Chronic social stress induces generalized hyper-sensitivity to aversion: A mouse model with translational validity for understanding and treating negative valence disorders

Abstract

The RDoC framework focuses on neurobehavioral processes often dysfunctional in mental disorders and commensurate with translational research. Generalized hyper-sensitivity to aversion/threat is common in various stress-related emotional disorders; increased Pavlovian aversion learning-memory (PAL, PAM) provides a translational paradigm for its study. Here we present the development and application of a mouse model for the study of generalized hyper-sensitivity to aversion/threat. In male adult mice, chronic exposure to social aversion (chronic social stress, CSS) leads, relative to controls (CON), to increased acquisition and expression of tone-footshock conditioned freezing behavior. The altered neurobehavioral state of CSS mice is expected to involve structure-function changes in amygdala: in CSS mice, higher levels of both PAL and PAM freezing behavior co-occurred with fewer lateral/basal amygdala glutamate neurons expressing the immediate early-gene protein c-Fos. A current antidepressant, SSRI escitalopram, reversed excessive PAM freezing behavior in CSS mice with sub-chronic dosing. The model was applied to investigate 3 compounds with novel mechanisms of action: indoleamine dioxygenase 1 (IDO 1) inhibition, somatostatin receptor 4 (SSTR4) agonism, and transient receptor potential canonical channels 4 and 5 (TRPC4/5) inhibition. For each, there was evidence for attenuation of excessive PAL and/or PAM in CSS mice. Preclinical validation of TRPC4/5 channels inhibition contributed to the decision to investigate, and accurately predicted, clinical efficacy, measured as reduced amygdala and emotional reactivities to aversion in major depressive disorder. Future work will focus on (back-)translational studies that address stress-induced changes in amygdala reactivity and aversion processing, their underlying etio-pathophysiological causes, and neuropharmacological responsiveness.

Keywords: IDO1; Negative valence; Pavlovian conditioning; RDoC; SSTR4; TRPC4/5.