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Molecular mechanisms of D-cycloserine in facilitating fear extinction: insights from RNAseq

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Abstract

D-cycloserine (DCS) has been shown to be effective in facilitating fear extinction in animal and human studies, however the precise mechanisms whereby the co-administration of DCS and behavioural fear extinction reduce fear are still unclear. This study investigated the molecular mechanisms of intrahippocampally administered D-cycloserine in facilitating fear extinction in a contextual fear conditioning animal model. Male Sprague Dawley rats (n = 120) were grouped into four experimental groups (n = 30) based on fear conditioning and intrahippocampal administration of either DCS or saline. The light/dark avoidance test was used to differentiate maladapted (MA) (anxious) from well-adapted (WA) (not anxious) subgroups. RNA extracted from the left dorsal hippocampus was used for RNA sequencing and gene expression data was compared between six fear-conditioned + saline MA (FEAR + SALINE MA) and six fear-conditioned + DCS WA (FEAR + DCS WA) animals. Of the 424 significantly downregulated and 25 significantly upregulated genes identified in the FEAR + DCS WA group compared to the FEAR + SALINE MA group, 121 downregulated and nine upregulated genes were predicted to be relevant to fear conditioning and anxiety and stress-related disorders. The majority of downregulated genes transcribed immune, proinflammatory and oxidative stress systems molecules. These molecules mediate neuroinflammation and cause neuronal damage. DCS also regulated genes involved in learning and memory processes, and genes associated with anxiety, stress-related disorders and co-occurring diseases (e.g., cardiovascular diseases, digestive system diseases and nervous system diseases). Identifying the molecular underpinnings of DCS-mediated fear extinction brings us closer to understanding the process of fear extinction.

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Acknowledgments

This work is based upon research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation, South African Medical Research Council (self-initiated research grant) and Harry Crossley Foundation funding. We would also like to acknowledge Novartis Pharma AG of Basel, Switzerland for funding and performing all the library construction and next generation sequencing for this project.

Statement of interest

Novartis Pharma AG of Basel, Switzerland covered all the library construction and next generation sequencing costs for this project. Marc Altorfer and Edward Oakeley are full time employees of Novartis Pharma AG and Edward Oakeley privately holds Novartis stock. There are no conflicts of interest. There is no current collaboration between the authors of this manuscript and the preferred reviewers.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Ethics approval for the study was granted by the Stellenbosch University Research Ethics Committee: Animal Care and Use (Cape Town, South Africa). The Principles of laboratory animal care (NIH publication No. 86-23, revised 1985) were followed.

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Authors and Affiliations

  1. Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

    Stefanie Malan-Müller, Lorren Fairbairn, Soraya Seedat & Sîan Megan Joanna Hemmings

  2. Department of Human Physiology, University of KwaZulu-Natal, Durban, South Africa

    Willie M. U. Daniels

  3. University of the Western Cape, South African National Bioinformatics Institute, Cape Town, South Africa

    Mahjoubeh Jalali Sefid Dashti & Junaid Gamieldien

  4. Novartis Institutes for BioMedical Research, Biomarker Development - Human Genetics and Genomics, Genome Technologies, Basel, Switzerland

    Edward J. Oakeley & Marc Altorfer

  5. Centre for Statistical Consultation, Stellenbosch University, Stellenbosch, South Africa

    Martin Kidd

  6. SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

    Stefanie Malan-Müller & Sîan Megan Joanna Hemmings

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  1. Stefanie Malan-Müller
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Correspondence to Stefanie Malan-Müller.

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Junaid Gamieldien and Sîan Megan Joanna Hemmings are equally contributing senior authors.

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Malan-Müller, S., Fairbairn, L., Daniels, W.M.U. et al. Molecular mechanisms of D-cycloserine in facilitating fear extinction: insights from RNAseq. Metab Brain Dis 31, 135–156 (2016). https://doi.org/10.1007/s11011-015-9727-4

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