Control of the heart by neurones of the dorsal motor nucleus of the vagus nerve in health and disease.
Professor Alexander Gourine - Neuroscience, Physiology and Pharmacology
The Rosetrees Charitable Trust and Medical Research Council
Description of Project:
The strength, functional significance and origins of parasympathetic (vagal) control of left ventricular function remain controversial. Experimental studies in rats and mice using methods of functional neuroanatomical mapping, genetic neuronal targeting using pharmaco- and optogenetics will be used to test the hypothesis that parasympathetic control of the left ventricle is provided by vagal preganglionic neurones of the dorsal motor nucleus (DVMN).
Results of the planned experiments described in this study will able to answer if:
- The Activity of the DVMN vagal preganglionic neurones is responsible for tonic parasympathetic control of ventricular excitability and if it is mediated by nitric oxide or cholinergic mechanisms.
- 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 as these neurones are known to be subject to excessive oxidative stress in neurodegenerative conditions.
- The tonic muscarinic influence on left ventricular contractility is provided by a subpopulation of vagal preganglionic neurones in the DVMN if there is indeed a viscerotopic map.
- Reduced activity of the DVMN neurones is associated with a severely compromised aerobic exercise capacity and in turn if optogenetic recruitment of the DVMN neurones improves left ventricular performance and exercise capacity
- Optognetic enhancement of DVMN activity could alleviate the heart failure phenotype.
Positive findings from these experiments would provide the first insight into the central nervous substrate that underlie functional parasympathetic innervation of the ventricles and highlight its importance in controlling cardiac function.
PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice. Deas E, Piipari K, Machhada A, Li A, DWithers DJ, Wood NW, Abramov AY. Open Biology 2014
Brainstem hypoxia contributes to the development of hypertension in the spontaneously hypertensive rat. Marina N, Ang R, Machhada A, Kasymov V, Karagiannis A, Hosford P, Mosienko V, Teschmacher A, Vihko P, Paton J, Kasparov S & Gourine AV. Hypertension 2015
Control of ventricular excitability by neurons of the dorsal motor nucleus of the vagus nerve Machhada A, Ang R, Ackland GL, Ninkina N, Buchman VL, Lythgoe MF, Trapp S, Tinker A, Marina N, Gourine AV. Heart Rhythm 2015
Vagal modulation of atrial fibrillation. Machhada A, Gourine AV, Ackland GL. Journal of the American College of Cardiology 2015
Impaired baroreflex sensitivity induces Nox-2 mediated cardiac dysfunction through over-expression of GRK2. Ackland GL, Whittle J, Toner A, Gutierrez AA. Sanchez J, Machhada A,Stephens RCM, Reddy S, Dyson A, Sneyd R, Struthers R, Minto G Singer M, Shah A, Gourine AV. Journal of Critical Care Medicine 2016
Molecular mechanisms linking autonomic dysfunction and impaired cardiac contractility in critical illness. Ackland GL, Whittle J, Toner A, Machhada A, Del Arroyo AG, Sciuso A, Jenkins N, Dyson A, Struthers R, Sneyd JR, Minto G, Singer M, Shah AM, Gourine AV. Journal of critical care medicine 2016
Cardiac vagal preganglionic neurons: An update. Gourine AV, Machhada A, Trapp S, Spyer KM. Autonomic neuroscience 2016
- Teaching assistant practical lab exercises for pre-clinical years 1 and 2
- Mentoring for students enter the UCL Doctoral Training Programme in Medical Physics
Awards & Prizes:
- Poster Prize : Innovations in Cardiovascular Research Symposium 2013
- Societies Commendations for dedicated service to the Societies at UCL Union (09/10)
- Rosetrees Trust Research Grant for an extended year of research
- European Society for Cardiology Council on Basic Cardiovascular Science 2014 Basic research travel award
- Brain Research travel award
Activities and Societies:
- President - UCLU & RUMS Raise and Give Society (09/10)
- Intermediate 3 Rower - RUMS Boat Club (UCL) & Curlew Rowing Club (Greenwich)
- First Aid Worker - Red Cross (public events)
- Student representative - Medical students in their year of intercalation at UCL (10/11)
- Student academic representative (StaR qualification) - Medical Physics students (10/11)
Conferences Presented at:
- World Molecular imaging Congress 2016, New York (2 poster presentations)
- European Society for Cardiology Congress 2016, Rome (2 oral presentations)
- The Biomedical Basis of Elite performance (oral and poster presentation)
- World Molecular Imaging Congress 2015, Hawaii (2 poster presentations)
- Heart Rhythm Congress, 2015, Birmingham, UK (poster presentation)
- European Society for Cardiology Congress 2014, London (3 poster presentations)
- British Cardiovascular Society Annual Conference 2013, ExCel London, UK (poster presentation)
- International Union of Physiological Sciences (IUPS) 2013, Birmingham, UK (2 poster presentations)
- Innovations in Cardiovascular Research Symposium 2012, UCL institute of Child Health (poster presentation)