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Exploring epigenetic regulation of fear memory and biomarkers associated with post-traumatic stress disorder.

ABSTRACT: This review examines recent work on epigenetic mechanisms underlying animal models of fear learning as well as its translational implications in disorders of fear regulation, such as Post-traumatic Stress Disorder (PTSD). Specifically, we will examine work outlining roles of differential histone acetylation and DNA-methylation associated with consolidation, reconsolidation, and extinction in Pavlovian fear paradigms. We then focus on the numerous studies examining the epigenetic modifications of the Brain-derived neurotrophin factor (BDNF) pathway and the extension of these findings from animal models to recent work in human clinical populations. We will also review recently published data on FKBP5 regulation of glucocorticoid receptor function, and how this is modulated in animal models of PTSD and in human clinical populations via epigenetic mechanisms. As glucocorticoid regulation of memory consolidation is well established in fear models, we examine how these recent data contribute to our broader understanding of fear memory formation. The combined recent progress in epigenetic modulation of memory with the advances in fear neurobiology suggest that this area may be critical to progress in our understanding of fear-related disorders with implications for new approaches to treatment and prevention.

SUBMITTER: Maddox SA

PROVIDER: S-EPMC3697031 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Exploring epigenetic regulation of fear memory and biomarkers associated with post-traumatic stress disorder.

Maddox Stephanie A SA Schafe Glenn E GE Ressler Kerry J KJ

Frontiers in psychiatry 20130701

This review examines recent work on epigenetic mechanisms underlying animal models of fear learning as well as its translational implications in disorders of fear regulation, such as Post-traumatic Stress Disorder (PTSD). Specifically, we will examine work outlining roles of differential histone acetylation and DNA-methylation associated with consolidation, reconsolidation, and extinction in Pavlovian fear paradigms. We then focus on the numerous studies examining the epigenetic modifications of ...[more]

PMID: 23847551

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Project description:Structural brain studies of adult post-traumatic stress disorder (PTSD) show reduced gray matter volume (GMV) in fear regulatory areas including the ventromedial prefrontal cortex (vmPFC) and hippocampus. Surprisingly, neither finding has been reported in pediatric PTSD. One possibility is that they represent age-dependent effects that are not fully apparent until adulthood. In addition, lower-resolution MRI and image processing in prior studies may have limited detection of such differences. Here we examine fear circuitry GMV, including age-related differences, using higher-resolution MRI in pediatric PTSD vs healthy youth. In a cross-sectional design, 3 T anatomical brain MRI was acquired in 27 medication-free youth with PTSD and 27 healthy non-traumatized youth of comparable age, sex, and IQ. Voxel-based morphometry was used to compare GMV in a priori regions including the medial prefrontal cortex and amygdala/hippocampus. Compared with healthy youth, PTSD youth had reduced GMV but no age-related differences in anterior vmPFC (BA 10/11, Z=4.5), which inversely correlated with PTSD duration. In contrast, although there was no overall group difference in hippocampal volume, a group × age interaction (Z=3.6) was present in the right anterior hippocampus. Here, age positively predicted hippocampal volume in healthy youth but negatively predicted volume in PTSD youth. Within the PTSD group, re-experiencing symptoms inversely correlated with subgenual anterior cingulate cortex (sgACC, Z=3.7) and right anterior hippocampus (Z=3.5) GMV. Pediatric PTSD is associated with abnormal structure of the vmPFC and age-related differences in the hippocampus, regions important in the extinction and contextual gating of fear. Reduced anterior vmPFC volume may confer impaired recovery from illness, consistent with its role in the allocation of attentional resources. In contrast, individual differences in sgACC volume were associated with re-experiencing symptoms, consistent with the role of the sgACC in fear extinction. The negative relationship between age and hippocampal volume in youth with PTSD may suggest an ongoing neurotoxic process over development, which further contributes to illness expression. Future studies employing a longitudinal design would be merited to further explore these possibilities.

Project description:The biological underpinnings of post-traumatic stress disorder (PTSD) have not been fully elucidated. Previous work suggests that alterations in the immune system are characteristic of the disorder. Identifying the biological mechanisms by which such alterations occur could provide fundamental insights into the etiology and treatment of PTSD. Here we identify specific epigenetic profiles underlying immune system changes associated with PTSD. Using blood samples (n=100) obtained from an ongoing, prospective epidemiologic study in Detroit, the Detroit Neighborhood Health Study (DNHS), we applied methylation microarrays to assay CpG sites from over 14,000 genes among 23 PTSD-affected and 77 PTSD-unaffected individuals. We show that immune system functions are significantly overrepresented among the annotations associated with genes uniquely unmethylated among those with PTSD. We further demonstrate that genes whose methylation levels are significantly and negatively correlated with traumatic burden show a similar strong signal of immune function among the PTSD-affected. The observed epigenetic variability in immune function by PTSD is corroborated using an independent biological marker of immune response to infection, cytomegalovirus—a typically latent herpesvirus whose activity was significantly higher among those with PTSD. These results provide the first report of peripheral epigenomic and CMV profiles associated with mental illness and suggest a new biological model of PTSD etiology in which an externally experienced traumatic event induces downstream alterations in immune function by reducing methylation levels of immune-related genes. Bisulfite conversion of whole blood-derived DNA samples was performed using the EZ-96 DNA methylation kit from Zymo Research. One microgram (μg) of each sample (including controls) was subjected to bisulfite conversion following manufacturer’s recommended protocol. 100 samples were analyzed of which 23 are PTSD affected and 77 are PTSD-unaffected. There were four technical replicates comprised of duplicate samples of two randomly selected individuals from the n=100 and duplicate samples of the control human methylated and unmethylated DNA.

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Dataset Information

Exploring epigenetic regulation of fear memory and biomarkers associated with post-traumatic stress disorder.

Publications

Exploring epigenetic regulation of fear memory and biomarkers associated with post-traumatic stress disorder.

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