Curculigoside facilitates fear extinction and prevents depression-like behaviors in a mouse learned helplessness model through increasing hippocampal BDNF

Authors: San-juan Yang1, Zhu-jin Song1, Xun-cui Wang1, Zheng-rong Zhang1, Sheng-bing Wu1,2, Guo-qi Zhu1,2
1 Key Laboratory of Xin’an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei 230038, China
2 Anhui Academy of Chinese Medicine, Hefei 230038, China
Correspondence to: Guo-qi Zhu:,
DOI: 10.1038/s41401-019-0238-4
Received: 9 January 2019
Accepted: 11 April 2019
Advance online: 26 April 2019


Curculigoside (CUR) is the main active component of traditional Chinese medicine Curculigoorchioides Gaertn (Xianmao in Chinese), which exhibits a variety of pharmacological activities. In this study we investigated the effects of CUR on fear extinction and related depression-like behaviors in mice. In fear conditioning task, we found that administration of CUR (1.6, 8, 40 mg·kg−1·d−1, ip, for 7 days) did not affect memory consolidation, but CUR at higher doses (8, 40 mg·kg−1·d−1) significantly facilitated fear extinction, especially on D3 and D4. Moreover, CUR administration significantly ameliorated the fear conditioning-induced depression-like behaviors, likely through promoting fear extinction. We showed that CUR increased the expression of brain-derived neurotrophic factor (BDNF) and phosphorylation of tropomyosin receptor kinase B (TrkB) in the hippocampus, and activated protein kinase B (Akt)-mammalian target of the rapamycin (mTOR) signaling pathway. Administration of the selective TrkB agonist 7,8-dihydroxyflavone (7,8-DHF, 5 mg·kg−1·d−1, ip) also facilitated fear extinction, ameliorated depression-like behaviors. We established a mouse learned helplessness (LH) model to evaluate the antidepressant activity of CUR. The spatial memory was assessed in Morris water maze. We showed that LH-induced depression-like behaviors, including prolonged immobility times in forced swim and tail suspension tests as well as spatial memory impairments; LH also downregulated BDNF expression and the Akt-mTOR signaling pathway in the hippocampus. Administration of CUR (1.6, 8, 40 mg·kg−1·d−1, ip, for 14 days) or 7,8-DHF (5 mg·kg−1·d−1, ip, for 3 days) prevented LH-induced depression-like behaviors and promoted BDNF expression and the Akt-mTOR signaling pathway. In conclusion, CUR can accelerate the fear memory extinction and ameliorate depression-like behaviors in mice via promoting BDNF expression and activating the Akt-mTOR signaling pathway in the hippocampus.
Keywords: depression; curculigoside; 7; 8-dihydroxyflavone; fear extinction; learned helplessness model; BDNF; TrkB; Akt-mTOR signaling pathway; hippocampus

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