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Reward system activation improves recovery from acute myocardial infarction

Nature Cardiovascular Research volume 3, pages 841–856 (2024)Cite this article

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Abstract

Psychological processes have a crucial role in the recovery from acute myocardial infarction (AMI), yet the underlying mechanisms of these effects remain elusive. Here we demonstrate the impact of the reward system, a brain network associated with motivation and positive expectations, on the clinical outcomes of AMI in mice. Chemogenetic activation of dopaminergic neurons in the reward system improved the remodeling processes and vascularization after AMI, leading to enhanced cardiac performance compared to controls. These effects were mediated through several physiological mechanisms, including alterations in immune activity and reduced adrenergic input to the liver. We further demonstrate an anatomical connection between the reward system and the liver, functionally manifested by altered transcription of complement component 3, which in turn affects vascularization and recovery from AMI. These findings establish a causal connection between a motivational brain network and recovery from AMI, introducing potential therapeutic avenues for intervention.

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Fig. 1: Effects of VTA activation on left-ventricular function after AMI.
Fig. 2: Effects of VTA activation on scar tissue formation and the immune response.
Fig. 3: Cardiac proteomic analysis.
Fig. 4: VTA neurons are anatomically connected to the liver.
Fig. 5: C3 involvement in the beneficial effects of VTA activation on cardiac recovery.

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Data availability

The source data generated and analyzed during the current study are included in the main article and associated files or available in the figshare repository (https://figshare.com/projects/Reward_System_Activation_Improves_Recovery_from_Acute_Myocardial_Infarction/203841)78. The MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD043448. Other information is available from the corresponding authors upon reasonable request. The UniProt database, available at https://www.uniprot.org/, facilitated the interpretation of the proteomics data by providing insights into protein functions and their primary cell synthesis. Source data are provided with this paper.

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Acknowledgements

We thank P. Hasson from the Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, O. Kobiler from the School of Medicine, Tel Aviv University, B. Englender and A. Kavushansky from the Rappaport Faculty of Medicine, Technion-Israel Institute of Technology for assistance with equipment, materials and mice. We thank Y. Kehat from the Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and J. Leor from the Sheba Medical Center, Tel‑Hashomer, Israel for their help in the study design. We thank the Rolls and Gepstein laboratory members and especially I. Huber, R. Yifa, D. Farfara, T. Koren, H. Hajjo, M. Amar, T. Bergman, T. Harran, I. Zalayat, M. Simons, M. Schiller and T. L. Ben-Shaanan for their help and discussion. We thank D. Carnevale from the Sapienza University of Rome, Italy, for her insightful comments. We thank S. Schwarzbaum for input and manuscript editing. L.G. is supported by the European Research Council (ERC) (2017-COG-773181-iPS-ChOp-AF). A.R. is supported by the Howard Hughes Medical Institute HHMI-Wellcome Trust, the Israel Science Foundation 1862/15, ERC 758952 and the Miriam and Sheldon G. Adelson Medical Research Foundation.

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Author notes

  1. These authors contributed equally: L. Gepstein, A. Rolls.

Authors and Affiliations

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

    H. Haykin, E. Avishai, M. Krot, M. Reshef, S. Merom, N. Boshnak, H. Azulay-Debby & A. Rolls

  2. Department of Neuroscience, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

    H. Haykin, E. Avishai, M. Krot, M. Reshef, S. Merom, N. Boshnak, H. Azulay-Debby & A. Rolls

  3. Department of Physiology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

    H. Haykin, M. Ghiringhelli, Y. Abboud & L. Gepstein

  4. Department of Genetics and Developmental Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

    S. Melamed

  5. Smoler Proteomics Center, Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion-Israel Institute of Technology, Haifa, Israel

    T. Ziv

  6. Cardiology Department, Rambam Health Care Campus, Haifa, Israel

    L. Gepstein

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Contributions

H.H., A.R. and L.G. developed the concept, designed the experiments and wrote the paper. H.H. led all the in vivo and in vitro experiments, supported by E.A., M.K. and M.G. H.H. collected and analyzed the data with the assistance of Y.A., S. Melamed and S. Merom. T.Z. performed the proteomic analysis. M.R., N.B. and H.A.-D. provided technical support.

Corresponding authors

Correspondence to L. Gepstein or A. Rolls.

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Competing interests

We have filed a US Non-Provisional Patent jointly with the Technion and Rambam Medical Center (Ehrlich ref. 99473; TRDF ref. 2021095-02, Rambam ref. 9178). The named inventors are A.R., L.G., H.H. and H.A.-D. The proteomic analysis results detailed in the paper are part of the subject matter covered in the patent application. The other authors declare no competing interests.

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Nature Cardiovascular Research thanks Aldons Lusis, Filip Swirski and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Effects of VTA activation on physiological parameters.

a, Representative composite micrograph demonstrating mCherry+ expression exclusively in the VTA and exclusively in TH+ cells, following DEADD injection. Scale bar, 1000µm. b, Quantification of TH+ cells in the right VTA area: 4 days post-AMI and daily CNO injection, 15 days post AMI and daily CNO injection and sham-AMI operated mice following 15 days of daily CNO injection (two-way ANOVA, followed by Tukey’s test; n=30). c, 15-day survival analysis of mice of control and VTA-Gq mice separated by sex using the log-rank test. d, LVEF of male mice on days 1 and 14 post-AMI. Comparison shows no difference between the groups on day 1 and on day 14 (two-way ANOVA mixed model, followed by Tukey’s test; n=16). e, LVEF of female mice on days 1 and 14 post-AMI. Comparison shows no difference between the groups on day 1 and on day 14 (two-way ANOVA mixed model, followed by Tukey’s test; n=14). f, Body weight of mice on day 1 and day 15 (two-way ANOVA mixed model with Benjamin, Krieger, and Yekutieli correction; n=24). g, Distance moved by mice within 30 minutes following CNO administration (two-tailed unpaired t-test; n=13). h, Time spent moving by mice within 30 minutes following CNO administration (two-tailed unpaired t-test; n=13). i, Lung weight of VTA-Gq and control mice, normalized either to body weight or to tibia length (two-tailed unpaired t-test; n=19). j, Heart weight, normalized either to body weight or to tibia length (two-tailed unpaired t-test; n=18). Data from individual mice are shown and values are represented as mean ± SEM. TH, tyrosine hydroxylase; VTA, Ventral tegmental area; SNC, substantia nigra pars compacta.

Source data

Extended Data Fig. 2 Effects of VTA activation on sham-AMI operated mice.

a, LVEF on postoperative days 1 and 14. Comparison shows no difference between groups on day 1 and day 14 (two-way ANOVA mixed model, followed by Tukey’s test; n=19). b, End-systolic volume on postoperative days 1 and 14. Comparison shows no difference between groups on day 1and day 14 (two-way ANOVA mixed model, followed by Tukey’s test; n=19). c, End-diastolic volume on postoperative days 1 and 14. Comparison shows no difference between the groups on day 1 and day 14 (two-way ANOVA mixed model, followed by Tukey’s test; n=19). d, Stroke volume on postoperative days 1 and 14. Comparison shows no difference between the groups on day 1 and day 14 (two-way ANOVA mixed model, followed by Tukey’s test; n=19). e, Masson trichrome staining of cardiac tissues of control and VTA-Gq mice, 15 days following sham-operation. Scale bar, 1000µm. f, Fibrosis area percentage in VTA-Gq and control mice (two-tailed unpaired t-test; n=8). g, Quantification of the number of vWF+ lumens (two-tailed unpaired t-test; n=10). h, Quantification of the number of α-SMA+vWF+ lumens (two-tailed unpaired t-test; n=10). i, Quantification of number of CD45+ cells from DAPI+ cells in sham-operated mice (two-tailed unpaired t-test; n=10). Data from individual mice are shown and values are represented as mean ± SEM. vWF, Von Willebrand factor; α-SMA, alpha smooth muscle actin.

Source data

Extended Data Fig. 3 Effects of VTA inhibition on cardiac structure.

a, Percentage of c-Fos+ cells from mCherry+ TH+ cells in mice following AMI and 15 days of daily CNO injection (control vs, VTA-Gq p<0.0001, control vs. VTA-Gi p=0.04; one-way ANOVA, followed by Tukey’s test; n=15). b, Midline length infract size analysis (two-tailed unpaired t-test; n=18). c, Masson trichrome staining of cardiac tissues of control and VTA-Gi mice 15 days following AMI. Scale bar, 1000µm. d, Fibrosis area percentage of control and VTA-Gi mice (two-tailed unpaired t-test; n=8). e, Quantification of the number of vWF+ lumens (two-tailed unpaired t-test; n=8). f, Quantification of the number of α-SMA+vWF+ lumens (two-tailed unpaired t-test; n=8). Data from individual mice are shown and values are represented as mean ± SEM. TH, tyrosine hydroxylase; vWF, Von Willebrand factor; α-SMA, alpha smooth muscle actin.

Source data

Extended Data Fig. 4 VTA activation following AMI does not affect bone-marrow.

a, Total count of CD45+ cells in bone marrow extracts isolated from the left femur and tibia (n=16). b, Percentage of CD45+ki-67+ cells in the bone marrow (n=16). c, ki-67+ Mean Fluorescence Intensity of CD45+ cells in the bone marrow (n=16). d, Percentage of Lin-Sca-1+c-kit+ cells in the bone marrow (n=16). e, Percentage of Lin-Sca-1+c-kit+CD34+ cells in the bone marrow (n=16). f, Percentage of Lin-Sca-1+c-kit+CD34+CD127+ cells in the bone marrow (n=16). g, Percentage of Lin-Sca-1-c-kit+ cells in the bone marrow (n=16). h, Percentage of Lin-Sca-1-c-kit+CD34+ cells in the bone marrow (n=16). i, Percentage of CD11b+Ly6G+ cells in the bone marrow (n=16). j, Percentage of CD11b+Ly6C+ cells in the bone marrow (n=16). k, Total count of CD45+ cells in 1ml of blood (n=22). Two-tailed unpaired t-test analysis was used; data from individual mice are shown, and values are represented as mean ± SEM.

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Extended Data Fig. 5 Effects of VTA activation on cell condition.

a, Representative images of immunohistochemical staining of cardiac tissues of control and VTA-Gq mice on day 4 post-AMI for CD68, CD80, and CD206. Scale bar, 100µm. b, Percentage of CD80+ from CD68+ cells (two-tailed unpaired t-test; n=10). c, Percentage of CD206+ out of CD68+ cells (] two-tailed unpaired t-test with Welch’s correction; n=10). d, Representative images of CD4 immunohistochemical staining of cardiac tissues of control and VTA-Gq mice on day 4 post-AMI. Scale bar, 100µm. e, Quantification of CD4+ cells (two-tailed unpaired t-test with Welch’s correction; n=10). f, Percentage of CD4+ from CD45+ cells (two-tailed unpaired t-test with Welch’s correction; n=10). g, Representative images of immunohistochemical staining of cardiac tissues of control and VTA-Gq mice on day 4 post-AMI for CD8. Scale bar, 100µm. h, Quantification of CD8+ cells (two-tailed unpaired t-test with Welch’s correction; n=10), i, Percentage of CD8+ from CD45+ cells (two-tailed unpaired t-test with Welch’s correction; n=10). j, Representative images of TUNEL staining of cardiac tissues of control and VTA-Gq mice on day 4 post-AMI, arrows indicate TUNEL+ cells. k, Quantification of TUNEL+ cells from DAPI+ cells (two-tailed unpaired t-test; n=9). l, Quantification of TUNEL+ cells out of Troponin I+ cells (two-tailed unpaired t-test; n=9). Data from individual mice are shown and values are represented as mean ± SEM.

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Extended Data Fig. 6 VTA neuronal tracing.

a, Representative micrographs demonstrating neurons expressing PRV in the liver. Scale bar, 100 µm; b, celiac ganglion. Scale bar, 1000 µm; and c, spinal cord. Scale bar, 100 µm. d, Representative composite micrograph of the brainstem nuclei demonstrating PRV+ cells following liver injection. Scale bar, 1000 µm. e, Representative composite micrograph of the brain VTA demonstrating PRV+ cells following spleen injection. Scale bar, 1000 µm. f, Relative spleen NA levels, day 4 post AMI (two-tailed unpaired t-test; n=11). Data from individual mice are shown, and values are represented as mean ± SEM. PRV, pseudorabies; TH, tyrosine hydroxylase; NA, noradrenaline; DMV, dorsal motor nucleus of the vagus; NTS, nucleus tractus solitarius; RVLM, rostral ventrolateral medulla; LC, locus coeruleus.

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Extended Data Fig. 7 C3 is essential for the beneficial effect of VTA activation.

a, Representative images of tube formation assay of endothelial cells 3 hours after treatment with liver protein extract, plasma, and C3 inhibitor (Cp40). b, Total segment area; c, Total branching area; and d, Branching interval. Measurements were quantified using an image analysis tool (Multiple unpaired two-sided t-tests with Benjamin, Krieger, and Yekutieli correction; n=20). e, Representative short-axis ultrasound images of mice following LAD ligation on day 1 and day 14. f, Systolic left ventricular internal diameter on postoperative days 1 and 14 in control and VTA-Gq mice treated with saline vs. Cp40. Comparisons show no difference between groups on day 1 and a significant difference on day 14 (two-way ANOVA mixed model, followed by Tukey’s test; n=20). g, Diastolic left ventricular internal diameter on postoperative days 1 and 14 in control and VTA-Gq mice treated with saline vs. Cp40. Comparisons show no difference between groups on day 1 and a significant difference on day 14 (two-way ANOVA mixed model, followed by Tukey’s test; n=20). h, Quantification of the number of vWF+ lumens in control and VTA-Gq mice treated with Cp40 (two-tailed unpaired t-test; n=9). i, Quantification of the number of α-SMA+vWF+ lumens in control and VTA-Gq mice treated with Cp40 (two-tailed unpaired t-test; n=9). Data from individual mice are shown and values are represented as mean ± SEM.

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Extended Data Table 1 Secreted proteins primarily synthesized by the liver, whose levels were upregulated in the proteomic analysis
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Supplementary information

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Flow cytometry gating strategy.

Reporting Summary

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Haykin, H., Avishai, E., Krot, M. et al. Reward system activation improves recovery from acute myocardial infarction. Nat Cardiovasc Res 3, 841–856 (2024). https://doi.org/10.1038/s44161-024-00491-3

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