UC Berkeley

Eating food and drinking water are fundamental requirements for animal survival. Understanding how animal nervous systems regulate these behaviors has been a focus of neuroscience research for over a century. Until recently, however, a lack of experimental tools has made it challenging to identify the molecules and neurons that orchestrate food and water ingestion behaviors. Here, I use the fruit fly Drosophila melanogaster as a model to identify such molecules and neurons. I find that a group of four neurons regulates both food and water ingestion in Drosophila, and that they accomplish this by co-expression of molecules that confer on them sensitivity to internal signals of both hunger and thirst.

In the first part of this dissertation (chapter 2), I describe the discovery of a novel group of neurons in the Drosophila brain, and show that they are regulators of both food and water ingestion. This work is presented in the form of a published co-first author manuscript. Using genetic tools, behavioral assays, and calcium imaging, I show, together with co-authors Brendan Mullaney and Kevin Mann, that these neurons, which we name ISNs (Interoceptive SEZ Neurons), are sensitive both to an internal signal of nutrient deprivation, the glucagon-like peptide adipokinetic hormone (AKH), and an internal signal of water abundance, extracellular osmolality. We further show that this dual sensitivity arises because ISNs co-express a G-protein coupled receptor, the adipokinetic hormone receptor (AKHR), and a conserved TRPV channel, Nanchung (Nan), which act as molecular sensors of AKH and osmolality, respectively. Finally, we show that ISN activity is sufficient to regulate both sugar and water consumption in a manner that promotes homeostasis.

In the second part of this dissertation (chapter 3), I use a combination of behavioral genetics and calcium imaging to characterize neural circuits downstream of ISNs. I show that ISNs likely express and release the peptide dILP-3, an insulin-like peptide, and determine the anatomy of neurons post-synaptic to ISNs. Finally, I use large-scale calcium imaging to characterize how AKH (and, by extension, ISN activity) modulates neural responses to the taste of sugar and water.

In the final part of this dissertation (chapter 4), I place the above results in the context of mammalian studies of food and water ingestion. I argue that understanding how nervous systems regulate the ingestion of food and water will require a deeper understanding of the interactions between neural regulators of these behaviors. This work is presented as a published first author manuscript.