The Zebrafish Heart: an Archetype for Neurocardiology

The intracardiac nervous system (ICNS) is the final common pathway for reflex control of cardiac output by the autonomic nervous system (ANS). The normal operation of this system is key to supporting cardiovascular homeostasis, and ANS dysfunction or remodelling can contribute to the development of multiple cardiopathies. Thus the role of the ICNS in cardiac control is essential, however our current understanding of this role is incomplete. The majority of work on the ICNS to date has been in mammalian models, but because the neural elements comprising this network are embedded in cardiac tissues, visualization and experimental access to the entire network for integrative studies of neuronal function has been limiting. To address these issues, we have developed the zebrafish, a cyprinid teleost, as an alternate model for cardiac anatomical and neurophysiological studies. In this ancestral vertebrate the two‐chambered heart, although anatomically distinct from the mammalian four chamber arrangement, is dually innervated by sympathetic and parasympathetic limbs of the ANS and has a well‐developed ICNS which is functional in spontaneously beating isolated preparations. Activation of extrinsic cardiac nerves evokes tachycardia (via B 2 ‐adrenoceptors) and bradycardia (M 2 muscarinic receptors). Thus the essential features of ANS control of the heart are conserved across the vertebrates. We have mapped the general innervation patterns of the sinoatrial valve region (SAR), atrium and ventricle. A ganglionated plexus in the SAR surrounds the valve and contains most of the intracardiac neuronal somata; the majority is cholinergic with the remainder adrenergic, nitrergic and serotonergic. Furthermore, peptidergic axon terminals contact plexal somata. Optical mapping of the isolated heart confirms the site of origin of normal primary pacemaker activity within the SAR, where cells in the base of the valve leaflets express Islet‐1 (Isl‐1) and hyperpolarization‐activated, cyclic nucleotide‐gated channel 4 (HCN4), known markers for mammalian pacemaker cells. In addition, intracellular recordings from these cells display spontaneous diastolic membrane depolarization patterns typical of pacemaker cells. Extrinsic cardiac nerve stimulation, in addition to evoking bradycardia, can displace the pacemaker site to a secondary pacemaker in the atrioventricular region (AVR), where a population of cells also expresses Isl‐1 and HCN4. A small ganglion containing cholinergic somata is present in the AVR, suggesting local neural control of atrioventricular pacemaker activity. We have thus established the zebrafish heart as a viable model for studies of integrative neural control of pacemaker function. In particular, this model provides a platform to use optogenetic techniques to target intracardiac neurons and pacemaker cells, in combination with traditional electrophysiological methods, to perform detailed analyses of the intracardiac neuronal circuitry involved in cardiac control. This work will provide a solid foundation for further studies of ANS‐related cardiac pathophysiologies in zebrafish analogs of human cardiac disease states. Support or Funding Information Natural Sciences and Engineering Research Council of Canada (FMS, TAQ, RPC) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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