Abstract 142: Apoptosis After Psychological Stress is Associated With FoxO1-Mediated Inflammation in the Rodent Brain

Abstract

Introduction: Although the capacity of social stress to cause psychological perturbations is well-known, investigations undertaken in recent years have elaborated a novel field of study: the neurophysiological corollary of these perturbations. This corollary often involves the innate immune system, which can be activated by psychological stress to promote inflammatory pathology. Because psychological stress increases apoptotic cell death in the hippocampus and temporal cortex, we therefore hypothesized that innate immune-induced inflammation may be responsible for this effect. To test this hypothesis, we investigated whether FoxO1, an important regulator of molecular signals in many tissues (including tumor, liver, and brain) that has been found to mediate inflammation following cerebral hemorrhage, could promote inflammation in the context of stress, leading to apoptosis. Methods: Six-week-old male C57BL/6J mice were subjected to 10 consecutive days of Acute Social Defeat stress, in which they were placed (individually) for 10 min into the residence of a large male CD1 aggressor mouse, who investigated, attacked, and defeated them. C57BL/6J and CD1 mice were then separated by a transparent partition with stomata for 24 h, allowing the C57BL/6J intruder to receive continued sensory contact from the resident. To quantify the resulting depression, body weight, tail suspension, and sucrose preference were tested daily, along with ELISA-determined serum corticosterone, epinephrine, and IL-6. Protein levels of brain IL-6, TNF-α, FoxO1, apoptotic Bax and anti-apoptotic Bcl2 were measured by Western blot. Results: In stress-induced mice, the tail suspension and sucrose preference tests elicited depression-like behavior. Body weight decreased, while serum corticosterone and epinephrine levels increased. Brain IL-6 and TNF-α, as well as serum IL-6, were also significantly upregulated in this group. Brain expression of FoxO1 was increased, protein levels of Bax were upregulated, and Bcl2 was downregulated. Conclusion: Acute social stress promoted depression and brain apoptosis, in association with an inflammatory reaction. Our results suggest that these psychological stress-mediated changes were caused by increased FoxO1 expression.