Depression is partially caused by inflammation in central nervous system. This study investigated the ameliorative effects of phenol glycosides (PG) from Ligustrum lucidum Ait. (Oleaceae) on neuroinflammation and depressive-like behavior in mice hypothalamus as well as the molecular mechanism. Mice were administered with PG extract for 2 weeks prior to treatment with LPS. The mice treated with PG extract showed resistance to LPS-induced reduction in body weight and LPS-induced depressive-like behaviors shown by sucrose preference, tail suspension test, forced swimming test and open field test. LPS-induced activation of microglial cells and elevation in protein expression of inflammatory cytokines including IL-1β, RANTES and MCP-1 in hypothalamus of mice were abrogated by pre-treatment with PG extract. This extract down-regulated expression of TLR4, MyD88, NLRP3, renin and angiotensin II and decreased proportional area of Iba-1 + microglias in hypothalamus. Pretreatment with PG extract inhibited LPS-triggered activation of CaSR/G α11 signaling, stimulated 1-OHase expression in hypothalamus, and enhanced circulating 1,25 (OH) 2 D 3 level. Overall, pre-treatment with PG extract ameliorated LPS-induced depressive-like behaviors by repressing neuroinflammation in mice hypothalamus which was attributed to its suppression on activation of microglia and production of inflammatory cytokines via acting on TLR4 pathway, CaSR and RAS cascade associated with improving vitamin D metabolism. K E Y W O R D S depression, Fructus Ligustri Lucidi, hypothalamus, renin-angiotensin system, vitamin D 1 | INTRODUCTION Depression, one of the most common mental disorders, is considered to be the second leading global cause of years of life lived with disability (Bab & Yirmiya, 2010a), and affects approximately 15-20% of the global population (Zhang & Cheng, 2019). The current prevalence in US is estimated to 10-14 million annually which is more than 5% of the population (Bab & Yirmiya, 2010b). Lifetime and 12-month prevalence of major depressive disorder in China were 6.8 and 3.6%, respectively (Huang, Wang, et al., 2019). Depression has been even implicated as a possible risk factor for other chronic diseases, such as osteopenia characterized by loss of bone minerals (Schweiger et al., 2016). However limited therapeutic options for the treatment of depression are available, creating a great individual and societal burden (Li et al., 2019). Thus, development of novel antidepressant drugs is a pressing task (Zhang & Cheng, 2019).