Gestational environment programs adult depression-like behavior through methylation of the calcitonin gene-related peptide gene

Early life exposure to specific environmental factors can increase risk for developing psychopathology including major depression in adulthood. However, the molecular pathways and epigenetic mechanisms that mediate the effects of early environments on adult mood remain poorly understood. We examined the effects of different gestational and rearing conditions on adult anxiety-and depression-like behavior using a combined reciprocal outcrossing and cross-fostering design in Balb/cJ (cJ) and C57BL/6J (B6) mouse strains. First filial (F1) hybrid offspring, which were gestated by B6 or cJ dams and then reared by either strain, were evaluated for behavior and whole-genome hippocampal gene expression during adulthood. Adult hybrid mice gestated by B6 dams showed increased depression-like behavior in the forced swim and sucrose preference tests, increased hippocampal expression of alpha calcitonin gene-related peptide (alpha CGRP) transcripts, and decreased methylation of the alpha CGRP promoter compared with those gestated by cJ dams. Differential expression of alpha CGRP in adulthood did not result from genomic imprinting, and differences between B6 and cJ mitochondrial DNA were not responsible for behavioral phenotypes observed. Finally, central administration of alpha CGRP to adult hybrid mice increased depression-like behavior, whereas the CGRP(1) receptor antagonist CGRP(8-37) reduced depression-like behavior in the forced swim test. Our findings suggest that gestational factors influence adult depression-like behavior through methylation of the alpha CGRP gene.