[R35] Mechanisms of Gut-Brain Communication Underlying Behavioral State Transitions

Ente: National Institute of General Medical Sciences

Scadenza: 2031-01-31

Importo max: 435.829 EUR

Paese: US

Descrizione

5. ABSTRACT The Alkema lab investigates how internal states and environmental cues are integrated to regulate behavior. We are particularly interested in how animals prioritize competing drives and how these behavioral choices are shaped by signals from both the nervous system and the intestine. We use C. elegans as a model because it offers a uniquely powerful combination of a defined neural circuit, robust genetic tools, optical transparency, and a simple gut-brain axis. Our work examines how the nervous system sustains stable behavioral states like foraging, while preserving the flexibility to switch rapidly into high-arousal states like escape in response to threat. We have shown that tyramine, the invertebrate analog of adrenaline, coordinates the independent motor programs of the flight response. While tyramine drives escape and arousal responses, serotonin promotes feeding and the exploitation of food resources. We are testing the hypothesis that these two neuromodulators interact through mutual inhibition, forming a dynamic switch that prioritizes behavior based on internal state and environmental context. A second major question we address is how the nervous system regulates gut physiology. We find that tyramine and serotonin produce strikingly different patterns of intestinal calcium dynamics. We are using these differences to uncover molecular mechanisms of how the nervous system modulates gut function and internal states. We have developed tools to track behavior and intestinal calcium dynamics in real time, enabling us to investigate how neural, genetic, and microbial factors regulate gut activity. We have identified novel mutants that disrupt intestinal calcium rhythms, implicating metabolic signals as key regulators of gut-brain communication. Finally, we are working to define how physiological states, such as hunger, satiety and stress, are encoded in the gut and how gut-derived signals, in turn, influence brain function. Our findings support the view that the intestine acts as a neuroendocrine organ, integrating neural, metabolic, and microbial cues to regulate the release of gut-derived peptides, including insulin-like and neuropeptides. By combining behavioral assays, genetics, metabolomics, and in vivo imaging, our lab aims to uncover molecular mechanisms by which the gut and brain coordinate internal state and adaptive behavior. Understanding how internal and behavioral states are generated and modulated is essential for defining the general principles of gut-brain communication. This research will illuminate how neuromodulatory, metabolic, and intestinal signals are integrated to shape adaptive behavior. Given the evolutionary conservation of these pathways, discoveries in C. elegans may reveal novel and broadly relevant mechanisms of brain-gut signaling that are important for human mental and physiological health. Istituzione: UNIV OF MASSACHUSETTS MED SCH WORCESTER PI: Mark Alkema Progetto: 1R35GM164099-01

Settori: National Institute of General Medical Sciences

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