Acid-sensing ion channel 1a regulates the specificity of reconsolidation of conditioned threat responses.

Erin E Koffman,Jianyang Du,Kritika Singh,Charles M Kruse,Jennifer Egbo,Mark Houdi,Jacek Debiec,Melissa A Curtis,Hui Lu,Boren Lin,Farzaneh Sadat Naghavi

doi:10.1172/jci.insight.155341

Abstract

Recent research on altering threat memory has focused on a reconsolidation window. During reconsolidation, threat memories are retrieved and become labile. Reconsolidation of distinct threat memories is synapse dependent, whereas the underlying regulatory mechanism of the specificity of reconsolidation is poorly understood. We designed a unique behavioral paradigm in which a distinct threat memory can be retrieved through the associated conditioned stimulus. In addition, we proposed a regulatory mechanism by which the activation of acid-sensing ion channels (ASICs) strengthens the distinct memory trace associated with the memory reconsolidation to determine its specificity. The activation of ASICs by CO2 inhalation, when paired with memory retrieval, triggers the reactivation of the distinct memory trace, resulting in greater memory lability. ASICs potentiate the memory trace by altering the amygdala-dependent synaptic transmission and plasticity at selectively targeted synapses. Our results suggest that inhaling CO2 during the retrieval event increases the lability of a threat memory through a synapse-specific reconsolidation process.

Highlights

Threat memory research in both rodents and humans has focused on a reconsolidation window after threat memory retrieval, in which the memory is labile and subject to intervention [1,2,3,4]
CO2 selectively enhances the lability of auditory threat memory in the amygdala
We evaluated the outputs of the threat conditioning through the percentage of the freezing time within the time of conditioned stimulus (CS)

Summary

Introduction

Threat memory research in both rodents and humans has focused on a reconsolidation window after threat memory retrieval, in which the memory is labile and subject to intervention [1,2,3,4]. Studies using rodent models have indicated that pharmacological intervention within the reconsolidation window successfully erases the retrieved specific threat memory [5,6,7]. Enhancing a memory trace associated with threat conditioning increases the efficiency of memory retrieval, resulting in more efficient memory erasure after an extinction procedure is carried out. These prior discoveries led us to ask the following questions: Do the initial threat conditioning and retrieval events induce the same synapse, or do they induce separate synapses that share similar characteristics? These prior discoveries led us to ask the following questions: Do the initial threat conditioning and retrieval events induce the same synapse, or do they induce separate synapses that share similar characteristics? is there a mechanism that allows us to manipulate reconsolidation more efficiently?

Methods

Results

Conclusion