Persistent activation of central amygdala CRF neurons helps drive the immediate fear extinction deficit

Yong S Jo,Larry S Zweifel,Garret D Stuber,Vijay Mohan K Namboodiri

doi:10.1038/s41467-020-14393-y

Yong S Jo, Larry S Zweifel + Show 2 more

Open Access

https://doi.org/10.1038/s41467-020-14393-y

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Abstract

Fear extinction is an active learning process whereby previously established conditioned responses to a conditioned stimulus are suppressed. Paradoxically, when extinction training is performed immediately following fear acquisition, the extinction memory is weakened. Here, we demonstrate that corticotrophin-releasing factor (CRF)-expressing neurons in the central amygdala (CeA) antagonize the extinction memory following immediate extinction training. CeA-CRF neurons transition from responding to the unconditioned stimulus to the conditioned stimulus during the acquisition of a fear memory that persists during immediate extinction training, but diminishes during delayed extinction training. Inhibition of CeA-CRF neurons during immediate extinction training is sufficient to promote enhanced extinction memories, and activation of these neurons following delay extinction training is sufficient to reinstate a previously extinguished fear memory. These results demonstrate CeA-CRF neurons are an important substrate for the persistence of fear and have broad implications for the neural basis of persistent negative affective behavioral states.

Highlights

Fear extinction is an active learning process whereby previously established conditioned responses to a conditioned stimulus are suppressed
To test whether central amygdala (CeA)–corticotrophin-releasing factor (CRF) neurons contribute to the immediate extinction deficit, we selectively silenced these cells by blocking synaptic transmission through expression of tetanus toxin light chain (TeTx)[13,18]
Impairments in extinction memory recall are dependent on the activity of CeA–CRF neurons and the production of CRF

Summary

Introduction

Fear extinction is an active learning process whereby previously established conditioned responses to a conditioned stimulus are suppressed. CeA-CRF neurons transition from responding to the unconditioned stimulus to the conditioned stimulus during the acquisition of a fear memory that persists during immediate extinction training, but diminishes during delayed extinction training. Inhibition of CeA-CRF neurons during immediate extinction training is sufficient to promote enhanced extinction memories, and activation of these neurons following delay extinction training is sufficient to reinstate a previously extinguished fear memory. CeA–CRF neurons display diminished responsiveness to the CS during delayed fear extinction training and during recall Activation of these neurons during delay extinction is sufficient to induce an extinction deficit and to reinstate a previously extinguished conditioned threat response

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