Neuronal Pathways of Sleep and Anaesthesia

Modern surgery would be impossible without general anaesthetics, yet the underlying mechanisms by which these chemicals produce unconsciousness and pain relief are only now being discovered. In parallel with these insights about anaesthetic action, neuroscientists have identified some of the mechanisms that control and regulate natural sleep and consciousness. The aim of our Programme of research is to bring these aspects together so as to better understand how general anaesthetics and sedative drugs act in the brain. We hope to build upon the great advances that have been made over recent years in identifying the protein targets for some of these drugs and use this specificity to guide us towards pinpointing the neuronal pathways important for their actions. The drugs currently used to anaesthetise and sedate patients are far from perfect, providing a mix of desirable (such as loss of consciousness) and undesirable (such as respiratory depression) effects. Different anaesthetics and sedative drugs act on different pathways. Working out which pathways are responsible may help us develop better drugs with fewer side-effects. The dangers of current anaesthetics, and the absence of effective remedies for insomnia, are sadly illustrated by the death of the singer Michael Jackson following the inappropriate administration of the general anaesthetic propofol. However, even in the controlled environment of a hospital, many patients suffer from undesirable side-effects caused by the anaesthetic and analgesic drugs used during perioperative care. Serious risks can be provoked in already compromised patients, a considerable concern in our ageing population. Our work on anaesthetic action tackles a major intellectual problem in basic neuroscience, and at the same time, researching anaesthetic mechanisms and natural sleep pathways, and how they are related, can be expected to provide important information that has practical applications. For example, our work should provide insights into how natural sleep pathways work, information that is likely to aid in the treatment of sleep disorders, which are increasingly common in society.

Every year, 230 million patients worldwide are given general anaesthetics, drugs that remove our most precious human attribute ? consciousness. The induction of safe and reversible loss of consciousness is a pillar of modern medicine. It also poses one of the most long-standing puzzles in neuroscience. Anaesthesia is a routine procedure, but we do not really understand how it works. Although it is clear that general anaesthetics act at a relatively small number of targets, finding the links between these receptors and anaesthetic-induced loss of consciousness presents a fascinating and important challenge. In this Programme Grant application, we propose to test and elaborate our hypothesis that anaesthetics exert their sedative/hypnotic effects by recruiting natural sleep pathways. We will combine mouse genetics, electrophysiology, and synthetic chemistry to identify the neuronal pathways that underlie the actions of anaesthetics and sedative drugs whose molecular targets have been established. By exploiting what is known at the molecular level, our research should provide insights into both how natural sleep is regulated, as well as how anaesthetics act at the level of neuronal networks. This should inform strategies for the development of new drugs, including those to treat sleep disorders.

The Programme has five related projects:

In Project 1 we will measure cortical EEG changes simultaneously with changes in the local field potentials of selected thalamic nuclei during anaesthetic-induced loss of consciousness. This will provide fundamental reference data on thalamocortical connectivity in normal animals; these experiments will be repeated for the novel mice we plan to construct, in which known targets are either deleted, or made anaesthetic-insensitive. In Project 2 we will test the hypothesis that anaesthetics such as propofol exert their major effects by acting directly on GABA-A receptors on thalamic neurons. In Project 3 we will pursue an important recent discovery that the sedative/hypnotic agent dexmedetomidine (DEX) does not, as previously thought, act on adrenergic neurons. We will exploit the highly restricted expression of alpha2A-adrenergic receptors, the target for dexmedetomidine?s sedative actions, to test the idea that this drug acts at specific cortical sites. In Project 4, we will develop some exciting new findings of our own that point to an important role for TASK-3 potassium channels in anaesthesia, and we will test the hypothesis that their high cortical expression is responsible. In Project 5 we will investigate the mechanisms by which the hypothalamic tuberomammillary nucleus is inhibited during both anaesthesia and natural sleep.