Mapping the hypothalamic functional architecture underlying appetite control in the PWS brain

Funding Summary

Working with the Autism BrainNet, Dr. Yeo and his team will examine hypothalamic tissue samples from six individuals with PWS. The research team apply cutting edge molecular analysis to these precious samples and to map the architecture of the PWS hypothalamus, providing insight into the changes underlying appetite control. They will create a comprehensive hypothalamic single cell database and a preliminary spatial map of hypothalamic cells in PWS, which will guide neurobiology research in the field.

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip. 

Lay Abstract

Despite extensive research, the mechanisms underlying the complex characteristics seen in Prader Willi Syndrome (PWS), in particular the severe hyperphagia and obesity, are still largely unknown. There are two key reasons for this. First, because genetic studies point to the brain, in particular a region known as the hypothalamus, as having a crucial role in appetite regulation, this has, for obvious reasons, 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. This leads to the second key reason, that mouse models of PWS fail to faithfully reproduce the full repertoire of the human condition. Now, a recent important collaboration with the UK Medical Research Council Brain Bank Network, has allowed us access to human donor brain samples. These samples, coupled with recent developments in single-cell sequencing technology, have provided us the opportunity to map the architecture of the human hypothalamus underlying appetite control. Over the past three years, we have generated a database of more than 350,000 human hypothalamic cells from eight normal weight donors with no known genetic conditions. This unique resource, even as a work in progress, is already unparalleled in its scope and size. While of interest in of itself, the long-term value of this data, given the central role of the hypothalamus in maintaining energy balance, is as a baseline to study this brain region in states of energy imbalance, such as in PWS. It is clear that to further understand the mechanisms underlying PWS, we must study the hypothalami from donors who had suffered from the condition. Thus, building on our growing database, as well as the methodologies and expertise we have accrued, we will map the hypothalamic architecture underlying food intake control in the PWS human brain. Working with the Autism BrainNet, we have identified rare hypothalamic samples from six individuals with diagnosed PWS. Here, using these precious samples, we propose to produce a comprehensive hypothalamic single cell database, and a preliminary spatial map of PWS. We will make this valuable resource fully searchable, and freely available to the community. In comparing the single cell and spatial data from donors with and without PWS, we hope to identify dysregulated appetitive feeding circuitry, and hence potentially therapeutically relevant targets.