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Activation of dopaminergic VTA inputs to the mPFC ameliorates chronic stress-induced breast tumor progression |
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| Authors: | Xi-Rong Xu Qian Xiao Yu-Chuan Hong Yun-Hui Liu Yue Liu Jie Tu |
| Affiliation: | 1. The Brain Cognition and Brain Disease Institute (BCBDI), CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Institutes of Advanced Technology, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Chinese Academy of Sciences, Shenzhen, China University of Chinese of Academy of Sciences, Beijing, China;2. University of Chinese of Academy of Sciences, Beijing, China Center of Brain Science, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, China;3. The Brain Cognition and Brain Disease Institute (BCBDI), CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Institutes of Advanced Technology, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Chinese Academy of Sciences, Shenzhen, China |
| Abstract: | AimsChronic stress plays an important role in promoting the progression and migration of cancers. However, little is known of any direct impact on tumor progression related to the regulation of emotion‐related circuitry. The aim of this study was to explore the neural‐circuit mechanisms underlying stress‐induced progression of cancers and the impact of emotion‐related regulation of circuitry on tumor growth.MethodsOptogenetic manipulation was applied to unpredictable chronic mild stress (UCMS)–treated mice bearing breast tumor cell. The stress‐related hormones, tumor‐related cytokines, the tyrosine hydroxylase (TH)–positive neurons and their fibers, dopamine receptor–positive cells, and anxiety level were measured using ELISA, immunohistochemical staining, fluorescence in situ hybridization, and behavioral test, respectively.ResultsBy investigating breast cancer mouse models with a chronic mild stress model, optogenetic stimulation, and behavioral analysis, we show that chronic stress induced anxiety‐like behavior in mice and increased serum concentration of norepinephrine and corticosterone, hormones closely related to stress and anxiety. Optogenetic activation of VTA TH terminals in the mPFC rescued anxiety‐like behavior induced by chronic stress. Chronic stress resulted in marked progression of breast tumors, and repetitive optogenetic activation of VTA TH terminals in the mPFC significantly attenuated stress‐induced progression of breast cancers and reduced serum concentration of norepinephrine and corticosterone. Furthermore, there was a positive correlation between serum norepinephrine or corticosterone concentration and tumor size.ConclusionsThese findings indicate a positive role of an emotion regulation circuit on the progression of breast cancer and reveal a link between stress, emotion regulation, and the progression of breast cancers. Our findings provide new insights pertinent to therapeutic interventions in the treatment of breast cancers. |
| Keywords: | cancer emotion neuromodulation neurotransmitter optogenetic unpredictable mild stress |