Depression is a common non-motor symptom in patients with Parkinson’s disease (PD) and difficult to treat. Crocin is a natural multipotential neuroprotective compound that has been shown to elicit antidepressant activity and is promising for the therapy of neuropsychological diseases. Here, we investigated the therapeutic effect of crocin in a mouse model of Parkinson’s disease depression (PDD) and clarified the underlying mechanism. We prepared 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced subacute mouse model of PD, and found that around 60% of the model mice showed depression-like behavior, using the forced swimming test (FST). A regime of 10-day treatment of crocin alleviated the PDD symptoms. The crocin reduced the structural damage in soma volume and axon length of neurons and inhibited their spontaneous discharge in dopaminergic (DA) neurons in the ventral tegmental area (VTA). Notably, the MPTP-treated mice showed the decrease in the critical signaling for synaptic plasticity, including the proteins of PSD-95, synapsin-1, and GluR-1, in the medial prefrontal cortex (mPFC) where it receives efferent from VTA and regulates depression-like behavior. However, crocin treatment rescued the defect of the mammalian target of rapamycin (mTOR) signaling in PDD mice. Furthermore, the antidepressant action of crocin was blunted after blockade of mTOR signaling with the antagonist rapamycin. In conclusion, our study demonstrated that crocin protected the DA projection neurons in the VTA through activating mTOR, which subsequently improved the neural synaptic plasticity of mPFC, and ameliorated depression-like behavior in PD mice.

抑郁症是帕金森氏病（PD）患者的常见非运动症状，难以治疗。番红花是一种天然的多能神经保护化合物，已被证明具有抗抑郁活性，有望用于治疗神经心理学疾病。在这里，我们调查了番红花在帕金森氏病抑郁症（PDD）小鼠模型中的治疗效果，并阐明了其潜在机制。我们制备了1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD亚急性小鼠模型，使用强迫游泳方法，发现约60％的模型小鼠表现出抑郁样行为测试（FST）。番红花的10天治疗方案减轻了PDD症状。藏红花减少了腹侧被盖区（VTA）中多巴胺能（DA）神经元的躯体体积和神经元轴突长度的结构损伤，并抑制了它们的自发放电。值得注意的是，用MPTP处理的小鼠在前额叶内侧皮层（mPFC）处接受了VTA和HLA的释放，其中突触可塑性的关键信号包括PSD-95，synapsin-1和GluR-1的信号降低。调节类似抑郁症的行为。然而，藏红花素治疗挽救了PDD小鼠中雷帕霉素（mTOR）信号转导的哺乳动物靶标的缺陷。此外，用拮抗剂雷帕霉素阻断mTOR信号传导后，crocrocin的抗抑郁作用减弱。总之，我们的研究表明，番红花通过激活mTOR来保护VTA中的DA投射神经元，