黑质-海马-蓝斑-迷走运动背核通路在帕金森病抑郁和胃动力障碍中的作用

Parkinson’s disease (PD) is a common neurodegenerative disorder. Although PD is considered a prototypical movement disorder, depression and digestive dysfunction markedly affects the life quality of PD patients. Antidepressant drugs can alleviate the functional gastrointestinal disorders. However, the underlying mechanism is unclear. Destroying substantia nigral (SN) induces depressive-like behavior in PD animal models, which is directly correlated with deficits in hippocampal serotonin. In our previous study, the rats treated with a bilateral microinjection of 6-hydroxydopamine (6-OHDA) in the SN presented reduced cholinergic neurons in the dorsal motor nucleus of the vagus (DMV), accompanied by impaired gastric motility and depression-like behavior. It is reported that dopaminergic neurons in the SN can excite the hippocampus (HPC), which could affect excitability of adrenergic neurons in the locus ceruleus (LC). Norepinephrine (NE) released from the LC is able to stimulate the DMV via α1 receptor. We hypothesize that loss of dopaminergic neurons in the SN would induce hippocampal serotonin reduction, leading to LC neuronal dysfunction, which may contribute to the depression in PD. Neuronal dysfunction of the LC might elicit gastric dysmotility via affecting neuronal activity in the DMV. In the present project, we aim to explore the relationship between depression and gastroparesis in PD by using PD animal models, and reveal the effect of SN-HPC-LC-DMV pathway in PD, providing a rationale for treatment of depression and gastroparesis associated with PD.

帕金森病（PD）除躯体运动功能障碍外，常伴有抑郁和胃肠功能紊乱。临床上抗抑郁药物可明显改善功能性胃肠疾病患者的症状，但机制并不明了。有报道黑质损伤可以引起海马5-HT水平降低，与抑郁症状有关。我们前期研究发现用6-OHDA损毁大鼠双侧黑质可以引起迷走运动背核（DMV）胆碱能神经元明显减少、胃肠功能紊乱及抑郁样表现。研究资料显示黑质多巴胺（DA）能神经元通过影响海马5-HT的释放调节蓝斑肾上腺素能神经元的兴奋性，而后者与DMV之间存在交互作用。我们认为黑质DA能神经元减少将引起海马5-HT水平降低，进而引发蓝斑肾上腺素能神经元功能紊乱，导致抑郁症状发生；而蓝斑功能紊乱将通过影响DMV进而引发胃功能紊乱。本项目拟通过动物模型制备深入研究PD抑郁与胃动力障碍之间的神经生物学基础，揭示黑质-海马-蓝斑-DMV通路在PD抑郁和胃功能紊乱发生中的作用，为两者之间的病理基础及防治提供理论和实验依据。

帕金森病（PD）除躯体运动功能障碍外，常伴有抑郁和胃肠功能紊乱。临床上抗抑郁药物可明显改善功能性胃肠疾病患者的症状，但机制并不明了。本项目通过制备6-OHDA PD大鼠模型，采用HPLC-MS、Western blot、免疫组织化学、神经示踪技术、植入式小动物遥测技术等研究手段深入探讨PD大鼠抑郁与胃动力障碍之间的神经生物学基础及具体的机制。本研究发现通过6-OHDA损毁SD大鼠双侧黑质所制备的6-OHDA PD大鼠表现有抑郁症状、胃肌电和在体胃动力减弱及胃排空延迟现象。6-OHDA大鼠黑质损毁后导致其多巴胺（DA）能神经元减少。从黑质释放到海马的DA降低，与上调的抑制性D2受体结合引起海马释放到蓝斑的5-HT减少；5-HT与蓝斑中去甲肾上腺素（NE）能神经元上上调的抑制性5-HT3受体的结合，使蓝斑释放到迷走运动背核（DMV）的NE减少；此外，黑质损伤也导致下丘脑释放到DMV的NE降低，NE在6-OHDA大鼠通过α1受体对DMV胆碱能神经元的兴奋性降低，引起迷走神经释放到胃部的乙酰胆碱减少，从而使胃肌电和胃动力减弱。黑质-海马-蓝斑通路功能的紊乱参与了6-OHDA大鼠抑郁症状的发生，而蓝斑和小丘脑功能的异常通过影响DMV神经元的活性引起胃动力障碍。激活5-HT4受体或拮抗D2受体则可以改善PD大鼠的胃肌电和胃动力情况。本研究可为PD抑郁和胃功能紊乱两者之间的病理基础及防治提供理论和实验依据。