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

• Published in: eLife 2023-05, Vol.12
• Main Authors: Sharma, Sachin, Littman, Russell, Tompkins, John D, Arneson, Douglas, Contreras, Jaime, Dajani, Al-Hassan, Ang, Kaitlyn, Tsanhani, Amit, Sun, Xin, Jay, Patrick Y, Herzog, Herbert, Yang, Xia, Ajijola, Olujimi A
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Autonomic nervous system; Cardiac arrhythmia; Cardiac function; Coronary artery disease; Data analysis; Fluorescence; Gene Expression Profiling; Genetic engineering; Green fluorescent protein; Heart; Heart diseases; Labeling; Medicine; Mice; neurocardiology; neuronal subtypes; Neurons; Neurons - metabolism; Neuropeptide Y; Neuropeptide Y - metabolism; Neuropeptides; Neuroscience; Physical characteristics; RNA sequencing; Scientific equipment and supplies industry; scRNAseq; Stellate ganglion; Stellate Ganglion - metabolism; Sympathetic nerves; sympathetic neurons; Transcription factors; Transcriptomes; Transcriptomics; Transgenic mice
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.86295

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.