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Crocin Reverses Depression-Like Behavior in Parkinson Disease Mice via VTA-mPFC Pathway

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Abstract

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.

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Funding

This work was supported by the National Natural Science Foundation of China (no.81603089, no. 81873096) and the Natural Science Foundation of Jiangsu Province (BK20161044).

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Authors and Affiliations

  1. School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Juanjuan Tang, Linyu Lu, Qisheng Wang, Wenda Xue, Tong Zhou, Liantiao Xu, Kai Wang, Die Wu, Fei Wei & Weiwei Tao

  2. Interdisciplinary Institute for Personalized Medicine in Brain Disorders, and Research Center for Formula and Syndromes, Jinan University, Guangzhou, 510632, China

    Gang Chen

  3. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, Jiangsu, China

    Gang Chen

  4. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University, Shanghai, China

    Hou Liu

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  1. Juanjuan Tang
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  2. Linyu Lu
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  3. Qisheng Wang
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  4. Hou Liu
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Contributions

Special thanks to all authors who contributed to this research. Juanjuan Tang and Gang Chen designed the whole study together. Linyu Lu provided all pictures in the manuscript. Qisheng Wang, Kai Wang, and Die Wu prepared the animal model. Hou Liu and Tong Zhou took responsibility for the data of patch clamp. Wenda Xue guided the statistics of the manuscript. Weiwei Tao and Liantiao Xu took responsible for preparation and identification of β-D-gentiobiosyl crocetin. Juanjuan Tang wrote the whole paper and organized all supplemental information materials. Gang Chen and Fei Wei provided corrections for the paper.

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Correspondence to Gang Chen.

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Tang, J., Lu, L., Wang, Q. et al. Crocin Reverses Depression-Like Behavior in Parkinson Disease Mice via VTA-mPFC Pathway. Mol Neurobiol 57, 3158–3170 (2020). https://doi.org/10.1007/s12035-020-01941-2

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