Research Interest

Specific Aims

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Animals maintain homeostasis by integrating physiological signals arising from the gut, circulatory system, and immune system with central brain function. The central hypothesis of this project is that vagus-like neural circuits in Drosophila relay gut hormone signals, microbiota-derived metabolites, cardiovascular inputs, and inflammation-associated cues to the brain, thereby regulating growth, metabolism, sleep, feeding, hypoxia adaptation, and immune homeostasis. During the first five years, this project will focus exclusively on Drosophila and systematically dissect these multiorgan interactions through HCG-centered vagus-like neurons. Specifically, we will determine how gut-derived endocrine and microbial signals shape brain circuits and behavior, how brain–cardiovascular communication regulates cardiac physiology and hypoxia responses, and how inflammatory and ROS-related signals are transmitted through gut–brain pathways to control immune and behavioral homeostasis. These studies will establish the conceptual and technical foundation for later extension into mammalian systems.

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Aim 1. Define how gut hormones and microbiota-derived signals engage vagus-like neurons to regulate brain circuits, growth, metabolism, and behavior in Drosophila.

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This aim will determine how vagus-like neurons in Drosophila, particularly specific subpopulations within the hypocerebral ganglion (HCG), detect gut-derived endocrine and microbial signals and relay them to the brain. Preliminary data indicate that under protein deprivation, gut enterocyte-derived CNMa acts through CNMa receptor-expressing sNPF+ HCG neurons to drive essential amino acid preference. In addition, multiple receptors for gut-derived peptides, including CCHa1, CCHa2, Dh31, Tachykinin, AstA, and AstC, are enriched in these vagus-like neurons. The proposal also suggests that microbiota-derived GABA and other secondary metabolites may modulate sleep and feeding behavior through the same pathway. Therefore, this aim will: (1) define the vagus-like gut-to-brain circuits that transmit CNMa and other gut hormone signals; (2) determine how microbiota-derived GABA and related metabolites alter brain activity, sleep, and feeding through these neurons; and (3) functionally subdivide HCG neurons based on receptor expression and circuit connectivity to generate a comprehensive vagus-like neuron-to-brain connectivity map. Together, these studies will reveal how internal gut states are translated into growth, metabolic, feeding, and sleep-related neural outputs.

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Aim 2. Determine how vagus-mediated brain–cardiovascular communication controls cardiac physiology and hypoxia responses in Drosophila.

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This aim will define how vagus-like brain–cardiovascular circuits regulate cardiac function and adaptive responses to hypoxia in Drosophila. The research plan cites prior identification of aorta sensory neurons in larvae that convey aortic information to the brain, suggesting the existence of a dedicated brain–cardiovascular sensory pathway. In addition, the team has established preliminary feasibility for measuring heartbeat and hemolymph flow in adult flies using high-resolution ultrasound imaging. The proposal further notes that hypoxia exposure induces immune activation, sleep suppression, and increased locomotor activity, consistent with rapid functional communication between the cardiovascular system and the brain. Accordingly, this aim will: (1) establish a platform for long-term real-time measurement of heartbeat and circulation in living adult flies; (2) determine how aging, nutritional state, and microbiota composition influence cardiovascular decline; and (3) define how brain–cardiovascular neural pathways mediate cardiac, locomotor, and sleep responses under hypoxic conditions. These studies will provide a mechanistic framework for understanding how cardiovascular sensory states are integrated into adaptive behavioral and homeostatic responses.

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Aim 3. Elucidate how inflammation- and ROS-associated signals are relayed through vagus-like gut–brain pathways to regulate immune and behavioral homeostasis in Drosophila.

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This aim will investigate how inflammation-related and oxidative stress-associated signals generated in the gut and peripheral tissues are transmitted through vagus-like pathways to the brain, where they influence immune and behavioral homeostasis. The research plan proposes that pathogen infection and tissue damage may induce distinct gut endocrine outputs, some of which may act through vagus-like neurons to modulate brain function. It also highlights the importance of innate immune signaling pathways, including Toll and NF-κB-related components, in coordinating organismal responses to internal challenge. Based on this framework, this aim will: (1) define gut hormone secretion patterns induced by pathogen infection or tissue injury; (2) identify the vagus-like neuronal populations that express the corresponding receptors and map the resulting inflammation-to-brain signaling circuits; and (3) determine how these pathways regulate immune activation, ROS-related physiological responses, and associated behavioral adaptations. These studies will establish fundamental principles by which inflammatory signals from the gut and peripheral organs are integrated into brain-directed homeostatic control.