徐州医科大学肖诚研究小组取得一项新突破。他们的最新研究揭示了在6-OHDA损伤诱导的偏帕金森小鼠中，丘脑下多巴胺能回路的功能障碍与焦虑和抑郁样行为有关。2025年5月6日，国际知名学术期刊《中国药理学报》发表了这一成果。

由于多巴胺能（DA）系统和丘脑底核（STN）参与运动控制和情绪加工，课题组人员在此研究了多巴胺能回路在丘脑底核中调节帕金森小鼠抑郁的作用。右内侧前脑束（MFB）注射6-羟多巴胺（6-OHDA），去西帕明(20毫克/公斤,i.p)。注射30颅内注射前Min。在空旷场试验和阿吗啡诱导的对位旋转和旋转棒试验中监测运动功能；采用开阔场地测试、高架迷宫测试、悬尾测试和强迫游泳测试评估焦虑和抑郁样行为。该课题组研究人员发现半帕金森小鼠在不同的时间点表现出运动功能障碍和抑郁样行为。纤维光度记录显示STN神经元对焦虑和抑郁样刺激敏感；STN神经元的化学发生抑制减轻了焦虑和抑郁样行为。多巴胺释放在帕金森小鼠的STN中显著减少，以应对焦虑和抑郁样刺激，D1和D2样多巴胺受体的表达发生时间依赖性改变。向STN内注射D1或D2样多巴胺受体激动剂可减轻帕金森小鼠的焦虑和抑郁样行为。课题组得出结论，STN-DA回路可能是治疗PD患者焦虑和抑郁的有希望的靶点。

据悉，焦虑和抑郁是严重影响帕金森病患者生活质量的常见非运动症状，但其潜在的病理生理机制尚不清楚。

附：英文原文

Title: Dysfunction of subthalamic dopaminergic circuitry contributes to anxiety- and depression-like behaviors in 6-OHDA lesion-induced hemiparkinsonian mice

Author: Zhang, Jia-qi, Li, Shu-yi, Yin, Cui, Ji, Ying, Zhang, Xiang, Liu, Dan-yang, Yang, Hang, Niu, Yong, Cui, Gui-yun, Zhou, Chun-yi, Xiao, Cheng

Issue&Volume: 2025-05-06

Abstract: Anxiety and depression are common non-motor symptoms severely affecting the quality of life in patients with Parkinson’s disease, but the underlying pathophysiological mechanisms remain elusive. As dopaminergic (DA) system and the subthalamic nucleus (STN) are involved in motor control and emotional processing, we herein investigated the role of DA circuitry in the STN in regulating depression in parkinsonian mice. A hemi-parkinsonian mouse model was established by injection of 6-OHDA into the right medial forebrain bundle (MFB), desipramine (20mg/kg, i.p.) was injected 30min before the intracranial injection. Motor function was monitored in open field test and apomorphine-induced contra-lesional rotation and rotarod tests; anxiety- and depression-like behaviors were assessed with the open field test, elevated plus maze, tail suspension test and forced swim test. We found that the hemi-parkinsonian mice displayed motor dysfunction and depression-like behaviors at different time points. Fiber photometry recording revealed that STN neurons were hypersensitive to anxiety- and depression-like stimulation; chemogenetic inhibition of STN neurons mitigated anxiety- and depression-like behaviors. While dopamine release was significantly reduced in the STN of the parkinsonian mice in response to anxiety- and depression-like stimulation, the expression of D1- and D2-like dopamine receptors was time-dependently changed. Intracranial injection of either D1- or D2-like dopamine receptor agonist into the STN mitigated anxiety- and depression-like behaviors in the parkinsonian mice. We conclude that STN DA circuitry may be promising targets to treat anxiety and depression in PD.

DOI: 10.1038/s41401-025-01570-2

Source: https://www.nature.com/articles/s41401-025-01570-2