Dynamic Patterns of Threat-Associated Gene Expression in the Amygdala and Blood

Stress and trauma profoundly influence psychiatric biobehavioral outcomes. The identification of treatment and biomarker targets would be accelerated by a broad understanding of the biological responses to these events. The goal of this study was to determine genes responsive to auditory fear conditioning (FC), a well-characterized amygdala-dependent rodent model of threat-exposure, in the presence or absence of prior stress history, providing insight into the physiological processes underlying response to trauma. RNA-sequencing was performed in blood and amygdala from mice that underwent fear conditioning with (Immo+FC) and without (FC) prior immobilization stress, a paradigm that induces HPA axis, and behavioral stress sensitization. In the amygdala, 607 genes were regulated by FC vs. home-cage (HC) controls, and 516 genes differed in stress-sensitized mice (Immo+FC vs. FC). In the former, we observed an enhancement of specific biological processes involved in learning and synaptic transmission, and in the latter processes associated with cell proliferation and the cellular response to drugs. In the blood of stress-sensitized animals, 468 genes were dynamically regulated when compared to FC, and were enriched for the biological pathways of inflammation and cytokine signaling. This study identified genes and pathways that respond to threat in the amygdala and blood of mice with and without a prior stress history and reveals the impact of stress history on subsequent inflammation. Future studies will be needed to examine the role of these dynamically regulated genes may play in human clinical stress and trauma-related disorders.