Positive expectations contribute to the clinical benefits of the placebo effect1,2. Such positive expectations are mediated by the brain's reward system3,4; however, it remains unknown whether and how reward system activation affects the body's physiology and, specifically, immunity. Here we show that activation of the ventral tegmental area (VTA), a key component of the reward system, strengthens immunological host defense. We used 'designer receptors exclusively activated by designer drugs' (DREADDs) to directly activate dopaminergic neurons in the mouse VTA and characterized the subsequent immune response after exposure to bacteria (Escherichia coli), using time-of-flight mass cytometry (CyTOF) and functional assays. We found an increase in innate and adaptive immune responses that were manifested by enhanced antibacterial activity of monocytes and macrophages, reduced in vivo bacterial load and a heightened T cell response in the mouse model of delayed-type hypersensitivity. By chemically ablating the sympathetic nervous system (SNS), we showed that the reward system's effects on immunity are, at least partly, mediated by the SNS. Thus, our findings establish a causal relationship between the activity of the VTA and the immune response to bacterial infection.
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We would like to thank A. Ziv-Kenet for his help with CyTOF data analysis, A.D. Eban-Rothchild, C. Tourino, D. Melamed, N. Karin, G. Wildbaum, R. Hershberg and M. Rahat for helpful discussions, A. Mor, F. Zaknoon, J. Jammal, S. Yaron and S. Katz for their help with bacterial experiments, Y. Posen, G. Ginzburg and E. Reisin-Tzur for editing the paper, H. Amitay for her help with the behavioral analysis, and O. Goldberger and the Biomedical core facility at the Technion Faculty of Medicine for technical support. This research was supported by the FP-7-CIG grant 618654 (A.R.), the Israel Science Foundation (ISF) grants 1862/15 (A.R.) and 1365/12 (S.S.S.-O.), the Technion V.P.R. Fund–Malat Family (A.R.), the Adelis Foundation (A.R.) and the Rappaport Institute of Biomedical Research (S.S.S.-O.).
The authors declare no competing financial interests.
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Ben-Shaanan, T., Azulay-Debby, H., Dubovik, T. et al. Activation of the reward system boosts innate and adaptive immunity. Nat Med 22, 940–944 (2016). https://doi.org/10.1038/nm.4133
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