Fetal Growth Restriction Mice Are More Likely to Exhibit Depression-Like Behaviors Due to Stress-Induced Loss of Dopamine Neurons in the VTA

Background: Fetal growth restriction (FGR) is a severe perinatal complication that can cause increased risk for mental illness, while the mechanism is still unclear. We used FGR mouse model to study the mental state of the FGR offspring in adulthood. Methods: FGR mouse model was conducted as following: pregnant C57BL/6J mice were injected with dexamethasone (1 mg/kg) intraperitoneally from E14.5 to E18.5 or restricted with low-protein diet. Adult FGR mice were examined in a series of behavioral tests pre-and post- environmental stress. Immunofluorescent staining and HPLC were used to detect the neuron number and neurotransmitter level. Furthermore, RNA sequencing was used to capture transcriptome-wide alterations in the midbrain of neonatal FGR mice compared to the control ones. Findings: The FGR mice were more likely to exhibit depression-like behaviors than control mice after environmental stress exposure. The main cause of that was significantly fewer dopaminergic neurons in the ventral tegmental area (VTA) induced by environmental stress. Abnormal regulation of NMDAR activity in FGR mice caused the loss of midbrain VTA dopaminergic neurons exposed to environmental stress. Consistently, the NMDA receptor antagonist memantine inhibited neuronal apoptosis and relieved the stress-induced depression-like behaviors of FGR mice. Interpretation: We demonstrated abnormal regulation of NMDAR activity in FGR mice caused the loss of midbrain VTA dopaminergic neurons and depression-like behaviors exposed to environmental stress, and memantine can ameliorate stress-induced depression-like behaviors of FGR mice. Funding Statement: This work was supported by the National Natural Science Foundation of China (grants 81530042, 31871495, 31571529, 31571519), the Ministry of Science and Technology (grant 2016YFA0101300). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All procedures involving animals were approved by the Laboratory Animal Care Committee of Tongji University in accordance with the Guide for the Care and Use of Laboratory Animals (NIH).