Prefrontal projections to the thalamic nucleus reuniens mediate fear extinction

Karthik R Ramanathan,Martin R Payne,Stephen Maren,Jingji Jin,Thomas F Giustino

doi:10.1038/s41467-018-06970-z

Abstract

The thalamic nucleus reuniens (RE) receives dense projections from the medial prefrontal cortex (mPFC), interconnects the mPFC and hippocampus, and may serve a pivotal role in regulating emotional learning and memory. Here we show that the RE and its mPFC afferents are critical for the extinction of Pavlovian fear memories in rats. Pharmacological inactivation of the RE during extinction learning or retrieval increases freezing to an extinguished conditioned stimulus (CS); renewal of fear outside the extinction context was unaffected. Suppression of fear in the extinction context is associated with an increase in c-fos expression and spike firing in RE neurons to the extinguished CS. The role for the RE in suppressing extinguished fear requires the mPFC, insofar as pharmacogenetically silencing mPFC to RE projections impairs the expression of extinction memory. These results reveal that mPFC-RE circuits inhibit the expression of fear, a function that is essential for adaptive emotional regulation.

Highlights

The thalamic nucleus reuniens (RE) receives dense projections from the medial prefrontal cortex, interconnects the mPFC and hippocampus, and may serve a pivotal role in regulating emotional learning and memory
Because mPFC-HPC circuits have been implicated in contextual processing[2,27], we were interested in whether RE inactivation might influence the context-dependence of the extinction memory
Post-hoc comparisons revealed that CNO-injected animals showed elevated levels of freezing compared to SAL-injected animals during both retrieval (p = 0.031) and renewal (p = 0.011) sessions. These results are consistent with the effects that we previously showed with RE inactivation alone and reveal that projections from the mPFC to the RE are involved in extinction learning

Summary

Introduction

The thalamic nucleus reuniens (RE) receives dense projections from the medial prefrontal cortex (mPFC), interconnects the mPFC and hippocampus, and may serve a pivotal role in regulating emotional learning and memory. Functional disconnection of the vHPC and either the prelimbic (PL) prefrontal cortex or BLA impairs fear renewal[12] These studies support a circuit model in which vHPC projections to the mPFC and BLA facilitate the retrieval of CS-US memories when an extinguished CS is encountered outside the extinction context[12,13]. Using Pavlovian fear conditioning and extinction procedures in rats, we show that pharmacological inactivation of the RE dramatically increases freezing behavior during both the encoding and later retrieval of an extinction memory This pattern of extinction deficits was reproduced by selective pharmacogenetic silencing of mPFC neurons (or their terminals) projecting to the RE Taken together, these data reveal a novel role for the prefrontal-reuniens circuit in the inhibition of fear after extinction. This circuit may function to oppose fear expression after threat has passed

Methods

Results

Conclusion