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UCLA Cardiac Arrhythmia Center and Neurocardiology Research Program of Excellence, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.
J Physiol. 2025 Mar;603(7):2043-2070. doi: 10.1113/JP286714. Epub 2024 Nov 8.
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.
心脏内在神经元（ICNs）对心脏的正常功能起着至关重要的作用；然而，关于人类ICNs的数据却很匮乏。我们采用多学科方法，对小鼠、猪和人类的ICNs的结构和功能进行了详细的细胞比较。通过对完整和切片神经节进行免疫组织化学、透射电子显微镜、细胞内微电极记录以及用于定量形态学的染料填充，来确定这些神经元在不同物种间的神经生理学、组织化学和超微结构。小鼠中密集排列的较小ICNs缺乏树突，形成轴体连接，且具有构成强制性突触的高突触效能。在猪的ICNs中，阈下胆碱能输入汇聚到广泛的树突分支上，支持了突触输入的更大总和与整合。人类ICNs呈紧张性放电，突触刺激能诱发像小鼠一样的大的阈上兴奋性突触后电位（EPSPs），以及像猪一样的阈下电位。对突触终末的超微结构检查显示结构保守，但清亮小泡在猪和人类中更大。神经节神经肽的存在和定位各不相同，在人类神经节中观察到丰富的血管活性肠多肽，而在猪或小鼠神经节中则没有，并且猪神经节中几乎没有P物质或降钙素基因相关肽。动作电位波形相似，但人类ICNs的超极化后电位更大。内在兴奋性也不同；95%的人类神经元是紧张性的，所有猪神经元是相位性的，在小鼠中则同时观察到相位性和紧张性表型。综合起来，这个可公开获取的小鼠、猪和人类ICNs的多模态图谱确定了ICNs进化过程中的异同点。要点：心脏内在神经元（ICNs）对心脏功能的调节至关重要。我们研究了来自捐赠人类心脏的ICNs的神经化学、形态、超微结构、膜生理学和突触传递，并与对小鼠和猪的ICNs进行的相同研究并行，以创建一个可公开获取的细胞图谱，详细说明这些神经元在不同物种间的结构和功能。除了提供关于人类ICNs的基础数据外，这项比较研究还确定了这些神经元在哺乳动物中的保守和衍生属性。这些发现对于理解人类心脏自主神经功能的调节具有重要意义，并且可能极大地影响心房颤动和心力衰竭等病症中的神经调节策略。
