Acute stress imposed during adolescence yields heightened anxiety in Sprague Dawley rats that persists into adulthood: Sex differences and potential involvement of the Medial Amygdala

Abstract

Stressors experienced during adolescence have been demonstrated to have a long-lasting influence on affective behavior in adulthood. Notably, most studies to date have found these outcomes after chronic stress during adolescence. In the present study we tested how exposure to a single episode of acute footshock during early adolescence would modify subsequent adult anxiety- and depressive-like behaviors in male and female Sprague-Dawley rats. Adolescent rats were exposed to inescapable footshock (80 shocks, 5 s, 1.0 mA, 90 sec variable inter-trial interval (ITI)) at Post-natal day (PND) 29-30 and remained undisturbed until adulthood where they were evaluated with several behavioral assays for anxiety as well as depressive-like behavior via forced swim. In addition, gene expression changes were assessed immediately after a 30 min forced swim challenge in adulthood among several stress-related brain regions including the Central Amygdala (CeA), Medial Amygdala (MeA), ventral Hippocampus (vHPC), and Paraventricular Nucleus (PVN). Studies used real-time RT-PCR to examine the cytokines Interleukin-1β (IL-1β) and Interleukin-6 (IL-6), corticotropin-releasing hormone (CRH), the immediate early genes c-Fos, c-Jun, Egr1 and Arc, and several genes relating to corticosteroid receptor function (glucocorticoid and mineralocorticoid receptor (GR and MR, respectively), Gilz (glucocorticoid-induced leucine zipper), Sgk1 (Serum and Glucocorticoid regulated Kinase 1)). Behaviorally, males displayed signs of increased anxiety, most notably in the light-dark box, whereas females did not. No notable depressive-like behavior was observed in forced swim as a result of adolescent stress history, but adolescent footshock exacerbated the c-Fos response in the MeA produced by swim in both sexes. Forced swim led to increased IL-1β expression in the PVN regardless of adolescent stress history, whereas most HPA (hypothalamic-pituitaryadrenal) axis-related genes were largely unaffected in the vHPC. To determine the potential for β-adrenergic receptors to contribute to the male-specific anxiety-like behavior, two further studies applied a β-adrenergic agonist (isoproterenol) or antagonist (propranolol) in male rats. These studies found that propranolol administered 2 h after footshock led to a reduction in some anxiety-like behaviors as compared to controls. Overall, these findings suggest that exposure to a single, intense stress challenge imposed during adolescence may have sex-specific consequences across the lifespan and may implicate the MeA in developmental plasticity.

Keywords: Adolescence; Anxiety; Corticosterone; HPA-axis; Rat; Sex differences; Sprague Dawley; Stress.