Mapping the human hypothalamic functional architecture underlying food intake control

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Obesity is a growing public health problem. While our changing lifestyle and environment have undoubtedly driven this increase, there is a powerful genetic component that underlies the large variation in human body shape and size in this modern environment. Understanding the mechanisms controlling feeding behaviour that lead to this variability in body-weight will be important in informing any strategy to improve our health in this current food environment. While the preferred model in which to study food intake is clearly in humans, the fact that genetic studies point to a region in the brain called the hypothalamus as having a crucial role in modulating appetite has limited the mechanistic insights achievable through human research. The inaccessibility of the human hypothalamus has, to date, meant our understanding of brain circuits controlling food intake has emerged primarily from mouse studies. Now, an important collaboration with the Cambridge Brain Bank, is allowing us access to fresh human donor brain samples. This, coupled with recent developments in single-cell sequencing and in technologies allowing us to visualize single-molecules using fluorescence, provides us with a timely opportunity to map the functional architecture of the human hypothalamus, with a focus on appetitive behaviour. A functioning map requires two key elements; we first need to know the components of the map, and then we need to know where these components sit on the map, with respect to each other. Thus our two objectives are: A) using single-cell technologies, we will sequence 500,000 individual hypothalamic cells, in order to perform a molecular census of cell populations to identify components of the neuro-circuitry controlling food intake; B) using an approach called single-molecule fluorescent in-situ hybridization (smFISH), we will map the different components identified onto both mouse and human brains. We will examine the spatial expression of these genes in the human hypothalamus and compare this to the pattern seen in the mouse brain. Detailed mechanistic studies on the brain using modern genetic manipulation tools will, for obvious reasons, still require mouse models. Our rationale however, is that if a certain neuronal population is ONLY found in mice, then studying it makes little 'translatable' sense. It would be far better to focus finite resources on generating sophisticated mouse models once we can determine that a particular pathway or neuronal type actually exists in the human brain. Our goal of a comprehensive human hypothalamic atlas will be of utility to basic scientists and clinical researchers attempting to better understand the fundamental nature of energy balance regulation by the hypothalamus. This will hopefully allow us to manipulate these systems to improve the health of the population.