围绝经期抑郁症发病率高、危害大，但干预药物匮乏。该病的发生，与海马雌激素受体(ERs)信号下调有关，ERs调控途径可为该病新药发现提供靶向。我们前期研究发现，羟基补骨脂酚可通过单胺能途径抗普通型抑郁症，而补骨脂酚对ER有体外激动作用，提示羟基补骨脂酚可能对围绝经期抑郁症同样有效。因此，本项目采用去卵巢/应激动物（围绝经期抑郁症模型）和体外模型研究：1)羟基补骨脂酚对模型动物行为(绝望、运动、快感等)影响；2)抗抑郁机制，即对ERs→糖原合成酶激酶3β(GSK3β，系信号整合分子)→海马重塑路径的影响，从体外细胞→脑片水平，观测该药物对海马ERs、GSK3β、海马重塑标记物的影响，及ERs下调或GSK3β上调对该药物海马重塑效应的阻碍作用；以期解析其ERs亚型调控规律和信号通路整合特性。本项目旨在寻找新的抗围绝经期抑郁症药物，并初步明确其药理机制，进一步加深对围绝经期抑郁症发病机制的了解。

Perimenopausal depression is often a serious menance to woman, however, there is a dearth of effective intervention. Perimenopausal depression devepoment involves estrogen receptor signaling down-regulation in the hippocampus, thus offering a potential target for therapeutic drug development. Our previous studies showed that hydroxylbakuchiol produced antidepressant-like effects upon general types of depression models through a pathway involving monoamine transporter inhibition. On the other hand, bakuchiol was shown to act as an estrogen receptor agonist in vitro. These results indicate a potential role for hydroxylbakuchiol in the treatment of perimenopausal depression. Accordingly, we will, by using ovariectomized, stressed animals as in vivo models of perimenopausal depression and in vitro platforms, focus our studies as follows: 1) test the effects of hydroxylbakuchiol on depression behaviors (despair, locomotion, pleasure, etc.) in perimenopausal depression models; 2) search for an underlying hydroxylbakuchiol antidepression mechanism, i.e. regulating action on the pathway of estrogen receptors→glycogen synthase kinase-3β (an integrating molecular within signaling pathways)→hippocampus remodeling (in vitro models of cells and brain slices will be used to explore whether hydroxylbakuchiol has the ability to affect estrogen receptors, glycogen synthase kinase-3β, and markers of hippocampal remoldeling, and will be checked to see whether the hydroxylbakuchiol-induced hippocampal remoldeling is blocked following down-regulation of estrogen receptors or up-regulation of glycogen synthase kinase-3β-- for the purpose of uncovering hydroxylbakuchiol's estrogen receptor-subtype regulation and pathway integration). The meaningfulness of this study lies in exploring an effective intervention for perimenopausal depression and its primary pharmacological mechanism, and for further understanding the pathogenesis of perimenopausal depression.