A neural mechanism for learning from delayed postingestive feedback

Christopher A. Zimmerman (), Scott S. Bolkan, Alejandro Pan-Vazquez, Bichan Wu, Emma F. Keppler, Jordan B. Meares-Garcia, Eartha Mae Guthman, Robert N. Fetcho, Brenna McMannon, Junuk Lee, Austin T. Hoag, Laura A. Lynch, Sanjeev R. Janarthanan, Juan F. López Luna, Adrian G. Bondy, Annegret L. Falkner, Samuel S.-H. Wang and Ilana B. Witten ()
Additional contact information
Christopher A. Zimmerman: Princeton University
Scott S. Bolkan: Princeton University
Alejandro Pan-Vazquez: Princeton University
Bichan Wu: Princeton University
Emma F. Keppler: Princeton University
Jordan B. Meares-Garcia: Princeton University
Eartha Mae Guthman: Princeton University
Robert N. Fetcho: Princeton University
Brenna McMannon: Princeton University
Junuk Lee: Princeton University
Austin T. Hoag: Princeton University
Laura A. Lynch: Princeton University
Sanjeev R. Janarthanan: Princeton University
Juan F. López Luna: Princeton University
Adrian G. Bondy: Princeton University
Annegret L. Falkner: Princeton University
Samuel S.-H. Wang: Princeton University
Ilana B. Witten: Princeton University

Nature, 2025, vol. 642, issue 8068, 700-709

Abstract: Abstract Animals learn the value of foods on the basis of their postingestive effects and thereby develop aversions to foods that are toxic1–10 and preferences to those that are nutritious11–13. However, it remains unclear how the brain is able to assign credit to flavours experienced during a meal with postingestive feedback signals that can arise after a substantial delay. Here we reveal an unexpected role for the postingestive reactivation of neural flavour representations in this temporal credit-assignment process. To begin, we leverage the fact that mice learn to associate novel14,15, but not familiar, flavours with delayed gastrointestinal malaise signals to investigate how the brain represents flavours that support aversive postingestive learning. Analyses of brain-wide activation patterns reveal that a network of amygdala regions is unique in being preferentially activated by novel flavours across every stage of learning (consumption, delayed malaise and memory retrieval). By combining high-density recordings in the amygdala with optogenetic stimulation of malaise-coding hindbrain neurons, we show that delayed malaise signals selectively reactivate flavour representations in the amygdala from a recent meal. The degree of malaise-driven reactivation of individual neurons predicts the strengthening of flavour responses upon memory retrieval, which in turn leads to stabilization of the population-level representation of the recently consumed flavour. By contrast, flavour representations in the amygdala degrade in the absence of unexpected postingestive consequences. Thus, we demonstrate that postingestive reactivation and plasticity of neural flavour representations may support learning from delayed feedback.

Date: 2025
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DOI: 10.1038/s41586-025-08828-z

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