title: Molecular mechanisms of D-cycloserine in facilitating fear extinction: insights from RNAseq.
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.
authors.affiliation: Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. smalan@sun.ac.za.|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. smalan@sun.ac.za.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Malan-Müller
authors.affiliation: Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Lorren
authors.initials: L
authors.lastname: Fairbairn
authors.affiliation: Department of Human Physiology, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Willie M U
authors.initials: WM
authors.lastname: Daniels
authors.affiliation: University of the Western Cape, South African National Bioinformatics Institute, Cape Town, South Africa.
authors.forename: Mahjoubeh Jalali Sefid
authors.initials: MJ
authors.lastname: Dashti
authors.affiliation: Novartis Institutes for BioMedical Research, Biomarker Development - Human Genetics and Genomics, Genome Technologies, Basel, Switzerland.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Oakeley
authors.affiliation: Novartis Institutes for BioMedical Research, Biomarker Development - Human Genetics and Genomics, Genome Technologies, Basel, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Altorfer
authors.affiliation: Centre for Statistical Consultation, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Martin
authors.initials: M
authors.lastname: Kidd
authors.affiliation: Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Soraya
authors.initials: S
authors.lastname: Seedat
authors.affiliation: University of the Western Cape, South African National Bioinformatics Institute, Cape Town, South Africa.
authors.forename: Junaid
authors.initials: J
authors.lastname: Gamieldien
authors.affiliation: Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.|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.
authors.forename: Sîan Megan Joanna
authors.initials: SM
authors.lastname: Hemmings
mesh_terms: D000223:Adaptation, Psychological / Q000187:drug effects; D000818:Animals; D003523:Cycloserine / Q000494:pharmacology*; D015536:Down-Regulation / Q000235:genetics; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus; D008297:Male; D008845:Microinjections; D012313:RNA / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017423:Sequence Analysis, RNA
chemical_list: D012313:RNA; D003523:Cycloserine
keywords: Anxiety disorders; D-cycloserine; RNA sequencing; fear extinction; transcriptomics