5-HT1B受体介导内侧视前区β-内啡肽能神经元参与射精调控的神经环路机制研究

早泄是男性最常见的性功能障碍之一，严重困扰众多男性患者，影响家庭关系的和睦。5-HT系统失调是早泄重要的发病机制，近年来，功能学研究发现5-HT1B受体可显著抑制大鼠射精行为，具体机制尚不清楚。在前期研究中，我们发现临床上5-HT1B受体与达泊西汀疗效个体差异有关，内侧视前区（MPOA）和下丘脑室旁核（PVN）参与5-HT1B受体调节射精过程。我们推测MPOA-PVNβ-内啡肽能投射可能是5-HT1B受体参与射精调控的一个神经环路基础。为验证这一猜想，本课题组拟运用行为学、电生理学、光遗传学、分子生物学等技术结合药理学手段，研究脑区/投射特异性神经元与5-HT1B受体参与射精调控的因果联系并揭示环路特异性分子机制。本课题的完成将揭示一个新的调控射精行为的丘脑相关神经环路及其投射特异性分子机制，进一步完善射精的生理调控机制，为开发新的、特异性治疗药物/策略提供了靶点。

Premature ejaculation (PE) is one of the most common sexual dysfunction diseases in men, which seriously bothers many male patients and affects the harmony of family relationship. The disorders in 5-HT system play an essential role in the pathogenesis of PE. Recently, functional investigations indicate that stimulation of 5-HT1B receptors inhibits ejaculation in the male rats, but the mechanisms are still unclear. Based on our previous research, we found that 5-HT1B receptors were related to the efficacy of dapoxetine. Medial preoptic area (MPOA) and hypothalamic paraventricular nucleus (PVN) were involved in the process of 5-HT1B receptor-mediated regulation of ejaculation. We hypothesize that β-endorphingergic projection in MPOA-PVN neural circuit may be a basis for this process. To validate this hypothesis, we intend to investigate potential causal links between brain region/circuit activity and 5-HT1B receptor-mediated regulation of ejaculation and clarify circuit-specific molecular mechanisms using ethology, electrophysiology, optogenetics and molecular biology techniques combined with traditional pharmacological approaches. The approaches proposed here will provide a novel thalamic circuit controlling ejaculatory behaviors as well as its pathway-specific molecular mechanisms. The findings of this project will not only contribute to our basic understanding of physiology of ejaculation, but also guide the development of new, potent, and specific therapies for ejaculation disorders.