Project 170480

Stressful events are known to promote major depressive disorder, and the occurrence of such an outcome is more pronounced among individuals that had previously experienced major life stressors. Indeed, it seems that with each stressor experience, and with each episode of depression, the interval between depressive episodes becomes shorter, the depression more severe and long lasting, and the stressor severity necessary to promote the episode is less intense. Activation of the inflammatory immune system, and particularly activation of immune signaling molecules (termed cytokines), engenders neuroendocrine and brain chemical changes like those elicited by stressors, and might thus come to elicit depression. The intent of the proposed experiments is to determine the contribution two particular cytokines, namely interleukin-1 and interleukin-6, in promoting brain chemical changes thought to underlie depression. Of particular interest is to establish whether initial immune activation exacerbates neurochemical and behavioral responses ordinarily elicited by later immune and stress challenges. Moreover, we will establish whether and how stressful events influence the response to later immune challenges and determine the processes by which sensitization and cross sensitization effects occur. The recurrence of depression is a major obstacle in the treatment of this disorder, and the proposed studies may help to identify factors that contribute to illness recurrence.