基于抑郁症PFC-NAc-VTA神经环路与下丘脑摄食相关信号的中枢外周效应研究“肝郁犯胃”的发生机制

TCM regards that chronic liver-qi depression can influence stomach, which in turn develops syndrome of stomach disorder induced by liver-qi depression. Depression often causes gastrointestinal motility disorders. In the aspects of etiology, clinical symptoms, TCM symptom of liver depression is similar to the anhedonia caused by mutual projection disorders of Depression PFC-NAc-VTA neural circuit; TCM syndrome of stomach disorder induced by liver-qi depression is also similar to peripheral gastric motility disorders, as well as the changes of feeding-related signals in hypothalamic. As a breakthrough point, the purpose of this research is to study the mechanism of syndrome of stomach disorder induced by liver-qi depression, based on central and peripheral effect of Depression PFC-NAc-VTA neural circuit and feeding-related signals of hypothalamic. The research is to dynamically observe the changes of neurotransmitter (DA, GABA, Glu) and synaptic plasticity in PFC-NAc-VTA neural circuit, feeding-related signals (ghrelin, orexin, CCK, NPY, leptin, containing receptors mRNA ) in hypothalamic, and the effect of Shugan Hewei Decoction, applied advanced methods, including behaviorstics, HPLC, Western Blot, ELISA, RT-PCR, adopted the model rats which were made by the method of chronically psychological stress and separately raised. The research will provide the experimental basis, which reveals the nerve - endocrine mechanism of syndrome of stomach disorder induced by liver-qi depression, as well as to provide experimental basis for developing Chinese patent medicine to sooth liver and harmonize stomach, and lay the theoretical and profound foundation for studying transmission of TCM Zang and Fu mutual disease.

中医认为肝郁日久，影响及胃，形成肝郁犯胃证；抑郁症常常引起胃肠动力障碍。在病因、临床表现方面，中医肝郁与抑郁症PFC-NAc-VTA神经环路相互投射失调导致的快感缺失相似；中医肝郁犯胃与抑郁症出现下丘脑摄食相关信号变化及胃动力障碍相似。课题以此为切入点，从抑郁症PFC-NAc-VTA神经环路与下丘脑摄食相关信号的中枢外周效应观察“肝郁犯胃”发生机制。课题采用慢性心理应激加孤养法制作抑郁模型，应用行为学、 HPLC、Western Blot、ELISA、RT-PCR等方法，动态观察PFC-NAc-VTA神经环路DA、GABA和Glu等神经递质及突触可塑性变化，下丘脑摄食信号ghrelin、orexin、CCK、NPY、leptin及其受体mRNA变化，以及疏肝和胃汤的影响。研究将为揭示“肝郁犯胃”的神经-内分泌机制，研发疏肝和胃中药提供实验依据，并为深入研究中医脏腑之间的相互传变奠定基础。

中医认为肝郁日久，影响及胃，形成肝郁犯胃证；抑郁症常常引起胃肠功能障碍。在病因、临床表现方面，中医“肝郁”与抑郁症PFC-NAc-VTA神经环路相互投射失调导致的快感缺失相似；中医“肝郁犯胃”与抑郁症出现下丘脑摄食相关信号变化及胃动力障碍相似。课题以此为切入点，从抑郁症PFC-NAc-VTA神经环路与下丘脑摄食相关信号的中枢外周效应观察“肝郁犯胃”发生机制。课题采用慢性心理应激加孤养法制作抑郁模型，应用行为学、HPLC、Western Blot、ELISA、RT-PCR等方法，动态观察PFC-NAc-VTA神经环路DA、GABA和Glu等神经递质及突触可塑性变化，下丘脑摄食信号ghrelin、orexin、CCK、NPY、Leptin及其受体mRNA变化，以及疏肝和胃汤的影响。研究结果表明慢性应激引起抑郁样行为与PFC-NAc-VTA神经环路DA含量的降低、Glu含量的升高、GABA含量的相应改变，以及NAc区突触相关蛋白PSD95、NR2B及其mRNA表达的下降有关；抑郁模型大鼠摄食冲动下降及胃排空延迟与血清NPY、Ghrelin、Orexin含量下降，Leptin、CCK含量上升，下丘脑、胃组织NPY、Ghrelin、Orexin水平及其mRNA表达下降、Leptin、CCK水平及其mRNA表达上升，下丘脑室旁核NPY-Y1R、OX1-R及其mRNA表达下降，CCK-AR及其mRNA表达上升，下丘脑弓状核GHS-R及其mRNA表达下降，胃组织中GHS-R、OX1-R及其mRNA表达下降，CCK-AR及其mRNA表达上升有关。因此，疏肝和胃汤对上述指标的调节作用，可能是其抗抑郁及其改善抑郁所致的胃排空延迟的作用机制之一；中医“肝郁犯胃”的发生机制可能与应激导致的PFC-NAc-VTA神经环路的失调及下丘脑、胃组织中相关摄食信号的异常改变有关。本研究部分揭示了“肝郁犯胃”的神经-内分泌机制，并将为研发疏肝和胃中药提供实验依据，为深入研究中医脏腑之间的相互传变奠定基础。