A lateralized pathway for associating nutrients with flavors

Grove, J. C. R.; Li, Q.; Backes, H.; Kuzmanovic, B.; Choi, J.; Ubadiah, V.; Qiu, L.; Zhang, J.; Liu, Z.; Small, D. M.; Tittgemeyer, M.; Knight, Z. A.

doi:10.1101/2025.02.09.637334

bioRxiv · 10.1101/2025.02.09.637334

A lateralized pathway for associating nutrients with flavors

Grove, J. C. R.·Li, Q.·Backes, H.·Kuzmanovic, B.·Choi, J.·Ubadiah, V.·Qiu, L.·Zhang, J.·Liu, Z.·Small, D. M.·Tittgemeyer, M.·Knight, Z. A.

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Abstract

Animals learn about the external world, in part, via interoceptive signals1,2. For example, the nutrient content of food is first estimated in the mouth, in the form of flavor, and then measured again via slower signals from the gut. How these signals from the mouth and gut are integrated to drive learning is unknown. Here we identify a lateralized dopamine pathway that is specialized for learning about the nutrient content of food. We show that dopamine neurons in the ventral tegmental area (VTADA) are necessary for associating nutrients with flavors, and that post-ingestive nutrients trigger DA release selectively in a small region of the anterior basolateral amygdala (BLA) but not canonical DA targets in striatum. Remarkably, this nutrient-triggered DA release occurs preferentially on the left side of the brain in both mice and humans, revealing that the DA system is functionally lateralized. We identify the gut sensors that are responsible for nutrient-triggered DA release; show that they activate BLA-projecting DA neurons defined by expression of cholecystokinin (CCK); and demonstrate that stimulation of DA axon terminals in the anterior BLA drives flavor-nutrient learning but not other aspects of feeding behavior. Two-photon imaging of neurons in the left anterior BLA reveals that they integrate gustatory and post-ingestive cues, and silencing these neurons prevents flavor-nutrient learning. These findings establish a neural basis for how animals learn about the nutrient content of their food. They also reveal unexpectedly that post-ingestive nutrients are differentially represented on the right and left sides of the brain.

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Grove, J. C. R., Li, Q., Backes, H., Kuzmanovic, B., Choi, J., Ubadiah, V., Qiu, L., Zhang, J., Liu, Z., Small, D. M., Tittgemeyer, M., Knight, Z. A.. 2025-02-10. A lateralized pathway for associating nutrients with flavors. https://doi.org/10.1101/2025.02.09.637334

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