Effects of chronic stress in pregnancy on hypothalamic gene expression patterns: interference with antidepressants and identified pathways
Final Report Abstract
Over the funding period, the project lead to significant advances on our understanding of the alterations that occur across the hypothalamic pituitary adrenal (HPA) axis in the peripartum period; both at baseline and following chronic stressors. We could validate a novel chronic psychosocial stress paradigm for use during pregnancy (PS) and reveal that it prevented the basal peripartum-associated increase in plasma corticosterone, but did not significantly affect the attenuated HPA axis response to an acute stressor at this time-point. We could further show that PS prevented the lactation-associated anxiolysis, but did not alter depression-like behaviour. Interestingly, and opposite to our expectations, PS increased the time the dam spent actively nursing (increase in arched back nursing). In addition, PS prevented the peripartum-associated increase in OXT mRNA expression and alteration in the MAPK pathway within the hypothalamic paraventricular nucleus (PVN). Paradoxically, stress in the first weeks of lactation attenuated the dampened hippocampal cell proliferation that is observed in lactation. These results lead us to perform a microarray to fully characterise alterations in the gene expression as a consequence of lactation as well as PS exposure. Here, we could demonstrate that a number of novel genes that were altered by reproductive status as well as PS. Bio-informatic analyses suggested that pathways involved in glutamate metabolism, mitochondrial function and circadian rhythm signalling, amongst others, were altered by reproductive status. Intriguingly, three members of the Wnt/ß-catenin pathway, USAG-1, membrane frizzle protein and ß-catenin, were found to be downregulated (up to 13-fold) in lactation and further downregulated by stress exposure. We could confirm via qPCR and Western Blot that this pathway is indeed altered in lactation. Moreover, to gain a deeper insight into genes that are important for maternal behavior, we performed an additional microarray study in HAB and LAB virgin and lactating rats. HAB and LAB rats were selected for their anxiety traits, but we have repeatedly shown that HAB dams exhibit high levels of maternal care, whereas LAB dams are poor mothers. Somewhat surprisingly, we observed fewer reproductive status changes in gene expression in HAB females (665) compared with LAB females (1900). Interestingly, the behavioral effects of PS were minimal, which may be due to the rigid genetic predisposition of the lines. A major surprise across the funding period were the significant and unexpected difficulties adding antidepressant treatment on top of the PS protocol. Therefore, this part of the grant could not be achieved. We also extended previous rat data to show that the adrenal gland undergoes substantial peripartum-associated adaptation in terms of the machinery mediating cholesterol supply for steroidogenesis also in mouse. Taken together, these findings have increased our understanding of the consequences of chronic stress exposure throughout pregnancy on behavioral, physiological, molecular and adrenal adaptations across the peripartum period and provide a number of interesting avenues for future research.
