GPCR-mediated calcium and cAMP signaling determines psychosocial stress susceptibility and resiliency

Chronic stress increases the risk of developing psychiatric disorders, including mood and anxiety disorders. Al-though behavioral responses to repeated stress vary across individuals, the underlying mechanisms remain unclear. Here, we perform a genome-wide transcriptome analysis of an animal model of depression and patients with clinical depression and report that dysfunction of the Fos-mediated transcription network in the anterior cingulate cortex (ACC) confers a stress-induced social interaction deficit. Critically, CRISPR-Cas9-mediated ACC Fos knockdown causes social interaction deficits under stressful situation. Moreover, two classical second mes-senger pathways, calcium and cyclic AMP, in the ACC during stress differentially modulate Fos expression and regulate stress-induced changes in social behaviors. Our findings highlight a behaviorally relevant mechanism for the regulation of calcium-and cAMP-mediated Fos expression that has potential as a therapeutic target for psychiatric disorders related to stressful environments.

Automated summary

Chronic stress increases the risk of developing mood and anxiety disorders, and dysfunction of the Fos-mediated transcription network in the ACC is implicated in stress-induced social interaction deficits. Calcium and cyclic AMP pathways in the ACC modulate Fos expression and regulate stress-induced changes in social behaviors. These findings provide a potential therapeutic target for psychiatric disorders related to stressful environments.