AUTHOR=Kocamaz Derya , Franzke Caroline , Gröger Nicole , Braun Katharina , Bock Jörg 

TITLE=Early Life Stress-Induced Epigenetic Programming of Hippocampal NPY-Y2 Receptor Gene Expression Changes in Response to Adult Stress

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=Volume 16 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2022.936979

DOI=10.3389/fncel.2022.936979

ISSN=1662-5102

ABSTRACT=Early Life Stress (ELS) can critically influence brain development and future stress responses and thus represents an important programming factor for mental health and disease. Neuropeptide Y (NPY) is discussed to be a key mediator of resilient vs. vulnerable adaptations and specifically the neuropeptide Y2 receptor (Y2R) may be involved in the pathophysiology of depression due to its negative regulation of NPY-release. The present study addressed the hypotheses that ELS as well as adult stress (AS) affect the expression of hippocampal Y2R and that exposure to ELS induces an epigenetically mediated programming effect towards a consecutive stress exposure at adulthood. The specific aims were to investigate if i) ELS or AS as single stressors induce changes of Y2 receptor gene expression in the hippocampus, ii) the predicted Y2R changes are epigenetically mediated via promoter-specific DNA-methylation, iii) the ELS-induced epigenetic changes exert a programming effect on Y2R gene expression changes in response to AS and finally iv) if the predicted alterations are sex-specific. Animals were assigned to the following experimental groups: 1) non-stressed controls (CON), 2) only ELS exposure (ELS), 3) only adult stress exposure (CON+AS), 4) exposure to ELS followed by AS (ELS+AS). Using repeated maternal separation in mice as ELS and swim stress as AS we found that both stressors affected Y2R gene expression in the hippocampus of male mice but not in females. Specifically, upregulated expression was found in the CON+AS group. In addition, exposure to both stressors ELS+AS significantly reduced Y2 gene expression when compared to CON+AS. The changes in Y2R expression were paralleled by altered DNA-methylation patterns at the Y2R promoter, specifically, a decrease of mean DNA-methylation in the CON+AS males compared to the non-AS exposed groups and an increase in the ELS+AS males compared to the CON+AS males. Also a strong negative correlation of mean DNA-methylation with Y2 expression was found. Detailed CpG-site specific analysis of DNA-methylation revealed that ELS induced increased DNA-methylation only at specific CpG-sites within the Y2R promoter. It is tempting to speculate that these ELS-induced CpG-site specific changes represent a “buffering” programming effect against elevations of Y2R expression induced by AS.