Intercalated amygdala clusters orchestrate a switch in fear state

Kenta M. Hagihara, Olena Bukalo, Martin Zeller, Ayla Aksoy-Aksel, Nikolaos Karalis, Aaron Limoges, Tanner Rigg, Tiffany Campbell, Adriana Mendez, Chase Weinholtz, Mathias Mahn, Larry S. Zweifel, Richard D. Palmiter, Ingrid Ehrlich, Andreas Lüthi () and Andrew Holmes ()
Additional contact information
Kenta M. Hagihara: Friedrich Miescher Institute for Biomedical Research
Olena Bukalo: National Institute on Alcohol Abuse and Alcoholism, NIH
Martin Zeller: Hertie Institute for Clinical Brain Research
Ayla Aksoy-Aksel: Hertie Institute for Clinical Brain Research
Nikolaos Karalis: Friedrich Miescher Institute for Biomedical Research
Aaron Limoges: National Institute on Alcohol Abuse and Alcoholism, NIH
Tanner Rigg: National Institute on Alcohol Abuse and Alcoholism, NIH
Tiffany Campbell: National Institute on Alcohol Abuse and Alcoholism, NIH
Adriana Mendez: National Institute on Alcohol Abuse and Alcoholism, NIH
Chase Weinholtz: National Institute on Alcohol Abuse and Alcoholism, NIH
Mathias Mahn: Friedrich Miescher Institute for Biomedical Research
Larry S. Zweifel: University of Washington
Richard D. Palmiter: University of Washington
Ingrid Ehrlich: Hertie Institute for Clinical Brain Research
Andreas Lüthi: Friedrich Miescher Institute for Biomedical Research
Andrew Holmes: National Institute on Alcohol Abuse and Alcoholism, NIH

Nature, 2021, vol. 594, issue 7863, 403-407

Abstract: Abstract 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 of the 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.

Date: 2021
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DOI: 10.1038/s41586-021-03593-1

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