基于PI3K-Akt-mTOR信号通路介导的中枢LH受体在围绝经期抑郁症中的神经内分泌机理探讨

围绝经期抑郁症被认为是卵巢老化、雌激素分泌减少诱发的情绪障碍，但补充雌激素不能产生预期疗效。本课题组首次发现失去雌激素的负反馈性调节而导致的促黄体生成素（LH）升高参与了本病的发生。我们发现大鼠脑内与情感相关的重要核团有LH受体表达，LH受体活动影响神经元放电和单胺类神经递质分泌。我们推测中枢LH受体可以通过PI3K-Akt-mTOR通路增强单胺类神经递质分泌，而mTOR持久兴奋导致了单胺类神经元损伤，诱导情绪低落和围绝经期抑郁症。为证实这一假设，我们将使用双侧卵巢切除和慢性不可预知温和刺激构建动物模型，采用颅内微灌注、免疫组化、钙成像等技术，探明干预中枢LH活动对mTOR及其相关的信号通路的影响，以及对单胺类神经元的影响。本研究将进一步揭示与衰老相关的生理激素在抑郁症中的作用，为有效防治该症提供思路和途径。

Menopausal depression is a mood disorder caused by ovary aging and decreased estrogen production, but estrogen replaceent therapy cannot get the epected results. For the first time, our research group found that the increased luteinizing hormone (LH) caused by the loss of negative response regulation of estrogen may be the main cause of menopausal depression. However, the role of LH in the central nervous system has been rarely reported. We found that LH receptors are expressed in many nuclei in the brain, and they can inhibit the firings of the neurons, decrease the monoamine neurotransmitter release. In view of this, we hypothesized that the central LH receptors could regulate the secretion of central monoamine neurotransmitters through the PI3K-Akt-mTOR pathway, playing an important role in peri-menopausal depression. In order to test this hypothesis, we will use ovariectomy and intracranial microperfusion of LH to make a model of climacteric depression, and use immunohistochemistry, calcium imaging and other techniques to observe the changes in the expression of central LH receptor and the signaling pathway that induce changes in neuron activity. This study will further reveal the mechanisms of senescence related physiological hormones in the occurrence and development of depression, and provide a new theory and drug treatment target for the effective prevention and treatment of peri-menopausal depression.