Comparative Specialization of Intrinsic Cardiac Neurons in Humans, Mice and Pigs.

Details

• Alternative Title:
  The Journal of Physiology, 2025, v. 603, no. 7: Comparative Specialization of Intrinsic Cardiac Neurons in Humans, Mice and Pigs.
• Journal Article:
  The Journal of Physiology
• Personal Author:
  Tompkins, John D. ; Hoover, Donald B. ; Havton, Leif A. ; Patel, Janaki C. ; Cho, Youngjin ; Smith, Elizabeth H. ; Biscola, Natalia P. ; Ajijola, Olujimi A. ; Shivkumar, Kalyanam ; Ardell, Jeffrey L.
• Description:
  Intrinsic cardiac neurons (ICNs) play a crucial role in the proper functioning of the heart; yet a paucity of data pertaining to human ICNs exist. We took a multidisciplinary approach to complete a detailed cellular comparison of the structure and function of ICNs from mice, pigs and humans. Immunohistochemistry of whole and sectioned ganglia, transmission electron microscopy, intracellular microelectrode recording and dye filling for quantitative morphometry were used to define the neurophysiology, histochemistry and ultrastructure of these neurons across species. The densely packed, smaller ICNs of mouse lacked dendrites, formed axosomatic connections and had high synaptic efficacy constituting an obligatory synapse. At pig ICNs, a convergence of subthreshold cholinergic inputs onto extensive dendritic arbors supported greater summation and integration of synaptic input. Human ICNs were tonically firing, with synaptic stimulation evoking large suprathreshold EPSPs like mouse, and subthreshold potentials like pig. Ultrastructural examination of synaptic terminals revealed conserved architecture, yet small clear vesicles were larger in pigs and humans. The presence and localization of ganglionic neuropeptides was distinct, with abundant vasoactive intestinal polypeptide observed in human but not pig or mouse ganglia, and little substance P or calcitonin gene-related peptide in pig ganglia. Action potential waveforms were similar, but human ICNs had larger after-hyperpolarizations. Intrinsic excitability differed; 95% of human neurons were tonic, all pig neurons were phasic, and both phasic and tonic phenotypes were observed in mouse. In combination, this publicly accessible, multimodal atlas of ICNs from mice, pigs and humans identifies similarities and differences in the evolution of ICNs. KEY POINTS: Intrinsic cardiac neurons (ICNs) are essential to the regulation of cardiac function. We investigated the neurochemistry, morphology, ultrastructure, membrane physiology and synaptic transmission of ICNs from donated human hearts in parallel with identical studies of ICNs from mice and pigs to create a publicly accessible cellular atlas detailing the structure and function of these neurons across species. In addition to presenting foundational data on human ICNs, this comparative study identifies both conserved and derived attributes of these neurons within mammals. The findings have significant implications for understanding the regulation of cardiac autonomic function in humans and may greatly influence strategies for neuromodulation in conditions such as atrial fibrillation and heart failure.
• Content Notes:
  Author manuscript
• Subjects:
  • Animals
  • Humans
  • Mice
  • Swine
  • Neurons
  • Male
  • Heart
  • Female
  • Mice, Inbred C57BL
  • Action Potentials
  More +
• Keywords:
  • cardiac physiology
  • autonomic ganglia
  • neurophysiology
  • neurocardiology
  • neuromodulation
  • intracardiac neuron
  • ganglionic neurotransmission
  • homo sapiens
• Source:
  The Journal of Physiology, 2025, v. 603, no. 7
• DOI:
  https://doi.org/10.1113/JP286714
• ISSN:
  0022-3751 ; 1469-7793
• Pubmed ID:
  39513933
• Pubmed Central ID:
  PMC11957936
• Document Type:
  Text
• Funding:
  OT2 OD026585/OD/NIH HHSUnited States/ ; OT2 OD023848/OD/NIH HHSUnited States/ ; P01 HL164311/HL/NHLBI NIH HHSUnited States/
• Genre:
  Journal Article
• Pages in Document:
  2043-2070 (44 pdf pages)
• Volume:
  603
• Issue:
  7
• Download URL:
  https://stacks.cdc.gov/view/cdc/261933/cdc_261933_DS1.pdf
• File Type:
  [PDF - 5.54 MB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:57a851d0c36331974122559968ce6511c0397d9c2897793a348ab7cad1c817d77f38d53739f96ceae9ab86e397846e0bc51e91b9ca16b367930b033e792bf3e1