The sympathetic nervous system is crucial for controlling multiple cardiac functions and its overactivity is associated with many cardiovascular diseases (CVD). Chronic intermittent hypoxia (CIH) is a current model for sleep apnea, which constitutes a major risk factor for CVD through sympathetic overactivity. However, a comprehensive neuroanatomical map of the sympathetic innervation of the heart is unavailable which impedes our understanding of the remodeling of this map in pathological conditions. First, we used a combination of state-of-the-art techniques, including flat-mount tissue processing, immunohistochemistry for tyrosine hydroxylase (TH, a sympathetic marker), confocal microscopy and Neurolucida 360 software to trace, digitize, and quantitatively map the topographical sympathetic innervation in the whole heart of mice. Then we integrated our tracing data onto a 3D heart scaffold. Second, we determined the remodeling of sympathetic innervation in CIH, by exposing mice to either room air or CIH for 8-10 weeks. We found that (1) 4–5 extrinsic TH-IR nerve bundles entered the right atrium from the superior vena cava and the left atrium from the left precaval vein. Although these bundles projected to different areas of the atria, their projection fields partially overlapped. (2) TH-IR axon and terminal density varied considerably between different sites of the heart with the greatest density of innervation near the sinoatrial node region (P < 0.05, n = 6). (3) TH-IR axons also innervated blood vessels and adipocytes. (4) In ventricles: TH-IR axons formed dense terminal networks in the epicardium, myocardium, and vasculature. (5) TH-IR axons were traced and integrated into 3D heart scaffolds. (6) CIH significantly increased TH-IR innervation and complexity in the heart. Collectively, this work provided detailed mapping of catecholaminergic axons and terminal structures in the whole heart at single-cell/axon/varicosity scale in normal and CIH conditions. This work may provide a foundation for the functional study of sympathetic control of the heart and valuable neuromodulation strategies to treat CVD.


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Graduation Date





Cheng, Zixi


Doctor of Philosophy (Ph.D.)


College of Medicine


Burnett School of Biomedical Sciences

Degree Program

Biomedical Sciences




CFE0009483; DP0027483





Release Date

May 2023

Length of Campus-only Access


Access Status

Doctoral Dissertation (Open Access)