pulsatility parameters, two sets of regression analysis were conducted: Pearson's correlation analysis was used to describe the relationship between each behavioral variable and corticosterone pulsatility parameters across the entire sample. The contribution of each variable that exhibited a significant correlation (or trend) was then evaluated using a multiple stepwise-regression analysis. Results Under basal conditions, the amplitude of ultradian oscillations of corticosterone levels, rather than the mean corticosterone level or the frequency of corticosterone pulsatility, was significantly reduced in individuals who displayed PTSD-phenotype 8 days later. In addition, extreme disruption of behavior on day 8 post-exposure was also characterized by a blunting of corticosterone response to the stressor. Animals with behavior that was only partially affected or unaffected displayed none of the above changes. Conclusions Blunted basal corticosterone pulse amplitude is a pre-existing susceptibility or risk factor for PTSD, which originates from prior (life) experiences and may therefore predict post-exposure PTSD-phenotype in rats. Further studies confirming these findings in animals and in human subjects are required to ascertain whether dysregulation in pulsatility indeed predisposes individuals to, or in fact underlies, faults in the HPA-axis response to stress and renders them vulnerable to PTSD.