Dataset Information

A novelty-retrieval-extinction paradigm leads to persistent attenuation of remote fear memories.

ABSTRACT: Exposure to a novel environment can enhance the extinction of recent contextual fear in mice. This has been explained by a tagging and capture hypothesis. Consistently, we show in mice that exposure to a novel environment before extinction training promoted the extinction of recent auditory fear. However, such a promoting effect of novelty was absent for remote memories. In the present study, we replaced the regular extinction training with a retrieval-extinction session which capitalized on a reconsolidation window. When novelty exposure was followed by a retrieval-extinction session, remote fear was distinguished more easily and permanently. We have termed it as a "novelty-retrieval-extinction" paradigm. This paradigm played a greater role in the extinction of remote fear when fear conditioning and retrieval-extinction occurred in two different contexts other than in one identical context. The mechanism underlying the facilitating effect of this paradigm might involve up-regulation of histone acetylation in the hippocampus, which has been reported to increase functional and structural neuroplasticity. The present work proposes an effective, drug-free paradigm for the extinction of remote fear, which could be easily adapted in humans with least side effects.

SUBMITTER: Huang F

PROVIDER: S-EPMC7039928 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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A novelty-retrieval-extinction paradigm leads to persistent attenuation of remote fear memories.

Huang Fulian F Zou Guangjing G Li Can C Meng Hui H Liu Xiaoyan X Yang Zehua Z

Scientific reports 20200224 1

Exposure to a novel environment can enhance the extinction of recent contextual fear in mice. This has been explained by a tagging and capture hypothesis. Consistently, we show in mice that exposure to a novel environment before extinction training promoted the extinction of recent auditory fear. However, such a promoting effect of novelty was absent for remote memories. In the present study, we replaced the regular extinction training with a retrieval-extinction session which capitalized on a r ...[more]

PMID: 32094477

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Project description:Ensembles of principal neurons in the basolateral amygdala (BLA) generate the initial engrams for fear memories, while projections from the BLA to the medial prefrontal cortex (mPFC) are essential for the encoding, transfer and storage of remote fear memories. We tested the effects of chronic pain on remote fear memories in mice. Male mice underwent classic fear conditioning by pairing a single tone (conditional stimulus, CS) with a single electric foot shock (unconditional stimulus, US). Sciatic nerve constriction was used to induce neuropathic pain at various time points before or after the fear conditioning. The mice with sciatic nerve cuffs implanted 48 h after the fear conditioning showed an increased freezing response to CS when compared to mice without cuffs or when compared to mice in which the nerve cuffing was performed 48 h before the fear conditioning. The enhancing effect of pain on consolidated fear memory was further tested and mice in which the nerve cuffing was performed 14 days after the fear conditioning also showed an increased fear response when tested 56 days later. We used immunostaining to detect morphological changes in the BLA that could suggest a mechanism for the observed increase in fear response. We found an increased number of calbindin/parvalbumin positive neurons in the BLA and increased perisomatic density of GAD65 on projection neurons that connect BLA to mPFC in mice with nerve cuffs. Despite the strong increase of c-Fos expression in BLA and mPFC that was induced by fear recall, neither the BLA to mPFC nor the mPFC to BLA projection neurons were activated in mice with nerve cuffs. Furthermore, non-injured mice had an increased fear response when BLA to mPFC projections were inhibited by a chemogenetic method. In conclusion, this study provides evidence that persistent pain has a significant impact on consolidated fear memories. Very likely the underlying mechanism for this phenomenon is increased inhibitory input onto the BLA to mPFC projection neurons, possibly from neurons with induced parvalbumin expression. Conceivably, the increased fear response to consolidated fear memory is a harbinger for the later development of anxiety and depression symptoms associated with chronic pain.

Dataset Information

A novelty-retrieval-extinction paradigm leads to persistent attenuation of remote fear memories.

Publications

A novelty-retrieval-extinction paradigm leads to persistent attenuation of remote fear memories.

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