Tiered sympathetic control of cardiac function revealed by viral tracing and single cell transcriptome profiling

Abstract
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Abstract

The cell bodies of postganglionic sympathetic neurons innervating the heart primarily reside in the stellate ganglion (SG), alongside neurons innervating other organs and tissues. Whether cardiac-innervating stellate ganglionic neurons (SGNs) exhibit diversity and distinction from those innervating other tissues is not known. To identify and resolve the transcriptomic profiles of SGNs innervating the heart we leveraged retrograde tracing techniques using adeno-associated virus (AAV) expressing fluorescent proteins (GFP or Td-tomato) with single cell RNA sequencing. We investigated electrophysiologic, morphologic, and physiologic roles for subsets of cardiac-specific neurons and found that three of five adrenergic SGN subtypes innervate the heart. These three subtypes stratify into two subpopulations; high (NA1a) and low (NA1b and NA1c) neuropeptide-Y (NPY) -expressing cells, exhibit distinct morphological, neurochemical, and electrophysiologic characteristics. In physiologic studies in transgenic mouse models modulating NPY signaling, we identified differential control of cardiac responses by these two subpopulations to high and low stress states. These findings provide novel insights into the unique properties of neurons responsible for cardiac sympathetic regulation, with implications for novel strategies to target specific neuronal subtypes for sympathetic blockade in cardiac disease.

Data availability

Data related to single-cell RNA seq analysis generated from this manuscript are available from the GEO database (GSE231924)

The following data sets were generated

(2023) Tiered Sympathetic Control of Cardiac Function Revealed by Viral Tracing and Single Cell Transcriptome Profiling
NCBI Gene Expression Omnibus, GSE231924.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE231924

Article and author information

Author details

Sachin Sharma

Neurocardiology Research Center of Excellence, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-6776-1061
Russell Littman

Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
John D Tompkins

Neurocardiology Research Center of Excellence, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-9496-7930
Douglas Arneson

Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Jaime Contreras

Neurocardiology Research Center of Excellence, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Al-Hassan Dajani

Neurocardiology Research Center of Excellence, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Kaitlyn Ang

Neurocardiology Research Center of Excellence, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Amit Tsanhani

Neurocardiology Research Center of Excellence, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Xin Sun

Department of Pediatrics, University of California, San Diego, La Jolla, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-8387-4966
Patrick Y Jay

Alnylam Pharmaceuticals, Cambridge, United States

Competing interests
Patrick Y Jay, is affiliated with Alnylam Pharmaceuticals..
Herbert Herzog

Neuroscience Division, Garvan Institute of Medical Research, Sydney, Australia

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-1713-1029
Xia Yang

Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Olujimi A Ajijola

Cardiac Arrhythmia Center, University of California, Los Angeles, Los Angeles, United States

For correspondence
OAjijola@mednet.ucla.edu

Competing interests
Olujimi A Ajijola, is a co-founder of NeuCures Inc.Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0001-6197-7593

Funding

NIH Office of the Director (DP2HL142045)

Olujimi A Ajijola

NHLBI Division of Intramural Research (R01HL162717)

Olujimi A Ajijola

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experiments complied with institutional guidelines and ethical regulations, and the study protocol was approved by the UCLA institutional Animal Care and Use Committee. (protocol number: 18-048).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.