Depression and anxiety disorders are associated with hyperactivation of the amygdala, a brain area important in negative emotional processing. Many researchers propose that overactivation of the amygdala is responsible for some of the debilitating symptoms associated with mood disorders such as increased occurrence of intrusive negative thoughts and rumination over aversive experiences. Exposure to some stressors, particularly chronic or severe acute stressors, can sensitize amygdala responses and facilitate the formation of aversive memories. The cause(s) are not fully understood, but are of high clinical significance given that stress is a major risk factor for the development of mood and anxiety disorders. The goal of this proposal is to identify the cells and cellular mediators involved in stress-induced sensitization of the amygdala. This proposal centers on the possibility that microglia play a critical role in sensitizing amygdala responses. Microglia are the innate immune cells in the brain and while they are typically in a quiescent (resting) state, they can shift into a primed state of activation such as following stress exposure. In a primed state, microglia do not actively release inflammatory mediators but rather they upregulate their response capabilities such that if and when they become activated greater inflammatory responses are generated. We provide evidence that repeated stress exposure primes microglia responses to ?-adrenergic receptor (?-AR) activation and, in contrast to an immune stimulus, activation of ?-ARs cause microglia to release factors that facilitate learning and memory processes. Here, we test the hypothesis that primed microglia and their release of interleukin-1beta contribute to the heightened formation of fear memories in organisms exposed to chronic stress.
The proposal examines the cellular and molecular processes by which stress exposure facilitates the formation of aversive memories. This is clinically significant because stress is a risk factor for the development of depression and anxiety disorders that are associated with intrusive negative thoughts and rumination over aversive memories.
