Cellular and Circuit Mechanisms of Neuropeptide Signaling

Project Summary The overall goal of NIGMS-funded research in my lab is to understand the cellular and circuit mechanisms by which neuropeptide signaling influences the neural circuits that control behavior. Neuropeptides are the most common signaling molecule in the central nervous system and among the best markers for cell types in the brain. These endogenous peptides transmit messages within the brain and across the body to control vital physiologic processes like energy homeostasis, as well as motivational and emotional states including sleep, arousal, pain, stress, and mood. Dysregulation of peptidergic signaling is implicated in medical conditions ranging from obesity to psychiatric disorders. A vast scientific literature has investigated the role of neuropeptides in physiology and behavior over decades, yet even for many well-studied circuits, their functional significance is still an open question. Because they are not restricted spatially by the anatomical wiring diagram nor temporally by rapid re-uptake or degradation, delineating the precise connectivity of neuropeptide circuits in whole animals has proved challenging. My lab seeks to address this gap by developing novel methods to monitor and selectively manipulate neuropeptide signaling in living animals, and to identify the fundamental enzymes that regulate neuropeptide communication. We employ advanced imaging, genetic, and biochemical approaches to investigate these questions using both worm and mouse model systems from the subcellular level all the way to behavioral output. Our goal is to understand the biochemical logic of circuit neuromodulation by neuropeptides with the same clarity that we understand fast neurotransmission at synapses. This research will provide fundamental new insight into longstanding questions about the spatial and temporal organization of neuropeptide signaling and lead to an understanding of how long-term changes are affected in the nervous system that result in different behaviors. As neuropeptides and their receptors are druggable targets implicated in a wide-range of diseases, we anticipate that mechanistic insight into their signaling is likely to have broad clinical relevance for diseases characterized by behavioral dysfunction.