Si-Ni-San alleviates early life stress-induced depression-like behaviors in adolescence via modulating Rac1 activity and associated spine plasticity in the nucleus accumbens

Lihong Ye; Jiayi Wu; Zuyi Liu; Di Deng; Shasha Bai; Lei Yang; Yao Xuan; Zehao Liu; Yafei Shi; Zhongqiu Liu; Rong Zhang; Jinlan Zhao

doi:10.3389/fphar.2023.1274121

Si-Ni-San alleviates early life stress-induced depression-like behaviors in adolescence via modulating Rac1 activity and associated spine plasticity in the nucleus accumbens

Front Pharmacol. 2023 Nov 1:14:1274121. doi: 10.3389/fphar.2023.1274121. eCollection 2023.

Authors

Lihong Ye¹, Jiayi Wu², Zuyi Liu¹, Di Deng¹, Shasha Bai¹, Lei Yang¹, Yao Xuan¹, Zehao Liu¹, Yafei Shi², Zhongqiu Liu¹, Rong Zhang¹, Jinlan Zhao¹

Affiliations

¹ Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
² School of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China.

Abstract

Background: Early life stress (ELS) is a major risk factor for depression in adolescents. The nucleus accumbens (NAc) is a key center of the reward system, and spine remodeling in the NAc contributes to the development of depression. The Si-Ni-San formula (SNS) is a fundamental prescription for treating depression in traditional Chinese medicine. However, little is known about the effects of SNS on behavioral abnormalities and spine plasticity in the NAc induced by ELS. Purpose: This study aimed to investigate the therapeutic effect and the modulatory mechanism of SNS on abnormal behaviors and spine plasticity in the NAc caused by ELS. Methods: We utilized a model of ELS that involved maternal separation with early weaning to explore the protective effects of SNS on adolescent depression. Depressive-like behaviors were evaluated by the sucrose preference test, the tail suspension test, and the forced swimming test; anxiety-like behaviors were monitored by the open field test and the elevated plus maze. A laser scanning confocal microscope was used to analyze dendritic spine remodeling in the NAc. The activity of Rac1 was detected by pull-down and Western blot tests. Viral-mediated gene transfer of Rac1 was used to investigate its role in ELS-induced depression-like behaviors in adolescence. Results: ELS induced depression-like behaviors but not anxiety-like behaviors in adolescent mice, accompanied by an increase in stubby spine density, a decrease in mushroom spine density, and decreased Rac1 activity in the NAc. Overexpression of constitutively active Rac1 in the NAc reversed depression-related behaviors, leading to a decrease in stubby spine density and an increase in mushroom spine density. Moreover, SNS attenuated depression-like behavior in adolescent mice and counteracted the spine abnormalities in the NAc induced by ELS. Additionally, SNS increased NAc Rac1 activity, and the inhibition of Rac1 activity weakened the antidepressant effect of SNS. Conclusion: These results suggest that SNS may exert its antidepressant effects by modulating Rac1 activity and associated spine plasticity in the NAc.

Keywords: Si-Ni-San; adolescent depression; early life stress; nucleus accumbens; spine plasticity.

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by National Natural Science Foundation of China (No. 82104623), Guangdong Basic and Applied Basic Research Foundation (No. 2020A1515110607), Traditional Chinese Medicine Bureau of Guangdong Province (No. 20241079), National Natural Science Foundation of China (Nos. 82274226, 82274443, 82074219, 82104557, and 81903943), Natural Science Foundation of Guangdong Province, China (Grant Nos. 2022A1515010230 and 2021A1515012572), Science and Technology Projects in Guangzhou (No. 202201011267), Scientific Research Team Major Project of Guangzhou University of Chinese Medicine (No. 2021xk29), Innovative training program for college student (202210572017), National Natural Science Foundation of China (Key Program) (No. 81930114), Guangdong Basic and Applied Basic Research Foundation (No. 2020B1515130005) and Key Laboratory of Guangdong Drug Administration (2021ZDB03).