The contribution of tanycyte signalling to the function of hypothalamic networks

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An area of the brain called the hypothalamus contains key neural circuits involved in the control of appetite, feeding and energy expenditure (collectively "energy balance"). Stimulated by the inexorable rise of obesity and consequent health problems, there has been intense study of these neural circuits. However, the possible role of non-neuronal cells in the brain has not been extensively considered. We have previously demonstrated that hypothalamic tanycytes, cells that contact cerebrospinal fluid in the ventricles of the brain and send processes into the hypothalamus, respond to both neuron-derived and circulating agents that signal energy status and arousal. Our data therefore suggest that tanycytes have the potential to actively participate in the control of energy balance. There is also abundant data from other researchers showing, for example, that processes of tanycytes come into close contact with neurons (very suggestive of communication passing between them) that supports the idea that tanycytes may be active players in the hypothalamic network.We propose to test directly the idea that tanycyte-neuron communication exists and to characterize where and how it occurs (which neurons receive signals from tanycytes and what are the chemical signals released by tanycytes to effect this communication). Our approach will employ and develop selective optical methods to allow us to activate only the tanycytes. We shall combine this with functional imaging methods to screen for consequent responses in individual neurons, giving an efficient and comprehensive way of mapping these interactions. While some selective approaches for selective tanycyte activation already exist (and we shall use them), an important aspect of our project is to develop new potentially more powerful genetic methods to accomplish this aim. We shall develop ways to target light sensitive ion channels so that they express only in tanycytes thereby allowing illumination of the correct wavelength of light to selectively activate them. We shall verify that our methods do indeed work and use this new approach, along with existing methods, to map the tanycyte-neuron interactions. A further important aspect of our approach will be to identify the types of neurons that tanycytes influence. The nature of these interactions, and the types of neurons that tanycytes communicate with is central to our being able to hypothesize the potential functional roles of tanycytes. Finally there is evidence that the way the hypothalamic network functions depends upon metabolic state (e.g. fasting, diet induced obesity). We shall therefore also examine whether tanycyte-neuron interactions also depends upon metabolic state.Our work will be influential in the design of future experiments both by proposing specific hypotheses for tanycyte function and by developing the tools necessary to rigorously link tanycyte signalling to behaviour. This has the potential to radically alter our understanding of how the brain controls energy balance and may suggest new ways to regulate appetite, and hence help to reduce the burden to society of obesity related illnesses.