Zebrafish heart as a model to study the integrative autonomic control of pacemaker function

Abstract

The cardiac pacemaker sets the heart's primary rate, with pacemaker discharge controlled by the autonomic nervous system through intracardiac ganglia. A fundamental issue in understanding the relationship between neural activity and cardiac chronotropy is the identification of neuronal populations that control pacemaker cells. To date, most studies of neurocardiac control have been done in mammalian species, where neurons are embedded in and distributed throughout the heart, so they are largely inaccessible for whole-organ, integrative studies. Here, we establish the isolated, innervated zebrafish heart as a novel alternative model for studies of autonomic control of heart rate. Stimulation of individual cardiac vagosympathetic nerve trunks evoked bradycardia (parasympathetic activation) and tachycardia (sympathetic activation). Simultaneous stimulation of both vagosympathetic nerve trunks evoked a summative effect. Effects of nerve stimulation were mimicked by direct application of cholinergic and adrenergic agents. Optical mapping of electrical activity confirmed the sinoatrial region as the site of origin of normal pacemaker activity and identified a secondary pacemaker in the atrioventricular region. Strong vagosympathetic nerve stimulation resulted in a shift in the origin of initial excitation from the sinoatrial pacemaker to the atrioventricular pacemaker. Putative pacemaker cells in the sinoatrial and atrioventricular regions expressed adrenergic β2 and cholinergic muscarinic type 2 receptors. Collectively, we have demonstrated that the zebrafish heart contains the accepted hallmarks of vertebrate cardiac control, establishing this preparation as a viable model for studies of integrative physiological control of cardiac function by intracardiac neurons.

The ventral peptidergic system of the adult ascidian Ciona robusta (Ciona intestinalis Type A) insights from a transgenic animal model

“…Interestingly, major nerve plexuses, termed sinoatrial plexus and atrioventricular plexus, surround the junctions of the sinoatrial valve and atrium and those of atrium and ventricle where the pacemaker cells exist in zebrafish 58,59 . The morphological feature and locations of the nerve plexuses of Ciona heart is reminiscent of those of zebrafish, suggesting that such cardiac nervous systems may be in part conserved in Ciona.…”

Cholinergic and β-adrenergic control of cardiovascular reflex responses to brief repeated asphyxia in term-equivalent fetal sheep

“…However, in fetal sheep, overshoot can occur well before the onset of fetal compromise (43), strongly inferring an autonomic mechanism, such as a combination of asphyxia-induced inhibition of vagal tone and unopposed ␤-adrenergic stimulation of the myocardium (43). Parasympathetic inhibition of heart rate (14) is mediated through the M2 muscarinic receptors on cardiac pacemaker cells (41). Although the impact of parasympathetic blockade during brief asphyxia is unknown, it is well established that the initial FHR deceleration during brief asphyxia is a chemoreflex and is mediated by parasympathetic efferents, as recently reviewed by Lear et al (29).…”

Neurohumoral Control of Sinoatrial Node Activity and Heart Rate: Insight From Experimental Models and Findings From Humans

“…Overall, it is clear that further work is needed for a complete, comprehensive understanding of the complex mechanisms involved in neurohumoral control of SAN function. This will be driven by technological advances in experimental techniques (Kohl and Quinn, 2014), such as higher resolution imaging and cell-specific optogenetics (Quinn et al, 2016), and may be further enhanced by the use of alternative experimental models (Stoyek et al, 2016 or computational modeling Kohl, 2011, 2013). Ultimately, by improving our knowledge of SAN control we will move toward a better understanding of how it responds to constantly changing physiological demands, and how we may better treat SAN dysregulation that leads to debilitating and often deadly cardiac diseases.…”