Investigating the neural circuits underlying food choice and (over)consumption
"And still they gazed, and still the wonder grew,
That one small head could carry all he knew..."

Oliver Goldsmith, The Deserted Village.
Peering into one small head... With their relatively tractable nervous system, enviable toolkit for genetic manipulations and nuanced behavior, Drosophila are an excellent model system in which to study how the brain organizes food-related information. Shown here is a confocal image of a fly brain carrying dNPF-gal4/UAS-GFP transgenes. We have reported these cells as critical in establishing food-odor value.

How are food cues processed in the brain?
Picture By coupling single-cell resolution imaging in the LIVE fly (x-axis) with odor preference behavior (y-axis) we are able to predict food choice with great accuracy just by looking at the neural response.
Though the fly brain is numerically simple it produces relatively complex behaviors, including those governing food choice. By focusing on this system, we were able to reveal specific neurons with known human homology that explicitly represent food odor value.   We found that activity of higher-order neurons expressing Drosophila Neuropeptide F (npf), homologous to mammalian orexigenic Neuropeptide Y (NPY), precisely defines a hierarchy of odor value with a near perfect correlation between neural activity and behavior: the greater the odor-evoked npf response, the greater the attraction to that odor. Npf neurons respond only to the category of food odors and responses increase with hunger.

This contrasted with responses of other higher order olfactory neurons that do not appear to make a distinction between ethologically relevant and synthetic odors, but rather code odor identity. This separation provides insight into more general characteristics of information processing in the brain, suggesting that there can be distinct representations of different attributes of external stimuli, in this case of odor identity and appetitive value.


Can we model obesity in flies?

With the global population facing overwhelming rises in the prevalence of obesity and obesity-related serious medical conditions the need for understanding the processes governing food selection and intake has become of paramount importance to human health.




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Flies lacking neural upd1 (right) are much larger after exposure to high-fat diet. They gain weight at 3x rate of flies lacking such manipulations.
In mammals, NPY-expressing neurons in the hypothalamus are directly inhibited by Leptin, a fat-derived hormone and major determinant of energy homeostasis whose absence produces obese animals.  Recent work demonstrates domeless receptors in Drosophila can be activated by human Leptin.  By manipulating the endogenous domeless agonist Unpaired 1 (upd1), we established, for the first time, a functionally conserved model of genetically-induced obesity in Drosophila.  By disrupting upd1 in the brain rather than adipose tissue of flies, we were able to create flies with all the hallmarks of mammalian obesity: greater attraction to food cues, increased food intake, and increased weight. Like the Leptin-NPY system in mammals, we found behavior-relevant domeless receptors are located on npf neurons with targeted receptor knockdown specifically to these cells replicating increased weight, attraction and intake phenotypes.   In vivo 2-photon imaging demonstrates upd1 acts as the homeostatic regulator of the npf food odor value signal, inhibiting npf activity as a function of satiety.


Finding this analogous organization in the fly not only demonstrates conservation of this key signaling pathway, it also provides an approachable means by which to identify previously unknown regulators of this neural circuit in vertebrates. 

It is hoped that going forward this work will be foundational to the development of new therapeutics for obesity treatment.