Central amygdala micro-circuits mediate fear extinction

Nigel Whittle,Andreas Lüthi,Jonathan Fadok,Christian Müller,Paolo Botta,Kathryn P Macpherson,Robin Nguyen,Steffen B E Wolff,Andrew Holmes,Philip Tovote,Stéphane Ciocchi,Cyril Herry,Nicolas Singewald

doi:10.1038/s41467-021-24068-x

Abstract

Fear extinction is an adaptive process whereby defensive responses are attenuated following repeated experience of prior fear-related stimuli without harm. The formation of extinction memories involves interactions between various corticolimbic structures, resulting in reduced central amygdala (CEA) output. Recent studies show, however, the CEA is not merely an output relay of fear responses but contains multiple neuronal subpopulations that interact to calibrate levels of fear responding. Here, by integrating behavioural, in vivo electrophysiological, anatomical and optogenetic approaches in mice we demonstrate that fear extinction produces reversible, stimulus- and context-specific changes in neuronal responses to conditioned stimuli in functionally and genetically defined cell types in the lateral (CEl) and medial (CEm) CEA. Moreover, we show these alterations are absent when extinction is deficient and that selective silencing of protein kinase C delta-expressing (PKCδ) CEl neurons impairs fear extinction. Our findings identify CEA inhibitory microcircuits that act as critical elements within the brain networks mediating fear extinction.

Highlights

Fear extinction is an adaptive process whereby defensive responses are attenuated following repeated experience of prior fear-related stimuli without harm
Neuronal correlates of fear extinction in subpopulations of central amygdala (CEA) neurons
Fear conditioning-related changes in the CS responses of all three neuronal subpopulations were reversed following fear extinction, i.e., elevated CS-related activity in CEm and CElon neurons was attenuated and the inhibited CS-related activity of CEloff neurons was diminished (Fig. 1c–e). These data suggest that changes in CS-related phasic activity within the CEA inhibitory microcircuits signal the extinction of fear responses

Summary

Introduction

Fear extinction is an adaptive process whereby defensive responses are attenuated following repeated experience of prior fear-related stimuli without harm. The CEA is not merely an output relay of fear responses but contains multiple neuronal subpopulations that interact to calibrate levels of fear responding. By integrating behavioural, in vivo electrophysiological, anatomical and optogenetic approaches in mice we demonstrate that fear extinction produces reversible, stimulus- and context-specific changes in neuronal responses to conditioned stimuli in functionally and genetically defined cell types in the lateral (CEl) and medial (CEm) CEA. We show these alterations are absent when extinction is deficient and that selective silencing of protein kinase C delta-expressing (PKCδ) CEl neurons impairs fear extinction. The activity of CEm output neurons is thought to be controlled by excitatory glutamatergic afferents from auditory thalamus and the basal amygdala (BA)[19]

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