Molecular taxonomy of hypothalamic neurons
Together with Brad Lowell and John Campbell's laboratories, we are systematically defining the specific cell types that compose the biological circuits underlying weight regulation using high throughput single cell/nuclei transcriptional profiling of the key brain regions involved in energy balance. We start by unbiased sampling of key brain regions by Drop-seq to define a "parts" list of constituent neuron types and the genetic markers that specify each of the unique cell types. Further, we have integrated these cell type-specific transcriptional profiles with human GWAS data to suggest phenotypes each unique cell type might affect. We can then use either existing recombinase lines or CRISPR-based genetic engineering to rapidly generate genetic tools that provide functional access to monitor each cell type's activity and connectivity. The importance of these cell classes in regulating distinct phenotypes is assessed by cell-type and area-specific activation or silencing using genetic, optogenetic or pharmacogenetic approaches. Specifically, we are utilizing such approaches to define neuron types and circuits underlying food and salt appetite, energy expenditure, glucose regulation, and gut function.