Abstract: OBJECTIVE To study the effect of helicid on the depression-like behavior, and neurocalcin-delta(NCALD) concentration in the blood and expression level in prefrontal cortex in chronic unpredictable mild stress(CUMS) rats, and to analyze the correlation between NCALD concentration in blood and prefrontal cortex. METHODS The CUMS and orphanage were continuously given to rats for six weeks to establish the rat depression model. The CUMS models were then divided into model group, fluoxetine hydrochloride group(5 mg·kg^-1) and helicid high, medium, low dose group(32, 16, 8 mg·kg^-1). All received CUMS and intragastric administration for another six weeks. The behaviour changes were assessed through body weight, sucrose preference test and open field test. The expression level of NCALD in the prefrontal cortex of each group was detected by Western blotting, and the concentration of NCALD in the blood was detected by ELISA, and the correlation between the two was discussed. RESULTS Helicid could reverse depression behaviors such as weight loss, reduce sucrose bias, voluntary activity, and willingness to explore, and reverse the increase of NCALD concentration in blood and up-regulation in prefrontal cortex expression in CUMS rats. The NCALD concentration in blood was positively correlated with prefrontal cortex expression level(r=0.771). CONCLUSION Helicid has antidepressant effect, and can improve the depression-like behavior caused by CUMS. The mechanism may be related to the inhibition of NCALD expression.