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

35 Pages Posted: 14 Jan 2020

See all articles by Li Ma

Li Ma

Tongji University - Clinical and Translational Research Center

Mengxue Tian

Tongji University - Clinical and Translational Research Center

Qiaoyi Sun

Tongji University - Clinical and Translational Research Center

Nana Liu

Tongji University - Clinical and Translational Research Center

Jianfeng Dong

Tongji University - Clinical and Translational Research Center

Ke Feng

Tongji University - Clinical and Translational Research Center

Yukang Wu

Tongji University - Clinical and Translational Research Center

Yuxi Wang

Tongji University - Clinical and Translational Research Center

Guiying Wang

Tongji University - Clinical and Translational Research Center

Wen Chen

Tongji University - Clinical and Translational Research Center

Jiajie Xi

Tongji University - Clinical and Translational Research Center

Jiuhong Kang

Tongji University - Clinical and Translational Research Center

More...

Abstract

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).

Keywords: fetal growth restriction; depression; environmental stress; dopaminergic neurons; memantine

Suggested Citation

Ma, Li and Tian, Mengxue and Sun, Qiaoyi and Liu, Nana and Dong, Jianfeng and Feng, Ke and Wu, Yukang and Wang, Yuxi and Wang, Guiying and Chen, Wen and Xi, Jiajie and Kang, Jiuhong, Fetal Growth Restriction Mice Are More Likely to Exhibit Depression-Like Behaviors Due to Stress-Induced Loss of Dopamine Neurons in the VTA (January 6, 2020). Available at SSRN: https://ssrn.com/abstract=3514641 or http://dx.doi.org/10.2139/ssrn.3514641

Li Ma

Tongji University - Clinical and Translational Research Center

1239 Siping Road
Shanghai, 200092
China

Mengxue Tian

Tongji University - Clinical and Translational Research Center

1239 Siping Road
Shanghai, 200092
China

Qiaoyi Sun

Tongji University - Clinical and Translational Research Center

1239 Siping Road
Shanghai, 200092
China

Nana Liu

Tongji University - Clinical and Translational Research Center

1239 Siping Road
Shanghai, 200092
China

Jianfeng Dong

Tongji University - Clinical and Translational Research Center

1239 Siping Road
Shanghai, 200092
China

Ke Feng

Tongji University - Clinical and Translational Research Center

1239 Siping Road
Shanghai, 200092
China

Yukang Wu

Tongji University - Clinical and Translational Research Center

1239 Siping Road
Shanghai, 200092
China

Yuxi Wang

Tongji University - Clinical and Translational Research Center

1239 Siping Road
Shanghai, 200092
China

Guiying Wang

Tongji University - Clinical and Translational Research Center

1239 Siping Road
Shanghai, 200092
China

Wen Chen

Tongji University - Clinical and Translational Research Center

1239 Siping Road
Shanghai, 200092
China

Jiajie Xi

Tongji University - Clinical and Translational Research Center ( email )

1239 Siping Road
Shanghai, 200092
China

Jiuhong Kang (Contact Author)

Tongji University - Clinical and Translational Research Center ( email )

1239 Siping Road
Shanghai, 200092
China

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