Control of the Heart by Neurones of the Dorsal Motor Nucleus of the Vagus Nerve (DVMN) in Health and Disease

The strength, functional significance and origins of parasympathetic (vagal) control of left ventricular function remain controversial. Experimental studies conducted on rats and mice using methods of genetic neuronal targeting, functional neuroanatomical mapping, and pharmaco- and optogenetics were employed to test the hypothesis that parasympathetic control of the left ventricle is provided by vagal preganglionic neurones of the dorsal motor nucleus (DVMN). The results of the experiments described in this thesis suggest that (i) activity of the DVMN vagal preganglionic neurones are responsible for tonic parasympathetic control of ventricular excitability, likely to be mediated by nitric oxide; (ii) synuclein deficiency (a model relevant to Parkinson’s disease) results in a reduction in the activity of the DVMN neurones affecting the electrophysiological properties of the ventricle; (iii) tonic muscarinic influence on left ventricular contractility is provided by a subpopulation of vagal preganglionic neurones located in the caudal region of the left DVMN; (iv) reduced activity of the DVMN neurones is associated with a severely compromised aerobic exercise capacity; (v) increased activity of the DVMN neurones improves left ventricular performance and exercise capacity; and (vi) recruitment of the DVMN activity is sufficient to preserve exercise capacity and left ventricular function in heart failure developing after a myocardial infarction. These findings provide the first insight into the central nervous substrate that underlies functional parasympathetic innervation of the ventricles and highlight its importance in controlling cardiac function. The data obtained suggest that the DVMN neuronal projections provide tonic restraining influence on the ventricular arrhythmic potential and contractility, and have a trophic effect maintaining the ability of the heart to mount an appropriate inotropic response during exercise. As such, DVMN activity has a significant beneficial effect on the healthy left ventricle as well as ventricular myocardium compromised by occlusion of a major coronary artery.