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Activation of the reward system boosts innate and adaptive immunity

Nature Medicine volume 22, pages 940–944 (2016)Cite this article

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Abstract

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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Figure 1: Activation of VTA neurons with DREADDs stimulates reward circuitry and behavioral responses.
Figure 2: Activation of VTA neurons improves the innate immune response to E.coli.
Figure 3: Activation of VTA neurons increases the adaptive immune response to E. coli challenge.
Figure 4: The effects of VTA activation on the immune system are partly mediated by the sympathetic nervous system.

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Acknowledgements

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.).

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Author notes

  1. Shai S Shen-Orr and Asya Rolls: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Immunology, Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel

    Tamar L Ben-Shaanan, Hilla Azulay-Debby, Tania Dubovik, Elina Starosvetsky, Ben Korin, Maya Schiller, Nathaniel L Green, Yasmin Admon, Fahed Hakim, Shai S Shen-Orr & Asya Rolls

  2. Center of Science and Engineering of Neuronal Systems, Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel

    Tamar L Ben-Shaanan, Hilla Azulay-Debby, Ben Korin, Maya Schiller, Nathaniel L Green & Asya Rolls

  3. Pediatric Pulmonary Unit, Rambam Health Care Campus, Haifa, Israel

    Fahed Hakim

  4. Faculty of Biology, Technion–Israel Institute of Technology, Haifa, Israel

    Shai S Shen-Orr

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Contributions

T.L.B.-S. designed and carried out all of the experiments, interpreted the results and wrote the manuscript; H.A.-D. contributed to the experimental design, carried out experiments, contributed to data analysis and to the manuscript; T.D. and E.S. designed, performed and analyzed the CyTOF experiments and contributed to the manuscript; B.K. and M.S. contributed to the experimental design and execution of the experiments, contributed to analysis of the results and contributed to the manuscript; N.L.G. contributed to the interpretation of the results and the writing the manuscript; Y.A. contributed to the CyTOF data analysis; F.H. contributed to the experimental design and data interpretation; S.S.S.-O. designed and analyzed the CyTOF experiments, contributed with the interpretation of results and wrote the manuscript; and A.R. conceived the project, contributed to the experimental design and the interpretation of results, and wrote the manuscript.

Corresponding authors

Correspondence to Shai S Shen-Orr or Asya Rolls.

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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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