基于fMRI/PET活体成像的围绝经期综合征肝郁证海马-下丘脑神经环路动态变化的调控机制研究

The changes of emotion and mind as main clinical manifestation of perimenopausal syndrome (PMS) associate with the physiological pathology feature of depression among predominantly women and liver as congenital. Based on the former solid work, the liver stagnation as the key pathogenesis of PMS connects with estrogen level disorder mediated neurotransmitters abnormality of hippocampus-hypothalamus, but it is a burning issue that the mechanism of functional connectivity networks of hippocampus-hypothalamus on dynamic regulation of PMS liver stagnation neural circuit in vivo. Therefore, a rat model for PMS liver stagnation by the natural aging and chronic immobilization stress methods will be established to do the following researches. (1) From the fMRI/PET in vivo imaging observes the changes of functional connectivity networks and metabolic characteristics in hippocampus- hypothalamus to explore the regulation mechanism of dynamic changes of liver stagnation neural circuit. (2) From the changes of 5-HT, NE, DA, Ach and GABA neurons distribution in hippocampus-hypothalamus, it explores the structural basis of liver stagnation neural circuit. (3) From the CREB-BDNF signal pathway mediated functional connectivity networks in hippocampus-hypothalamus, it explores the control targets of liver stagnation neural circuit. (4) Using Chaihu-Shugan-San treatment, it provides an experimental evidence for the syndrome differentiation and treatment by regulating liver from prescriptions corresponding to syndromes. These works are to enrich the pathogenesis of liver stagnation and furtherly interpret on the scientific connotation of depression among predominantly women providing a scientific basis for the traditional Chinese medicine diagnosis and efficacy evaluation of PMS.

情志精神变化是围绝经期综合征（PMS）的主要临床表现，与女子多郁、以肝为先天的生理病理特点相关。课题组研究发现肝郁是PMS的重要病机，与雌激素紊乱介导的海马、下丘脑神经递质表达异常相关，而在活体状态下海马-下丘脑功能网络动态调节肝郁神经环路的机制是亟待解决的问题。本研究以自然衰老与束缚法建立PMS大鼠肝郁证模型为研究对象：（1）从fMRI/PET活体成像，观察海马-下丘脑功能网络、代谢特征的变化，探讨肝郁神经环路动态变化的调控机制；（2）从海马-下丘脑5-HT、NE、DA、Ach、GABA神经元分布的变化，探讨肝郁神经环路的结构基础；（3）从CREB-BDNF信号通路调节海马-下丘脑功能网络，探讨肝郁神经环路的调控靶点；（4）采用柴胡疏肝散干预，从方证互参的角度为肝郁辨识与从肝论治提供实验依据。旨在丰富肝郁的病机理论，进一步诠释女子多郁的科学内涵，为PMS的中医诊疗与疗效评价提供科学基础。

肝郁证是围绝经期综合征（PMS）的常见证型，以情志变化为主要表现，与雌激素紊乱介导的海马-下丘脑神经环路改变相关，其中海马功能改变是关键的影响因素。本项目以PMS肝郁证大鼠模型为研究对象，采用病证结合与方证对应的方法，借助活体成像技术与细胞分子生物学技术，从分子、细胞、组织病理等多维度，初步揭示PMS肝郁证形成的神经环路；从基因、蛋白、能量代谢等多层次，初步阐明PMS肝郁证的中枢调节机制。.研究结果（1）初步明确了PMS肝郁证以神经递质为重要调节因子：从动物行为和激素水平变化，以及血清神经递质5-HT、DA、NE、Glu、GABA含量改变，验证PMS肝郁证模型建立成功；柴胡疏肝散调节神经递质改变，改善肝郁状态。（2）初步揭示了海马能量代谢异常是PMS肝郁证形成的中枢调节机制：PMS肝郁证海马/下丘脑CREB-BDNF、PI3K-Akt-mTOR信号通路的活性下降，海马中心碳代谢以三羧酸循环代谢物中的丙酮酸、异柠檬酸、延胡索酸、草酰乙酸异常改变为特征。（3）初步阐述了海马功能网络连接是PMS肝郁证神经环路的结构基础：fMRI活体成像，PMS肝郁证的海马、杏仁核、运动皮层等脑区功能网络连接明显改变，柴胡疏肝散改善海马、纹状体、嗅觉皮层、感觉皮层等脑区功能网络连接。（4）初步阐明了BDNF表达调控及受体信号是治疗PMS肝郁证的潜在药效靶点：柴胡疏肝散调节CREB-BDNF、PI3K-Akt-mTOR信号通路，上调BDNF表达，抑制能量代谢异常改变，维持海马神经环路的结构与功能，改善肝郁状态。.综上所述，本项目从活体海马功能网络连接改变、离体海马基因蛋白表达差异，部分解读了从肝脑相维辨识PMS肝郁证的生物学基础，进一步丰富了“女子多郁”的科学内涵。.本项目发表论文7篇，培养硕士研究生2名。