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Published April 26, 2019 | Submitted + Published + Supplemental Material
Journal Article Open

Identification of peripheral neural circuits that regulate heart rate using optogenetic and viral vector strategies


Heart rate is under the precise control of the autonomic nervous system. However, the wiring of peripheral neural circuits that regulate heart rate is poorly understood. Here, we develop a clearing-imaging-analysis pipeline to visualize innervation of intact hearts in 3D and employed a multi-technique approach to map parasympathetic and sympathetic neural circuits that control heart rate in mice. We identify cholinergic neurons and noradrenergic neurons in an intrinsic cardiac ganglion and the stellate ganglia, respectively, that project to the sinoatrial node. We also report that the heart rate response to optogenetic versus electrical stimulation of the vagus nerve displays different temporal characteristics and that vagal afferents enhance parasympathetic and reduce sympathetic tone to the heart via central mechanisms. Our findings provide new insights into neural regulation of heart rate, and our methodology to study cardiac circuits can be readily used to interrogate neural control of other visceral organs.

Additional Information

© 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 09 October 2018; Accepted 27 March 2019; Published 26 April 2019. Data availability: The data that support the findings of this study are available from the corresponding authors upon reasonable request. Viral vectors and protocols are available through Addgene or Beckman Institute for CLARITY, Optogenetics, and Vector Engineering Research for technology development and broad dissemination: http://www.beckmaninstitute.caltech.edu/clover.shtml. Code availability: Nerve fiber visualization and analysis algorithms used in this study are available are available at: https://www.ics.uci.edu/~fowlkes/SPARC/volume/. We thank the entire Shivkumar and Gradinaru group for discussions. This work was supported by a NIH Stimulating Peripheral Activity to Relieve Conditions (SPARC) awards (OT2OD023848 to K.S. and V.G.; OT2OD23864 to H.M.). The K.S. laboratory is also supported by a NIH National Heart, Lung, and Blood Institute (NHLBI) grant (R01HL084261) and a NIH SPARC award (U01EB025138-01 to K.S. and J.L.A.). The V.G. laboratory is also supported by a NIH Director's New Innovator Award (DP2NS087949), a NIH Presidential Early Career Award for Scientists and Engineers, a NIH National Institute on Aging grant (R01AG047664), a NIH BRAIN Initiative award (U01NS090577), the Defense Advanced Research Projects Agency (DARPA) Biological Technologies Office, the National Science Foundation NeuroNex Technology Hub (1707316), the Curci Foundation, the Beckman Institute, and the Rosen Bioengineering Center at Caltech. V.G. is a Heritage Principal Investigator supported by the Heritage Medical Research Institute. P.S.R. was supported by a NIH NHLBI F31 Predoctoral Fellowship (F31HL127974). R.C.C. was supported by an American Heart Association Postdoctoral Fellowship (17POST33410404). P.S.R. is a part of the UCLA-Caltech Medical Scientist Training Program. We thank Drs. Marmar Vaseghi (UCLA), Olujimi A. Ajijola (UCLA), and Ching Zhu (UCLA) for their comments on the manuscript. Author Contributions: P.S.R., R.C.C., J.L.A., V.G., and K.S. designed the study. P.S.R, S.H., and R.C.C. performed heart clearing. A.G. and P.S.R. performed lightsheet imaging of cleared hearts. K.Y.C., B.E.D., R.C.C., and V.G. designed viral constructs. R.C.C. and K.Y.C. produced viruses. R.C.C. and P.S.R. performed retro-orbital injections. C.C.F. developed computational pipeline, performed fiber tracing, and analyzed stellate ganglia CTB data. P.S.R. and R.C.C. performed immunohistochemistry. P.S.R. performed optogenetic experiments. J.D.T. helped with optogenetic experiments. M.C.J. performed cardiac CTB injections. P.S.R., P.H., S.H., B.A.G-.W., and G.S. analyzed data. H.M. provided guidance on TH mouse line selection. P.S.R. and R.C.C. prepared the figures. P.S.R. and K.S. wrote the manuscript. All coauthors contributed to the final version of the manuscript. The authors declare no competing interests.

Attached Files

Published - s41467-019-09770-1.pdf

Submitted - 456483.full.pdf

Supplemental Material - 41467_2019_9770_MOESM10_ESM.mp4

Supplemental Material - 41467_2019_9770_MOESM11_ESM.mp4

Supplemental Material - 41467_2019_9770_MOESM1_ESM.pdf

Supplemental Material - 41467_2019_9770_MOESM2_ESM.pdf

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Supplemental Material - 41467_2019_9770_MOESM4_ESM.pdf

Supplemental Material - 41467_2019_9770_MOESM5_ESM.mp4

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Supplemental Material - 41467_2019_9770_MOESM7_ESM.mp4

Supplemental Material - 41467_2019_9770_MOESM8_ESM.mp4

Supplemental Material - 41467_2019_9770_MOESM9_ESM.mp4


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August 19, 2023
October 20, 2023