Chemogenetic stimulation of the infralimbic cortex reverses alcohol-induced fear memory overgeneralization

M J Scarlata,I Soler,A L Mousley,G I Coste,A J Ng,A J Hiller,H C Bergstrom,S E Kandigian,K Lawson,Z Wang,J G Dishart,S H Lee,D Lee,G E Mintz,J L Bezek

doi:10.1038/s41598-019-43159-w

Abstract

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are often comorbid. Drinking tends to increase following trauma, which may exacerbate PTSD-related symptoms. Despite a clear relationship between excessive alcohol use and PTSD, how alcohol impacts the expression of traumatic fear remains unclear. This study aims to determine the neurobehavioral impact of chronic alcohol (ethanol; EtOH) on the expression of established fear memories in C57BL/6 N mice. We show that chronic EtOH selectively augments cued fear memory generalization and impairs fear extinction retrieval, leaving the expression of the original cued response intact. Immunohistochemistry for Arc/arg3.1 (Arc) revealed EtOH-induced decreases in Arc expression in the infralimbic cortex (IL) and basolateral amygdala complex (BLA) that were associated with cued fear memory overgeneralization. Chemogenetic stimulation of IL pyramidal neurons reversed EtOH-driven fear memory overgeneralization, identifying a role for the IL in cued fear memory precision. Considering the modulatory influence of the IL over conditioned fear expression, these data suggest a model whereby chronic EtOH-driven neuroadaptations in the IL promote fear memory overgeneralization. These findings provide new mechanistic insight into how excessive alcohol use, following exposure to a traumatic event, can exacerbate symptoms of traumatic fear.

Highlights

In those that develop post-traumatic stress disorder (PTSD), there is greater risk of developing an alcohol use disorder (AUD)[1,2]
We report that chronic EtOH exposure following cued fear conditioning selectively impacted retrieval performance
EtOH-induced fear memory overgeneralization was associated with a reduction in Arc/arg3.1 expression in the shallow layers of the infralimbic cortex (IL), BA, and CeA

Summary

Introduction

In those that develop post-traumatic stress disorder (PTSD), there is greater risk of developing an alcohol use disorder (AUD)[1,2]. Rodent models are advantageous for studying directional interactions between alcohol (ethanol; EtOH) and fear conditioning because EtOH can be precisely delivered, timed, and isolated to a circumscribed learning and memory phase. In most prior studies modeling the relationship between chronic EtOH exposure and fear conditioning, EtOH exposure was timed prior to learning. These studies tested the effects of EtOH on both learning and retrieval. This study aims to investigate the neurobehavioral impact of chronic EtOH on the expression of previously established fear and extinction memories in C57BL/6 N mice. Chronic EtOH exposure was isolated to a temporal window following the consolidation of auditory cued fear conditioning or extinction. To determine whether modulating mPFC signaling normalizes EtOH-induced changes in fear memory expression, a Gq-coupled, cell-type selective, Designer Receptors Exclusively Activated by Designer Drug (DREADD) system was used to excite principal neurons (CaMKIIa-hM3D-Gq) in the IL during cued fear memory retrieval

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