A sex-dependent delayed maturation of visual plasticity induced by adverse experiences in early childhood

Adverse experiences in early life have a long-term impact on the development of brain, which in turn increases the susceptibility to mental illness during adulthood, especially in female subjects. However, whether and how the visual cortex is affected by these adverse experiences as well as the mechanisms underlying the sex difference are largely unknown. Here, we established a new mouse model of early-life chronic mild stress (ECMS) without anxiety or depression-like behavior in adulthood. ECMS mice showed normal maturation of visual acuity and orientation/direction selectivity, whereas their visual cortical neurons preferred lower spatial frequency (SF) and higher temporal frequency (TF) than control mice. Meanwhile the development of ocular dominance (OD) plasticity was delayed. Specifically, compared with control mice, ECMS mice in the early stage of the critical period (CP) showed a reduction in GABA synthesis enzyme expression as well as lower OD plasticity which could be occluded by diazepam. In contrast, ECMS mice in the late stage of CP showed stronger OD plasticity, accompanied by higher expression of N-methyl-D-aspartate (NMDA) receptor NR2B subunit. Interestingly, only female ECMS mice at adulthood maintained juvenile-like OD plasticity as well as high NR2B expressions. Artificial increase in estradiol level in ECMS males via estradiol supplementary diminished this sex difference. Lastly, OD plasticity was abolished in adult ECMS females either performed with the bilateral ovariectomy in prepuberty, or directly infused with NR2B antagonist Ro 25-6981 into the visual cortex. Overall, our study demonstrates that early adverse experiences have a lasting effect on visual development of mice in a sex-dependent manner, which is mediated by the estradiol-NR2B pathway.