Tuesday, January 14, 2025
1/14/2025
Project Summary/Abstract Feeding is an essential behavior for animals to obtain nutrients for survival, but the influx of nutrients during and after feeding must be properly managed to avoid disruption of metabolic homeostasis. Neural circuits in the brain utilize sensory cues associated with food consumption, such as the taste of food and the amount of ingested food in the digestive tract, to prime endocrine systems for incoming nutrients and regulate feeding pace and amount. Although progress has been made in recent years to identify neural populations that regulate endocrine function and feeding behavior, the complete neural circuits that transform food sensory signals into endocrine regulation and feeding behavioral control are largely obscure. The long-term goal of the proposed research is to elucidate the complete neural circuits that carry out such sensory-endocrine/feeding transformations, and obtain a comprehensive circuit-level understanding of endocrine and feeding regulation and its function in health and disease. To achieve this goal, the fruit fly, Drosophila melanogaster, is used as a model system. Drosophila has long been a valuable model for neural circuit studies, providing insights into common principles for chemosensory processing and feeding regulation that are shared with mammals. The recent completion of an electron microscope connectome of the entire Drosophila brain at synaptic resolution provides an unprecedented opportunity to delineate complete neural circuits linking food sensory detection to endocrine and feeding control. Guided by our connectomic analyses, this proposal aims to test the central hypothesis that a subset of serotonergic neurons in the Drosophila brain integrates both external and internal food sensory signals to regulate endocrine function and the feeding motor program. Aim 1 will use state-of-the- art optogenetic and functional imaging approaches to test the hypothesis that serotonergic neurons integrate food-related gustatory and mechanosensory signals from multiple organs, including external and internal mouthparts and the digestive tract. Aim 2 will test the hypothesis that serotonergic neurons activate two parallel output pathways to (a) regulate endocrine function to promote sugar metabolism and digestive function, and (b) inhibit the feeding motor program to suppress food intake, using a combination of calcium imaging, optogenetic, metabolic, and behavioral approaches. These studies will reveal a complete neural circuit from food sensory inputs to endocrine/motor outputs, and provide mechanistic insights into the sensory integration of external chemosensation and gut interoception, gut-brain-endocrine interactions, and feeding behavior regulation. The findings from this research will advance our understanding of how neural circuits regulate feeding behavior and feeding-related endocrine function, providing a foundation for examining how compromised function of these circuits may contribute to endocrine dysfunction, eating disorders, and obesity.
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