SUN-021 Chronic Psychosocial Stress during Pregnancy Affects Maternal Behavior and Neuroendocrine Function and Modulates Hypothalamic CRH Signaling Pathway and Nuclear Steroid Hormone Receptor Expression

Abstract

Abstract Postpartum depression (PPD) affects up to 20% of women and exerts adverse consequences on mother and child. Gestational stress and abnormalities in neuroendocrine function have been implicated in the development of PPD. Here, we measured effects of chronic psychosocial stress during pregnancy on maternal behavior as well as hypothalamic-pituitary-adrenal (HPA) axis function and regulation in the early postpartum period. From gestational day 6.5 to 17.5, pregnant C57Bl/6 female mice were exposed to a novel chronic stress paradigm consisting of variable psychosocial stressors such as foreign object exposure, rat odor exposure, bedding removal and were assessed from postpartum day 2 to 7 for behavioral alterations in maternal care, depression, and anxiety as well as circadian and brief restraint-stress associated corticosterone response. mRNA changes in molecular regulators of the HPA axis were measured in 1mm micropunches of the hypothalamic paraventricular nucleus (PVN) via qPCR. Mice exhibited deficits in maternal care after undergoing chronic psychosocial stress during pregnancy displayed as increased latency to retrieve pups during pup retrieval task (p<0.01, n=17). Furthermore, they displayed a depressive-like phenotype as measured by increased time spent immobile in forced swim test (p<0.01, n=17) and increased anxiety as measured by increased time spent in dark zone in light/dark transition test (p<0.05, n=7-11). Abnormalities in the activity of the maternal HPA axis were also displayed as seen by a flattening of the circadian rhythm of CORT secretion (p<0.05, n=10-12), increased CORT release following 20 minutes of restraint stress (p<0.05, n=5-8), and increased adrenal gland weights (p<0.05, n=15-20). These changes were associated with increased PVN CRH mRNA (gestational day 17.5 (G17.5): 0.880+0.18 vs. 0.485+0.03, postpartum day 2 (PP2): 1.012+0.05 vs. 0.794+0.05, PP7: 0.775+0.04 vs. 0.487+0.05, p<0.05, n=6-7) and downregulation of CRH receptor 1 (G17.5: 0.821+0.07 vs. 1.03+0.05, PP2: 1.007+0.05 vs. 1.184+0.06, p<0.05, n=6-7) compared to non-stressed control dams, while vasopressin and oxytocin levels remained undisturbed. Furthermore, PVN glucocorticoid receptor (G17.5: 0.844+0.01 vs. 0.938+0.02, p<0.01, n=6-7) and progesterone receptor mRNA were downregulated (PP2: 1.008+0.03 vs. 1.196+0.047, p<0.01, n=6-7), and FK506 binding protein 5 mRNA, a co-chaperone known to negatively orchestrate GR/PR transcriptional activity, was upregulated (G17.5: 2.322+0.37 vs. 1.315+0.05, p<0.05, n=6-7). These results suggest hypothalamic changes in GR/PR signaling pathway as putative regulators of postpartum changes in CRH after stress exposure and postpartum maternal affective dysregulation. The mechanistic role GR/PR play in mediating these changes is further being investigated by selective spatiotemporal GR/PR modulation using Cre-loxP technology.