慢性应激诱导大鼠下丘脑内源性物质调控失衡机制及方剂干预

Depression is one of clinical manifestations of psychogenic emotion causing Depression/Yu. Clinical studies and our previous experimental findings show that chronic stress exposure developed the unbalance of endogenous substances including neuroendocrine regulators, inflammatory cytokines and glucose and lipids. In this project, we consider that chronic stress cause emotional injury in Heart and Brain, followed by the loss of its domination and coordination of Liver and Kidney function, leading to disorders of body endogenous substances. Therefore, this project put forward the hypothesis that the steady-state destruction of endogenous substance regulation in hypothalamus may be important pathology process of psychogenic emotion causing Depression/Yu. To test this hypothesis, this project will continue to explore that disorders of hypothalamus signaling and factor for the regulation of endogenous substances (hyperactivity of CRF system signaling, activation of the NLRP3 inflammasome with inflammatory cytokine elevation, impairment of insulin and leptin signal transduction pathway) and their adjustments play the important roles in the steady-state destruction of endogenous substances in depression model of rats exposed to chronic mild stress. Moreover, this project will investigate the reversal effects and integration mechanisms of effective Chinese prescriptions relieving Depression and eliminating phlegm (Banxia Houpo decoction and Huanglian Wendan decoction), discharging Liver and relieving Yu on the pathological process (Chaihu Jieyu San), and warming Kidney and strengthening Yang (Jinkui shengqi Wan) in this animal model according to Heart and Brain-Liver-Kidney treatment in traditional Chinese medicine (TCM) theory. These results from this project will reveal the link between Heart and Brain-Liver-Kidney-related dysfunction as well as depressive behaviors in rats caused by chronic stress,and provide theoretical and experimental evidences for the promotion of the translational medicine/research. On the other hand, this project will elaborate the mechanisms of Chinese prescriptions relieving Depression and eliminating phlegm, discharging Liver and relieving Yu and warming Kidney and strengthening Yang, which will be helpful in scientically interpreting psychogenic emotion causing Depression/Yu, as well as guiding for effective clinical practice in the prevention and treatment of depression.

抑郁症是情志致郁临床表现形式之一。基于临床报道和本组前期发现：抑郁状态下机体呈现神经内分泌调控因子、促炎性细胞因子与葡萄糖和脂质等内源性物质稳态失衡，本项目认为慢性应激导致心脑情志抑郁，继而对主宰和协调肝肾功能失控，引发内源性物质紊乱，提出下丘脑内源性物质调控失衡是情志致郁重要病机的假说。本项目继续研究慢性应激抑郁症大鼠下丘脑内源性物质调控信号与因子异常(CRF系统信号亢进、NLRP3炎性小体与炎性细胞因子异常、胰岛素和瘦素信号转导通路障碍）及相互间调控失衡在内源性物质稳态破坏中所起的重要作用；并从心脑、肝、肾论治，研究解郁化痰半夏厚朴汤和黄连温胆汤、疏肝解郁柴胡疏肝散、温肾壮阳金匮肾气丸对各病理环节的逆转作用及整合调控机制。揭示慢性应激引发心脑-肝-肾脏腑功能异常与抑郁行为的关联，为推进其转化医学研究提供理论和实验基础；对方剂作用机理进一步的阐述将佐以科学诠释情志致郁并指导中医有效治疗。

抑郁症是严重危害人类身心健康的常见精神性疾病。抑郁状态下神经内分泌-免疫-代谢等系统功能失常，机体内源性物质紊乱，其中病理机制仍不清楚。抑郁症是中医情志病临床表现形式之一，基于有效方剂干预佐证性研究以诠释“情志致郁”甚为重要。本项目在前期工作基础上，进一步证实了慢性应激引起大鼠产生抑郁行为、糖耐量受损、内源性物质紊乱等；发现慢性应激诱导大鼠中枢下丘脑、皮层、海马胰岛素信号转导障碍，促进中枢免疫炎症，其中NF-κB、NLRP3炎症小体激活及IL-1β升高最为明显；负调控胰岛素作用的糖皮质激素皮质酮和或LPS可激活神经胶质细胞NLRP3炎症小体等，也改变体外星形胶质细胞能量代谢，提高TXNIP等表达；初步说明了慢性应激导致肝肾组织胰岛素信号转导障碍新途径、通过miR-155靶向MyD88产生免疫炎症效应、及影响SGK1交互激活氧化应激和免疫炎症信号诱导肾损伤新机制等。这些中枢和外周免疫炎症干扰了胰岛素信号转导等，使机体内源性物质调控失衡，产生抑郁行为。基于上述新发现，各有侧重研究并揭示了半夏厚朴汤、柴胡疏肝散、黄连温胆汤、桂皮醛等逆转慢性应激所引起的中枢和肝肾组织免疫炎症和胰岛素信号受损，调控机体内源性物质平衡而改善抑郁行为的新机制、新途径。这些系列研究进一步明确慢性应激引发中枢“心脑”与外周肝-肾免疫代谢变化，并交互影响机体内源性物质调控失衡而产生抑郁行为，初步佐证了本项目提出的“慢性应激诱导下丘脑内源性物质调控失衡是情志致郁的重要病机”假说，确定NLRP3、TXNIP、SGK1等可能为其重要病理标志物，为科学诠释情志致郁并指导临床奠定实验基础。发表论文10篇，其中SCI 9篇；被NAT REV IMMUNOL、BRAIN、TRENDS BIOCHEM等重要SCI他引160篇次；入选Elsevier 2014-2017年中国高被引学者榜单(“药理、毒理和药剂学”项）。