DEVELOPMENTAL DIFFERENCES IN NEURAL RESPONSES TO ACUTE STRESS IN RELATION TO DNA METHYLATION OF ESTROGEN-RESPONSIVE NEURONAL GENES IN FEMALES

Sex-specific neuroendocrine changes during puberty are linked to heightened stress reactivity, which may contribute to vulnerability to internalizing disorders in females. However, little is known about the neuronal and epigenetic correlates of stress reactivity during female puberty. Therefore, this study aimed to explore brain activity during socio-evaluative performance stress and its correlation with epigenetic markers in pre- and postpubertal females.
31 healthy participants were categorized into two groups: 15 without breast development (mean age: 9.04 years) as prepubertal, and 16 having menstruation for at least a year (mean age: 16.40 years) as postpubertal. Whole-brain activity during the Montreal Imaging Stress Task (MIST) was analyzed using a puberty X condition interaction to test group differences between stress and control conditions (cluster-FWE, p<0.05). Saliva samples were analyzed for DNA methylation in candidate genes using pyrosequencing.
Postpubertal girls reported significantly higher perceived stress last month and following MIST (p<0.003). They exhibited hypermethylation of SLC12A5 and GRM2 (p=0.001 and p=0.024, respectively) and stronger stress-control activation difference in the right middle orbital gyrus (rMiOG) compared to prepubertal girls (k>70), characterized by greater stress and lower control activation. The rMiOG activity during stress positively correlated with SLC12A5 methylation and perceived stress levels in the whole group (p=0.003 for both correlations). While GRM2 methylation only correlated with baseline state anxiety (p=0.012).
The current findings are preliminary due to ongoing data collection. Given the role of MiOG in goal-directed attention, SLC12A5 methylation may indicate MiOG maturation, contributing to adaptive recalibration of stress reactivity during puberty.