- Astroglial Control of Vital Neural Networks
Interacting neural networks of the brainstem continually adjust our breathing and activity of the heart and blood vessels to meet the physiological and behavioural demands of the body. The brain also contains astrocytes - a group of brain cells known as glia (which means 'glue' in Greek). Glial cells are the most abundant cells in the human brain - outnumbering neurons by a factor of ten to one. Until recently, glial cells have been thought to merely provide neurones with structural and nutritional support. However, new experiments suggest that astrocytes are actively involved in brain information processing and control of complex behaviours. We aim to investigate the fundamental principles underlying glial influences over brain networks controlling breathing and cardiovascular activity. Results of these studies are expected to contribute towards our understanding of the fundamental principles of brain organization and function and may also help to reveal causes of devastating conditions associated with respiratory failure (e.g. sudden infant death syndrome) and alterations in brain control mechanisms contributing to the development of diseases like hypertension and heart failure.
- Autonomic Dysfunction in Critical Illness
We undertake basic and clinical studies to understand the role of the autonomic dysfunction in the development of acute and chronic multi-organ failure. By interrogating neural control in laboratory and human models, we explore how autonomic dysfunction at both cellular and integrative physiologic levels impacts on clinical diagnosis, treatment and management of sepsis, major surgery and other inflammatory/pathological disease states.
- Autonomic Dysfunction in Diabetes
Diabetes and its co-morbidities such as cardiovascular disease seriously impact on quality of life. Additionally, 10% of the NHS budget is spent on treatment of diabetes alone. Despite the epidemic scale of the problem, clinicians still lack reliable predictors, that help diagnose co-morbidities early, that serve as bench marks for treatment success, and that determine individual patients' prognosis. We hypothesize that changes in the autonomic nervous system, leading to imbalances between sympathetic and parasympathetic drives, promote the development of diabetes and related morbidities. The aim of this research is to develop a pre-clinical model of autonomic imbalance that allows us to systemically investigate its potential deleterious consequences.
- Cardiovascular Pathophysiology
We study the role of the autonomic nervous system in the pathogenesis of hypertension and heart failure. We employ a wide array of cutting-edge techniques, including optogenetics and pharmacogenetics for selective activation or inhibition of astrocytic and neuronal networks that control cardio-respiratory activity.
- Central Glucagon-Like Peptide-1
Glucagon-like peptide-1 (GLP-1) is an insulin-stimulating hormone released from cells in the intestine following ingestion of a meal. It is also released from neurons located in the brainstem, and GLP-1 within the brain has been shown to be a potent inhibitor of food intake. In our lab, we have been able to develop a molecular handle on this neuronal population in order to better understand its role in normal feeding behaviour, as well as in obesity and metabolic disease states.
- Neuronal Vascular Coupling
We regularly see brain scans in which parts of the brain are said to 'light up'. This is functional magnetic resonance imaging: an MRI scanner is used to acquire high resolution anatomical images of the brain, and changes in brain activity are shown as colour "blobs". These functional data are derived from local changes in blood flow which occur in response to changes in neuronal activity. Abbreviated as fMRI, this technique is commonly used in human subjects to conduct psychological and neurological investigations of the brain. In collaboration with CABI and University of Bristol we conduct optogenetic fMRI studies in experimental animals. The aim of this work is to better understand the precise cellular mechanisms responsible for changes in local blood flow. Understanding the cellular mechanisms of neurovascular coupling is essential if we want to contextualise the findings of fMRI studies in humans.
- Vagal Control of the Heart
We study the physiological and pathophysiological significance of parasympathetic (vagal) innervation of the left ventricle - an issue surrounded by controversies. This project spans across distinct research fields of myocardial ischaemia/reperfusion injury, innate cardioprotective mechanisms and central autonomic control and includes newly developed transgenic animal models and the latest advances in molecular neuroscience, pharmaco- and optogenetics for selective manipulation of vagal efferent outflow to the heart. These approaches enable unprecedented resolution and specificity and are used to determine the role of vagal innervation of the left ventricle in controlling its contractility and excitability, mediating cardioprotection against ischaemia/reperfusion injury and slowing the progression of chronic heart failure. Proposed studies may lead to the development of novel therapeutic strategies aimed to recruit beneficial vagal mechanisms which limit myocardial injury, reduce arrhythmia burden and slow heart failure progression.