Hunting down and TRAPing appetite neurones

In this project we have an unprecedented opportunity to interrogate the brain´s appetite ensembles - those culprit neurones contributing to eating disorders and obesity development - to find new pathways and molecular targets of importance for therapeutic development.

Our proposal concerns a novel targeted approach to locate, neurochemically identify, validate and sequence ensembles of appetite neurones.

Until now, this field has been fixated on the agouti-related peptide "hunger" neurones of the arcuate nucleus, but it is clear that other brain areas and pathways are involved (in the hypothalamus, brainstem and reward system).

We will use the Fos-TRAP system to gain genetic access to neurones activated by pro-appetite stimuli in TRAP2 mice.

Stimuli will include both intrinsic metabolic appetite signals (ghrelin, food restriction) and external food odor cues (for which preliminary data indicate that they target overlapping pathways to ghrelin).

Gaining genetic access (TRAPing) allows us to 1) Visualise activated ensembles (in TRAP2 mice crossed onto a reporter strain), showing their distribution. 2) Use chemogenetics and other viral vector tools to control the activity of prioritized ensembles and determine the behavioural outcome. 3) Explore the neurochemical identity of the activated cells (by RNAscope). 4)  Check for enrichment of genes known to be associated with obesity (from GWAS data), to prioritize further which neurons could be therapeutic targets.