Uncertainty-Dependent Extinction of Fear Memory in an Amygdala-mPFC Neural Circuit Model.

Yuzhe Li,Shin Ishii,Honda Naoki,Ken Nakae

doi:10.1371/journal.pcbi.1005099

Abstract

Uncertainty of fear conditioning is crucial for the acquisition and extinction of fear memory. Fear memory acquired through partial pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) is more resistant to extinction than that acquired through full pairings; this effect is known as the partial reinforcement extinction effect (PREE). Although the PREE has been explained by psychological theories, the neural mechanisms underlying the PREE remain largely unclear. Here, we developed a neural circuit model based on three distinct types of neurons (fear, persistent and extinction neurons) in the amygdala and medial prefrontal cortex (mPFC). In the model, the fear, persistent and extinction neurons encode predictions of net severity, of unconditioned stimulus (US) intensity, and of net safety, respectively. Our simulation successfully reproduces the PREE. We revealed that unpredictability of the US during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE. In addition, we extended the model to include amygdala subregions and the mPFC to address a recent finding that the ventral mPFC (vmPFC) is required for consolidating extinction memory but not for memory retrieval. Furthermore, model simulations led us to propose a novel procedure to enhance extinction learning through re-conditioning with a stronger US; strengthened fear memory up-regulates the extinction neuron, which, in turn, further inhibits the fear neuron during re-extinction. Thus, our models increased the understanding of the functional roles of the amygdala and vmPFC in the processing of uncertainty in fear conditioning and extinction.

Highlights

The associative memories acquired through both appetitive and aversive conditioning with uncertainty have been shown to exhibit substantial resistance to extinction, known as the “partial reinforcement extinction effect (PREE)” [1,2,3]
We revealed that unpredictability of the unconditioned stimulus (US) during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE
We considered a neural circuit consisting of nuclei in the amygdala and medial prefrontal cortex (mPFC); in this model, the LA, central nuclei of the amygdala (CEA) and ventral subdivision of the mPFC (vmPFC) were represented by the persistent, fear, and extinction neural units, respectively

Summary

Introduction

The associative memories acquired through both appetitive and aversive conditioning with uncertainty have been shown to exhibit substantial resistance to extinction, known as the “partial reinforcement extinction effect (PREE)” [1,2,3]. The fear memory acquired through a fear conditioning procedure in which the CS is probabilistically paired with the US (partial reinforcement) is more resistant to extinction than the fear memory acquired after full pairings of the CS and US (full reinforcement) (Fig 1A–1C) This initially sounds paradoxical because one may assume that the causal relationship between the CS and US is strong and weak in the cases of full and partial reinforcement, respectively [4]. The ventral subdivision of the mPFC (vmPFC), called the infralimbic cortex (IL) in rodents and the ventral mPFC in primates [16], plays an important role in the extinction of fear memory [17,18,19] Both the amygdala and mPFC function during partial reinforcement fear conditioning [20,21,22,23,24,25], their roles in the PREE have rarely been examined [26]. How the amygdala and mPFC are coordinated for the PREE remains elusive

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