Autonomic innervation and control of chronotropy in the zebrafish heart
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In the vertebrate heart the intracardiac nervous system is a common pathway for autonomic control of cardiac output, comprising a population of intracardiac neurons in ganglia embedded within nerve plexi. These neural elements modulate the activity of effectors within the heart to adjust cardiac output, maintaining optimal perfusion of the body tissues under a wide range of metabolic activities. Investigation of the specific functional roles of subpopulations of intracardiac neurons within the circuitry mediating cardiac control in vertebrates has been hampered by a lack of knowledge about the detailed anatomical organization of the intracardiac nervous system. This work has revealed within the zebrafish intracardiac nervous system a complex neuroanatomy in which extrinsic innervation reached all regions of the heart; populations of intracardiac neurons were present at the sinoatrial and atrioventricular junctions, and adrenergic, cholinergic, nitrergic and peptidergic neurotransmitter phenotypes were expressed. Stimulation of individual extrinsic cardiac nerves and application of cholinergic and adrenergic agents showed that the zebrafish heart contains all the classic vertebrate hallmarks of cardiac control, establishing this preparation as a viable model for studies of integrative autonomic control of cardiac function. Disruption of electrical activity within the sinoatrial region during periods of simulated extrinsic input to the heart illustrated the complex neural mechanisms involved in rate control. In addition, it was found, using detection of activity-dependent markers, that distinct populations of intracardiac neurons were activated during vagal stimulation. This represents the first use of these markers in the heart, establishing a new method to investigate cardiac function. Further, the use of the isolated zebrafish heart for studies of clinically relevant issues was validated. These studies focused on pathways that may be responsible for cardiac dysfunction known to occur in those on serontonergic anti-depressants as well as in patients during clinical anesthesia. The results of this work offer a new model for studies of the direct and neurally mediated pathways involved in heart rate regulation. Overall, the results from these studies contribute significant advances to the establishment of the zebrafish as a new model for studies of integrative autonomic cardiac control.