UC Merced

The role of homeostatic hormones in the control of ingestive behaviors is well established, however the understanding of how cortical and subcortical reward systems (like the dopaminergic reward pathways) integrate with hormonal signals and other brain regions to regulate motivational seeking is incomplete. To better understand the neuronal circuitry underlying the neurobiology of obesity and motivation, it is essential to address the pre-ingestive phase of motivated homeostatic seeking behavior, when individuals are actively seeking reward.

To understand the fundamental neural processes underlying basic behaviors, like food, water, and drug seeking, it is critical to evaluate the potential interactions between common and diverse neural substrates known to mediate complex behaviors, like food and drug addiction. In the first part of this dissertation (chapter 1) I review distinct and overlapping neural motifs underlying motivated food and drug-related behaviors in Drosophila melanogaster to better understand the circuit logic underlying motivational survival behavior hierarchies (hunger, thirst, fear avoidance, sleep, copulation).

In the second part of this dissertation (chapter 2), I provide evidence that dopaminergic wiring within the fly brain is necessary and sufficient to promote food-seeking behavior in a satiation-state dependent manner. Here, we use sophisticated genetic tools to reversibly activate and inactivate neuronal ensembles and have categorized the function of discrete dopaminergic clusters of neurons. I demonstrate their ability to promote or inhibit pre-ingestive food seeking behaviors by using a novel food seeking assay. More importantly, we show that expression of the D1 receptor, DopR, is necessary in the mushroom bodies to promote food seeking in starved animals.

In the final part of this dissertation (chapter 3) I show that a persistent state of thirst is evoked by the precise activation of six central brain neurons in adult Drosophila. In a neuronal activation screen, we identified a subset of GABA and AstA-expressing neurons that evoke robust thirst-related behaviors, including water seeking and intake; we named these neurons Janu, the Estonian for thirsty. These central brain neurons function downstream of sensory input and internal osmotic sensors to drive seeking to either open or inaccessible water. Importantly, activation of Janu neurons overrides food seeking in water replete but hungry flies. We also identified neuropeptide F receptor (NPFR)-expressing neurons that appear to function as a water seeking homeostat. Neurons expressing NPFR, the invertebrate homolog of the NPY receptor, also promote insatiable hunger and voracious feeding. Like Janu neurons but independent of them, activation of NPFR neurons overrides food seeking in water replete but hungry flies. Thus, neural circuit elements that regulate hunger and thirst are tightly integrated. These studies provide an entry point for mapping the fundamental homeostatic thirst neurons and the hierarchical wiring of neural circuits that encode opposing motivational states.