Acute and chronic stress exert opposite effects on formation and contextualrelated fear conditioning in rats.

OBJECTIVE: Stress and fear conditioning are both involved in the development of affective disorders, but their interconnected relationship remains unclear. Here in this study we employed acute and chronic stress model to investigate their respective effect on fear conditioning and the CRFR1 signaling change in the limbic areas including mPFC, hippocampus and BLA. METHODS: Male rats were subjected to acute restraint stress or chronic unpredictable mild stress before open field test and fear condition test. In situ hybridization was used to investigate CRFR1 mRNA expression in limbic region including mPFC, hippocampus and BLA. RESULTS: Our results demonstrated that acute and chronic stress have opposite effects on the acquisition of fear conditioning, which is correlated to CRFR1 mRNA expression in hippocampus; however, they have similar effects on fear extinction and both facilitated contextual-related fear conditioning. CONCLUSION: Our findings revealed acute and chronic stress led to distinct behavioral responses in fear conditioning and indicated CRFR1 is involved in the interaction of stress and fear conditioning, which help understand the connection between stress and fear memory.

High activity of the stress promoter contributes to susceptibility to stress in the tree shrew.

Stress is increasingly present in everyday life in our fast-paced society and involved in the pathogenesis of many psychiatric diseases. Corticotrophin-releasing-hormone (CRH) plays a pivotal role in regulating the stress responses. The tree shrews are highly vulnerable to stress which makes them the promising animal models for studying stress responses. However, the mechanisms underlying their high stress-susceptibility remained unknown. Here we confirmed that cortisol was the dominate corticosteroid in tree shrew and was significantly increased after acute stress. Our study showed that the function of tree shrew CRH - hypothalamic-pituitary-adrenal (HPA) axis was nearly identical to human that contributed little to their hyper-responsiveness to stress. Using CRH transcriptional regulation analysis we discovered a peculiar active glucocorticoid receptor response element (aGRE) site within the tree shrew CRH promoter, which continued to recruit co-activators including SRC-1 (steroid receptor co-activator-1) to promote CRH transcription under basal or forskolin/dexamethasone treatment conditions. Basal CRH mRNA increased when the aGRE was knocked into the CRH promoter in human HeLa cells using CAS9/CRISPR. The aGRE functioned critically to form the "Stress promoter" that contributed to the higher CRH expression and susceptibility to stress. These findings implicated novel molecular bases of the stress-related diseases in specific populations.