Inter- and transgenerational consequences of early life adversity on oxytocin-receptor gene expression
Exposure to one or multiple forms of early-life adversity (ELA) constitutes a major risk factor for developing somatic and behavioral disorders and in the etiology of a wide range of mental disorders. On the other hand there is also evidence that ELA exposure may lead to stress resilience. In our animal model for ELA behavioral profiling of offspring of ELA-exposed mothers will identify vulnerable and resilient individuals in which epigenetic and transcriptomic changes will be compared. Evidence is emerging that behavioral and brain structural/functional consequences of ELA can be transmitted to the next generations, however, the detailed mechanisms underlying inter- and transgenerational transmission of ELA are still poorly understood. In our animal model for ELA we will attempt to unveil causal relationships between ELA exposure, behavioral dysfunctions, changes in gene expression and underlying epigenetic modifications in brain and other organs/cells. So far, various genes in particular those integrated in HPA functions, have been identified, whose expression is altered in response to ELA. However, ELA-induced changes in gene transcription are much more complex and most likely affect specific cellular, physiological and biochemical signaling pathways, which are involved in developmental and adult synaptic plasticity. Based on our findings one aim of this project is guided by a hypothesis-driven approach and will assess i) whether changes of OxtR gene expression, which we observed in ELA exposed F0 mothers are transmitted to the next (F1, F2) generations, and ii) if these changes are epigenetically regulated via DNA-methylation. Considering transgenerational epigenetic inheritance via the maternal line in mammals and in particular human populations, we will also identify ELA transmission paths, i.e. if transmission is mediated via behavioral maternal traits or through epigenetic changes in oocytes.
To expand our knowledge on ELA-induced changes in gene expression, another aim of this project is to conduct a whole genome transcriptome analysis to i) further identify ELA-induced changes in genes encoding proteins that are part of OxtR-related intracellular signaling cascades and ii) to detect novel gene targets which are affected by ELA.
Most of what is known about the effects of ELA on brain development arises from experimental studies in male individuals, which is somewhat surprising in view of the considerable sex-bias in the prevalence of ELA-induced disorders. Consequently, another aim of this project is to deepen our knowledge about sex-specific effects of ELA and to characterize sex as vulnerability or resiliency factor.