Understanding and Breaking the Intergenerational Cycle of Abuse: Epigenetic mechanisms underlying perinatal stress (PNS)-induced transgenerational structural synaptic changes in prefronto-limbic-hypothalamic (PLH) circuits

A number of animal studies throughout the last decades, including ours, which induced chronic or repeated perinatal stress (e.g. maternal separation) to mimic human early childhood trauma and neglect, revealed that the maturation of neuronal pathways and socio-emotional behaviour is altered in these animals . So far, neither the brain functional, nor the epigenetic mechanisms underlying these trauma-induced neuronal and behavioural changes are understood and thus will be one focus of our project. Epigenetics is most commonly defined as the ensemble of heritable alterations in gene functions, that cannot be explained by changes in the DNA sequence itself. At the molecular level, epigenetic mechanisms are modifications of the DNA and histone proteins, the major constituents of chromatin. These mechanisms include direct modifications of the DNA, i.e. through DNA-methylation and specific modifications of histone proteins (i.e. acetylation, phosphorylation, methylation). Depending on the type of modification this can result in actively transcribed or silenced genes, and this strongly influences neuronal and synaptic development in the juvenile brain. There is increasing evidence that these changes affect higher cognitive functions and emotionality and that epigenetic factors mediate the relationship between early life experiences and the long-term behavioural outcome. The first focus of this project is to test the hypothesis that maternal care interferes with the functional maturation of prefronto-limbic-hypothalamic (PLH) pathways. Functionality of PLH pathways of traumatized animals will be assessed using functional imaging techniques (2-FDG, SPECT), which are established in our lab and which allow to monitor brain activity in awake, freely behaving animals. In direct correspondence to clinical projects of this network a modified version of an emotion recognition task used in the clinical studies will be applied as well as an acute stress challenge. Preliminary functional imaging experiments revealed that traumatized infant and preadolescent animals, display significantly reduced activation in prefrontal and limbic brain regions. The second focus will address the hypothesis that the brain functional and structural changes are induced by epigenetic alterations, evoked by changes in maternal care. First, DNA-methylation profiles on the promoters of 5-HTT and GR will be analyzed from samples of oral mucosa, which can be directly compared with the results of the clinical projects. In our lab we will search for histone modifications affecting other targets, including oxytocin, dopamine-receptors (DAR) and dopaminetransporters (DAT), egr-1 and arc/arg3.1.