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Differential Alterations in Cortico-Amygdala Circuitry in Mice with Impaired Fear Extinction

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Abstract

129S1/SvImJ (S1) mice exhibit selective impairments in fear extinction, though the mechanisms underlying these impairments are not fully understood. The medial prefrontal cortex (mPFC) consists of the prelimbic cortex (PL) and infralimbic cortex (IL), which are known to be involved in fear conditioning and extinction, respectively. The PL and IL project to the basolateral amygdala (BLA) that also plays an important role in both mechanisms. In the present study, we utilized optogenetic and electrophysiological approaches to measure inhibitory/excitatory ratios (I/E ratios) in mPFC-BLA circuits of S1 and control C57BL/6 (B6) mice following fear conditioning and extinction. As suggested previously, PL inputs to the BLA became more excitatory after fear conditioning in B6 mice. S1 mice also exhibited strengthened PL-BLA circuit following fear conditioning. Interestingly, fear extinction restored PL-BLA circuit strength to levels comparable to the baseline in B6 mice. However, PL-BLA circuit strength remained abnormally high even after extinction in S1 mice. The IL-BLA circuit became more inhibitory in B6 mice after fear extinction, whereas extinction failed to change the excitability of the IL-BLA circuit in S1 mice. These data suggest that the fear extinction impairments observed in S1 mice may be due to constantly decreased I/E balance in the PL-BLA circuit and lack of changes in I/E balance in the IL-BLA circuit. This further suggests that investigation of both pathways is instrumental in developing more effective therapeutics for psychopathologies that involve impairments in fear extinction, such as chronic pain and posttraumatic stress disorder.

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Acknowledgements

We thank all the members of the Chung lab for discussion and helpful comments.

Funding

This study was supported by Konkuk University in 2016.

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  1. Department of Biological Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, South Korea

    Kwanghoon Park & ChiHye Chung

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C.C. conceived this work and designed the experiments. K.P. performed the experiments and acquired the data. K.P. and C.C. analyzed and interpreted the data. C.C. and K.P. prepared the manuscript. All authors have approved the final version of the manuscript.

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Correspondence to ChiHye Chung.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (Institutional Animal Care and Use Committee of Konkuk University, Seoul, Korea). This article does not contain any studies with human participants performed by any of the authors.

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Park, K., Chung, C. Differential Alterations in Cortico-Amygdala Circuitry in Mice with Impaired Fear Extinction. Mol Neurobiol 57, 710–721 (2020). https://doi.org/10.1007/s12035-019-01741-3

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