Fear extinction requires infralimbic cortex projections to the basolateral amygdala

Daniel W Bloodgood,Jonathan A Sugam,Thomas L Kash,Andrew Holmes

doi:10.1038/s41398-018-0106-x

Abstract

Fear extinction involves the formation of a new memory trace that attenuates fear responses to a conditioned aversive memory, and extinction impairments are implicated in trauma- and stress-related disorders. Previous studies in rodents have found that the infralimbic prefrontal cortex (IL) and its glutamatergic projections to the basolateral amygdala (BLA) and basomedial amygdala (BMA) instruct the formation of fear extinction memories. However, it is unclear whether these pathways are exclusively involved in extinction, or whether other major targets of the IL, such as the nucleus accumbens (NAc) also play a role. To address this outstanding issue, the current study employed a combination of electrophysiological and chemogenetic approaches in mice to interrogate the role of IL-BLA and IL-NAc pathways in extinction. Specifically, we used patch-clamp electrophysiology coupled with retrograde tracing to examine changes in neuronal activity of the IL and prelimbic cortex (PL) projections to both the BLA and NAc following fear extinction. We found that extinction produced a significant increase in the intrinsic excitability of IL-BLA projection neurons, while extinction appeared to reverse fear-induced changes in IL-NAc projection neurons. To establish a causal counterpart to these observations, we then used a pathway-specific Designer Receptors Exclusively Activated by Designer Drugs (DREADD) strategy to selectively inhibit PFC-BLA projection neurons during extinction acquisition. Using this approach, we found that DREADD-mediated inhibition of PFC-BLA neurons during extinction acquisition impaired subsequent extinction retrieval. Taken together, our findings provide further evidence for a critical contribution of the IL-BLA neural circuit to fear extinction.

Highlights

Fear extinction, a process by which learned fear responses are reduced through new inhibitory learning, has emerged as a translationally valuable assay for studying anxiety and trauma-related disorders[1,2,3]
It remains unclear whether infralimbic prefrontal cortex (IL) projections to the nucleus accumbens (NAc) mediate extinction given reports that functional manipulations in the NAc, including dopamine D2 receptor blockade[14] and virally driven activation of the transcription factor cAMP response element binding protein (CREB)[15], can produce significant deficits in fear extinction
The current results substantiate much of the findings of earlier studies that establish a critical contribution of the IL to fear extinction

Summary

Introduction

A process by which learned fear responses are reduced through new inhibitory learning, has emerged as a translationally valuable assay for studying anxiety and trauma-related disorders[1,2,3]. Recent studies in mice have shown that neuronal outputs from the ventromedial PFC (vmPFC), containing the infralimbic cortex (IL) region, to the basolateral (BLA)[7,8,9] and basomedial (BMA)[10], as well as reciprocal connections from BLA to IL11,12 and projections from BLA to NAc13, are important for extinction. While these data suggest IL-BLA projection neurons represent a critical circuit for extinction, they require substantiation using alternative approaches. It remains unclear whether IL projections to the nucleus accumbens (NAc) mediate extinction given reports that functional manipulations in the NAc, including dopamine D2 receptor blockade[14] and virally driven activation of the transcription factor cAMP response element binding protein (CREB)[15], can produce significant deficits in fear extinction

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