Integration of circadian and homeostatic signals in a peptidergic circuit in Drosophila

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There is rapidly accumulating evidence that disruptions of circadian patterns of sleep, activity and feeding lead to deleterious health consequences. While circadian clock mechanisms are well-studied, the relationship between time-of-day cues and homeostatic drives such as hunger are poorly understood. The integration of circadian information with nutritional cues occurs downstream of the core clock cells in the brain at the intersection of multiple behavioral circuits. This proposal exploits the Drosophila melanogaster genetic model to examine the mechanism by which circadian signals integrate with feeding circuitry to coordinate locomotor rhythms with feeding behavior. The Drosophila pars intercerebralis (PI), an analog of the mammalian hypothalamus, is a peptidergic center that receives both time-of-day and nutritional state information. Based on published and preliminary findings, I propose that the PI receives excitatory input from core clock neurons via neuropeptide signals, as well as inhibitory inputs from cholinergic Hugin-producing gustatory interneurons. I hypothesize that each of the peptidergic PI populations (DH44+, insulin-like peptide producing, SIFamide+ and Taotie) receives a unique set of inputs, which must then be integrated within the PI to coordinate behavioral outputs, and that this integration occurs via intra-PI paracrine neuropeptide signaling. Thus, PI populations likely modulate both rest:activity rhythms and feeding behavior depending on nutritional state to allow responses to acute environmental cues. In the mentored phase of this project I will characterize the connectivity from the central brain clock (Aim 1) and the hugin+ gustatory interneurons (Aim 2) to the PI and examine how each of these circuits modulates feeding and rest:activity behavior (Aims 1 and 2). In the independent phase of this project I will use skills gained in the mentored phase to investigate how starvation overrides clock control of PI neuron physiology and behavior (Aim 3) and the role of intra-PI connectivity in coordinating locomotor rhythms and feeding behavior (Aim 4). To pursue these aims I will use a combination of genetic tools including RNAi and CRISPR, physiological assays including electrophysiology and calcium imaging, and behavioral assays for locomotor rhythms and feeding. Successful completion of this project will offer important advances at both the level of neural circuitry and behavior. First, it will begin to elucidate how intersecting circuits communicate using neuromodulatory peptides. Neuromodulatory signaling has proven difficult to study in mammalian systems, and this work can offer insights that will be applicable to studies of neuropeptidergic regions in mammals, particularly in the hypothalamus. Second, it will advance understanding of the complex interplay of circadian rhythms and feeding both at the circuit and behavioral levels. Understanding not only how circuitry shapes behavior, but how behavior such as altered feeding patterns feeds back to the brain is important for developing interventions to improve human health.