A ventral hippocampus-basolateral amygdala circuit regulates the unconditioned stimulus retrieval-induced reconsolidation of remote fear memory

Abstract

Introduction

Memory is retrieved and updated during reconsolidation, which provides a potential target for therapeutic intervention. Reconsolidation blockade following unconditioned stimulus (US) retrieval has shown increasing promise in disrupting persistent remote fear memory, yet the underlying neural mechanisms remain poorly understood.

Objectives

This study aims to elucidate the neural mechanisms involved in US retrieval-induced reconsolidation of remote fear memory.

Methods

We established a rat model of contextual fear conditioning to investigate recent and remote fear memory with reconsolidation induced by US or conditioned stimulus (CS) retrieval. Pharmacological intervention, retrograde tracing, immunofluorescence, fiber photometry, as well as chemogenetic manipulation were employed to identify and manipulate key circuits involved in reconsolidation of fear memory.

Results

In this study, we show that pharmacological disruption of the US retrieval-induced reconsolidation of fear memory had a relatively long-lasting effect and was also effective for remote fear memory. We further reveal that activity of ventral hippocampal CA1 (vCA1)–basolateral amygdala (BLA) circuit specially contributes to US retrieval-induced reconsolidation of remote fear memory. Specifically, pharmacological interventions and inhibition of this circuit after US retrieval effectively disrupted remote fear memory, which showed long-term efficacy and resistance to reinstatement. Conversely, activating this circuit blocked the disruptive effect of propranolol on the remote fear memory reconsolidation.

Conclusion

Our findings suggest that the vCA1-BLA circuit becomes increasingly important for remote fear memory reconsolidation, particularly induced by US retrieval. This study highlights the potential for targeting specific circuits involved in reconsolidation of remote fear memory for therapeutic interventions in fear-related disorders.