The amygdala instructs insular feedback for affective learning.

Affective responses depend on assigning value to environmental predictors of threat or reward. Neuroanatomically, this affective value is encoded at both cortical and subcortical levels. However, the purpose of this distributed representation across functional hierarchies remains unclear. Using fMRI in mice, we mapped a discrete cortico-limbic loop between insular cortex (IC), central amygdala (CE), and nucleus basalis of Meynert (NBM), which decomposes the affective value of a conditioned stimulus (CS) into its salience and valence components. In IC, learning integrated unconditioned stimulus (US)-evoked bodily states into CS valence. In turn, CS salience in the CE recruited these CS representations bottom-up via the cholinergic NBM. This way, the CE incorporated interoceptive feedback from IC to improve discrimination of CS valence. Consequently, opto-/chemogenetic uncoupling of hierarchical information flow disrupted affective learning and conditioned responding. Dysfunctional interactions in the IC↔CE/NBM network may underlie intolerance to uncertainty, observed in autism and related psychiatric conditions.