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Adaptive behaviour necessitates the formation of memories for fearful events, but also that these memories can be extinguished. Effective extinction prevents excessive and persistent reactions to perceived threat, as can occur in anxiety and 'trauma- and stressor-related' disorders1. However, although there is evidence that fear learning and extinction are mediated by distinct neural circuits, the nature ofthe interaction between these circuits remains poorly understood2-6. Here, through a combination of in vivo calcium imaging, functional manipulations, and slice physiology, we show that distinct inhibitory clusters of intercalated neurons (ITCs) in the mouse amygdala exert diametrically opposed roles during the acquisition and retrieval of fear extinction memory. Furthermore, we find that the ITC clusters antagonize one another through mutual synaptic inhibition and differentially access functionally distinct cortical- and midbrain-projecting amygdala output pathways. Our findings show that the balance of activity between ITC clusters represents a unique regulatory motif that orchestrates a distributed neural circuitry, which in turn regulates the switch between high- and low-fear states. These findings suggest that the ITCs have a broader role in a range of amygdala functions and associated brain states that underpins the capacity to adapt to salient environmental demands.
Animals are equipped with biological systems to detect and defend against environmental threats. Through associative learning, stimuli that predict threat mobilize defensive responses to mitigate harm7. When threat-associated stimuli become innocuous, these responses adapt through the process of extinction, whereby a new memory is formed that coexists in opposition to the original fear memory4,8,9. Specialized neural systems have evolved to subserve fear and extinction; when imbalanced, these systems can cause persistent reactions to threat.
ITC clusters are densely packed y-aminobutyric acid-releasing (GABAergic) neurons that surround the basolateral amygdala (BLA), and can be distinguished from neighbouring neurons by their electrophysiological and molecular properties10-13. The medial ITC clusters, in the intermediate capsule at the BLA-central amygdala (CeA) junction, receive input from the BLA and modulate CeA activity through feedforward inhibition2,14 in a manner that is potentiated by extinction15. Although medial ITC ablation impairs extinction16, recent studies suggest that medial ITC clusters are functionally10 and anatomically1718 heterogeneous. However, given their small size and location deep in the brain, it has proven difficult to elucidate the functions of these clusters.
ITC clusters signal an aversive...