Neural control of the heart: intrinsic cardiac ganglion neurons

The mammalian intrinsic cardiac nervous system comprises clusters of parasympathetic postganglionic efferent neurons, local interneurons, and afferent neurons dispersed throughout the atrial epicardium and interatrial septum of the heart. These intracardiac ganglia receive excitatory cholinergic innervation from preganglionic parasympathetic (vagal) fibres and are also innervated by sympathetic postganglionic nerve fibres, as well as afferent fibres from dorsal root and nodose (vagal) sensory ganglia. Together, neurons within these ganglia form a complex neural network characterised by neurochemical diversity, suggesting a level of functional sophistication beyond a simple relay station (Adams et al., 2022; Ardell & Armour, 2016; Herring et al., 2019). The diverse functional and neurochemical properties of these intracardiac neurons and their strategic location provide the final site of neural control in the heart, mediating local reflex responses to changes in cardiac performance or environmental factors within the myocardium such as those induced by ischaemia. Importantly, the final discharge pattern of these neurons regulates chronotropic and dromotropic elements of cardiac function. In this issue of The Journal of Physiology, Tompkins et al. (2025) present a detailed comparative analysis of intrinsic cardiac neurons (ICNs) across three species – mouse, pig, and human – using a multidisciplinary approach. A comprehensive atlas that highlights both similarities and differences in ICN structure and function among these species is presented. This resource enhances our understanding of ICNs in cardiac physiology and provides a basis for future research in cardiac neural control and potential therapeutic strategies. A key strength of the study is its methodical approach to characterizing ICNs from multiple perspectives: histochemical, ultrastructural, and neurophysiological. Immunohistochemistry and electron microscopy reveal details of ganglionic composition, neuropeptide expression and synaptic morphology, illustrating notable interspecies differences. For example, human ICNs show prominent vasoactive intestinal peptide immunoreactivity, distinguishing them from those in pigs and mice. This finding suggests that species-specific variations in neuropeptide expression may influence ICN function and modulation, an important consideration for translating animal research to human models. The comparison of synaptic function across species uncovers notable differences in synaptic efficacy and integration. In particular, it is observed that mouse ICNs, lacking dendrites, form axosomatic connections with high synaptic efficacy, sustaining high-fidelity neurotransmission. In contrast, pig ICNs possess extensive dendritic arbours, supporting greater integration of synaptic inputs, aligning with larger animals' physiological demands. These observations, akin to those for sympathetic ganglion neurons, emphasize the importance of dendritic architecture in ICN function, suggesting that neuronal morphology may influence the integrative capabilities of ICNs and, ultimately, their role in cardiac regulation across species. Additionally, the authors provide a compelling analysis of electrophysiological characteristics, noting significant differences in excitability between species. Human ICNs exhibit larger after-hyperpolarizations following the somatic action potential compared with those in mouse and pig, which may indicate distinct regulatory mechanisms in human cardiac autonomic function. The finding that the firing pattern of human ICNs is predominantly tonic while pig ICNs are phasic, with mouse ICNs displaying both phenotypes, suggests a potential evolution of excitability properties that aligns with the functional complexity of cardiac control in larger mammals. Changes in parasympathetic tone within intracardiac neurons are linked to increased risk of arrhythmias, heart failure and mortality. Exploratory clinical studies have shown that the activity of the intracardiac nervous system can predispose patients to paroxysmal atrial arrhythmias. Specifically, intracardiac neurons play a critical role in the development and propagation of atrial fibrillation (Ashton et al., 2025), a common cardiac arrhythmia characterised by irregular, rapid atrial contractions that disrupt the atrial function. The study by Tompkins et al. (2025) provides valuable insights into the translational relevance of its findings. By comparing ICN characteristics across species, it highlights the advantages and limitations of these animal models for studying human cardiac physiology. Notably, the study recognises mice as a valuable model for genetic manipulation, while highlighting pigs as closer physiological analogues to humans. This comparative approach could greatly benefit the development of neuromodulation therapies targeting cardiac autonomic dysfunction, as it allows for a better understanding of how animal models may or may not replicate human ICN function. However, the paper could have benefited from a more detailed discussion of potential clinical applications. While the authors briefly address neuromodulation techniques, elaborating on how their findings might inform or refine these approaches would add valuable context. Insights into unique excitability profiles and neuropeptide distributions of human ICNs could guide the development of targeted strategies for specific ICN populations, especially in treating dysregulated autonomic conditions, such as arrhythmias or heart failure. Overall, this paper represents a significant contribution to our understanding of intrinsic cardiac neurons, providing a thorough, well-structured analysis that highlights the complexity and evolutionary diversity of ICNs. While further studies are needed to translate these findings into clinical applications, this work lays a solid foundation for future exploration of the neurophysiological and neurochemical properties of intracardiac neurons. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. Sole author. None.