Early-Life Adversity Induces Epigenetically Regulated Changes in Hippocampal Dopaminergic Molecular Pathways.

Early-life adversity (ELA) represents a major risk factor for the development of behavioral dysfunctions and mental disorders later in life. On the other hand, dependent on type, time point, and duration, ELA exposure can also induce adaptations, which result in better stress coping and resilience later in life. Guided by the hypothesis that chronic exposure to ELA results in dysfunctional brain and behavior, whereas short exposure to ELA may result in resilience, the behavioral and neurobiological consequences of long-term separation stress (LTSS) and short-term separation stress (STSS) were compared in a mouse model for ELA. In line with our hypothesis, we found that LTSS induced depressive-like behavior, whereas STSS reduced depressive-like behavioral symptoms. We then tested the hypothesis that the opposite behavioral outcomes of the two stress paradigms may be mediated by functional, epigenetically regulated changes of dopaminergic modulation in the hippocampal formation. We found that STSS exposure elevated dopamine receptor D1 (DRD1) gene expression and decreased gene expression of its downstream modulator DARPP-32 (32-kDa dopamine- and cAMP-regulated phosphoprotein), which was paralleled by decreased H3 acetylation at its gene promoter region. In contrast, LTSS elevated DARPP-32 gene expression, which was not paralleled by changes in histone acetylation and DRD1 gene expression. These findings indicate that short- and long-term neonatal exposure to ELA induces changes in dopaminergic molecular pathways, some of which are epigenetically regulated and which either alleviate or aggravate depressive-like symptoms later in life.

Maternal stress during pregnancy induces depressive-like behavior only in female offspring and correlates to their hippocampal Avp and Oxt receptor expression.

The majority of studies examining the consequences of prenatal stress in rodent models analyze pups having been raised by their biological mother, i.e. the female which experienced stress during her pregnancy. To test whether pregnancy stress changes maternal behavior and thereby - in addition to stress exposure in utero - influences behavior and brain function of offspring, we implemented a fostering model, in which mouse pups that were not stressed in utero, are raised by dams which were exposed to stress during their pregnancy. We found that dams, which were stressed during pregnancy (PS foster dams), unexpectedly displayed slightly more active and passive light time nursing compared to unstressed dams (CON foster dams). Adult male offspring which were raised by a PS foster dam showed significantly less anxiety-like behavior compared to males raised by a CON foster dam, whereas adult female offspring which were raised by PS foster dams displayed increased depressive-like behavior as a tendency. Since the arginine vasopressin receptor 1a (AvpR1a) and the structurally related oxytocin receptor (OxtR) are both closely related to stress-responsiveness, anxiety and depression, mRNA expression of these genes were assessed in the hippocampus of adult male and female offspring. No significant differences in mRNA expression of both receptor types were observed, however, in female offspring of PS foster dams maternal licking/grooming correlated positively with AvpR1a and negatively with OxtR mRNA expression. These findings indicate that stress during pregnancy does not reduce, but slightly increase maternal behavior, which might lead to sex-specific behavioral outcomes and changes in hippocampal AvpR1a and OxtR mRNA expression in adult offspring.