Stress dynamically regulates co-expression networks of glucocorticoid receptor-dependent MDD and SCZ risk genes.

Early-life adversity is an important risk factor for major depressive disorder (MDD) and schizophrenia (SCZ) that interacts with genetic factors to confer disease risk through mechanisms that are still insufficiently understood. One downstream effect of early-life adversity is the activation of glucocorticoid receptor (GR)-dependent gene networks that drive acute and long-term adaptive behavioral and cellular responses to stress. We have previously shown that genetic variants that moderate GR-induced gene transcription (GR-response eSNPs) are significantly enriched among risk variants from genome-wide association studies (GWASs) for MDD and SCZ. Here, we show that the 63 transcripts regulated by these disease-associated functional genetic variants form a tight glucocorticoid-responsive co-expression network (termed GCN). We hypothesized that changes in the correlation structure of this GCN may contribute to early-life adversity-associated disease risk. Therefore, we analyzed the effects of different qualities of social support and stress throughout life on GCN formation across distinct brain regions using a translational mouse model. We observed that different qualities of social experience substantially affect GCN structure in a highly brain region-specific manner. GCN changes were predominantly found in two functionally interconnected regions, the ventral hippocampus and the hypothalamus, two brain regions previously shown to be of relevance for the stress response, as well as psychiatric disorders. Overall, our results support the hypothesis that a subset of genetic variants may contribute to risk for MDD and SCZ by altering circuit-level effects of early and adult social experiences on GCN formation and structure. Male Balb/c mice were exposed to either early-life adversity (limited nesting and bedding material; LM) or a caring environment (early handling, EH). LM was performed by placing the animals from postnatal day (P) 2 to P9 in a cage with a metal grid instead of bedding material and reduced nesting material, leading to fragmented maternal care. EH was performed by removing the offspring from the maternal cage to a new cage for 15 min per day on P2 to P9, a procedure that has been shown to increase maternal caregiving behavior. A group with an unmanipulated environment (i.e., animal facility reared mice) was explicitly omitted to test only two opposing rearing environments. At adulthood (12 weeks of age), animals of each group were then either housed with an ovariectomized female (OX; supportive social environment) or underwent chronic social defeat stress (CD; aversive social environment) for three consecutive weeks giving rise to four experimental groups exposed to different qualities of social experience (EHOX, EHCD, LMOX, and LMCD). From each treatment group, eight mouse brains were analyzed. Twelve different brain regions including AMY, bed nucleus of the stria terminalis, cerebellum (CER), dorsal hippocampal Cornu Ammonis (CA) 1 region (dCA1), dorsal hippocampal CA3 region (dCA3), dorsal dentate gyrus (dDG), prefrontal cortex, nucleus accumbens (Nac), paraventricular nucleus (PVN), ventral hippocampal CA1 region (vCA1), ventral hippocampal CA3 region (vCA3), and ventral dentate gyrus were collected.