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Hijacking Dorsal Raphe to Improve Metabolism and Depression-like Behaviors via BDNF Gene Transfer in Mice

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posted on 08.06.2021, 14:21 by Jianbo Xiu, Rongrong Han, Zeyue Liu, Jiayu Li, Shu Liu, Yan Shen, Yu-Qiang Ding, Qi Xu
Moods and metabolism modulate each other. High comorbidity of depression and metabolic disorders such as diabetes and obesity poses a great challenge to treat such condition. Here we report the therapeutic efficacy of brain-derived neurotrophic factor (BDNF) by gene transfer in the dorsal raphe nucleus (DRN) in a chronic unpredictable mild stress model of depression (CUMS) and models of diabetes and obesity. In CUMS, BDNF-expressing mice displayed antidepressant- and anxiolytic-like behaviors, which are associated with augmented serotonergic activity. Both in the diet-induced obesity model (DIO) and in db/db mice,BDNF ameliorated obesity and diabetes, which may be mediated by enhanced sympathetic activity, not involving DRN serotonin. Chronic activation of DRN neurons via chemogenetic tools produced similar effects as BDNF in DIO mice. These results established the DRN as a key nexus in regulating depression-like behaviors and metabolism, which can be exploited to combat comorbid depression and metabolic disorders via BDNF gene transfer.

Funding

This work was supported by the research grants from the National Key Research and Development Program of China (2016YFC1306700), the National Natural Science Foundation of China (81625008, 81930104, and 31970952), Beijing Municipal Science & Technology Commission (Z181100001518001), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-004), Science and Technology Program of Guangdong (2018B030334001), the Fundamental Research Funds for the Central Universities (3332018001), Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01) and Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01) and ZJLab to Y.D.

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