Interindividual Variability in Stress Susceptibility: A Role for Epigenetic Mechanisms in PTSD

Zovkic, Iva B.; Meadows, Jarrod P.; Kaas, Garrett A.; Sweatt, J. David

doi:10.3389/fpsyt.2013.00060

Cited by 56 publications

(49 citation statements)

References 304 publications

(485 reference statements)

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“…Stressful stimuli alter DNA methylation state (see above) (e.g. Zovkic et al, 2013b) and this increased methylation may result from upstream events, including increased glutamate transmission, neuropeptide transmission and increased transcription factor activation (Stankiewicz et al, 2013). The presence of CE is clearly a stressor for Lymnaea Lukowiak et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Enhanced memory persistence is blocked by a DNA methyltransferase inhibitor in the snail Lymnaea stagnalis

Lukowiak

Heckler

Bennett

et al. 2014

Journal of Experimental Biology

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Lymnaea stagnalis provides an excellent model system for studying memory because these snails have a well-described set of neurons, a single one of which controls expression of long-term memory of operantly conditioned respiratory behavior. We have shown that several different manipulations, including pre-training exposure to serotonin (5-HT) or methamphetamine, submersion of snails after training to prevent memory interference, and exposure to effluent from predatory crayfish (CE), enhance memory persistence. Changes in DNA methylation underlie formation of strong memories in mammals and 5-HT-enhanced long-term facilitation in Aplysia. Here we determined the impact of the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5-AZA; 87 μmol l −1 ), on enhanced memory persistence by all four manipulations. We found that 5-HT (100 μmol l −1 ) enhanced memory persistence, which was blocked by 5-AZA pretreatment. Snails pre-exposed to 3.3 μmol l −1 Meth 4 h prior to training demonstrated memory 72 h later, which was not present in controls. This memory-enhancing effect was blocked by pretreatment with 87 μmol l −1 5-AZA. Similarly, submersion to prevent interference learning as well as training in CE produced memory that was not present in controls, and these effects were blocked by pretreatment with 87 μmol l −1 5-AZA. In contrast, 5-AZA injection did not alter expression of normal (non-enhanced) memory, suggesting that these four stimuli enhance memory persistence by increasing DNA methyltransferase activity, which, in turn, increases expression of memory-enhancing genes and/or inhibits memory suppressor genes. These studies lay important groundwork for delineating gene methylation changes that are common to persistent memory produced by different stimuli.

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Section: Discussionmentioning

confidence: 99%

Enhanced memory persistence is blocked by a DNA methyltransferase inhibitor in the snail Lymnaea stagnalis

Lukowiak

Heckler

Bennett

et al. 2014

Journal of Experimental Biology

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“…Following pioneering work that indicated that differential methylation of the GR gene mediated the effects of different mothering styles on stress responses and maternal behavior in rats 166 , substantial evidence has shown that different components of the HPA axis are highly susceptible to epigenetic modulation by stress. Conversely, glucocorticoids themselves are important regulators of the epigenome 165 . Although the precise link with social behaviors is still scarce, the importance of these mechanisms in the link between stress and the social brain is illustrated by several examples.…”

Section: Epigenetic Mechanismsmentioning

confidence: 99%

“…An exploding body of evidence provides strong support for key roles of epigenetic mechanisms in mediating the effects of stress on brain and behavior, including gene-environment interactions at different developmental periods (for reviews, see 55,165 ). By regulating gene transcription, epigenetic mechanisms contribute to the effects of both stressors experienced in adulthood that have an immediate impact and those experienced early in life that have long-lasting effects on adult behavior and brain function.…”

Section: Epigenetic Mechanismsmentioning

confidence: 99%

Stress and the social brain: behavioural effects and neurobiological mechanisms

2015

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“…Recent studies have shown that epigenetic mechanisms are important for successful adaptation to a stressful environment and have a role in the development of PTSD (Zovkic et al, 2013). DNA methylation is an important epigenetic mechanism that is influenced by genetic and environmental factors (Malan-Muller et al, 2014), and reflects the transcriptional status of a particular gene (Schubeler, 2015).…”

Section: Introductionmentioning

confidence: 99%

SKA2 Methylation is Involved in Cortisol Stress Reactivity and Predicts the Development of Post-Traumatic Stress Disorder (PTSD) After Military Deployment

Boks

Rutten

Geuze

et al. 2015

Neuropsychopharmacol

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Genomic variation in the SKA2 gene has recently been identified as a promising suicide biomarker. In light of its role in glucocorticoid receptor transactivation, we investigated whether SKA2 DNA methylation influences cortisol stress reactivity and is involved in the development of post-traumatic stress disorder (PTSD). Increased SKA2 methylation was significantly associated with lower cortisol stress reactivity in 85 healthy individuals exposed to the Trier Social Stress Test (B = − 173.40, t = − 2.324, p-value = 0.023). Next, we observed that longitudinal decreases in SKA2 methylation after deployment were associated with the emergence of post-deployment PTSD symptoms in a Dutch military cohort (N = 93; B = − 0.054, t = − 3.706, p-value = 3.66 × 10 − 4 ). In contrast, exposure to traumatic stress during deployment by itself resulted in longitudinal increases in SKA2 methylation (B = 0.037, t = 4.173, p-value = 6.98 × 10 − 5 ). Using predeployment SKA2 methylation levels and childhood trauma exposure, we found that the previously published suicide prediction rule significantly predicted post-deployment PTSD symptoms (AUC = 0.66, 95% CI: 0.53-0.79) with an optimal sensitivity of 0.81 and specificity of 0.91. Permutation analysis using random methylation loci supported these findings. Together, these data establish the importance of SKA2 for cortisol stress responsivity and the development of PTSD and provide further evidence that SKA2 is a promising biomarker for stress-related disorders including PTSD.

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Interindividual Variability in Stress Susceptibility: A Role for Epigenetic Mechanisms in PTSD

Cited by 56 publications

References 304 publications

Enhanced memory persistence is blocked by a DNA methyltransferase inhibitor in the snail Lymnaea stagnalis

Enhanced memory persistence is blocked by a DNA methyltransferase inhibitor in the snail Lymnaea stagnalis

Stress and the social brain: behavioural effects and neurobiological mechanisms

SKA2 Methylation is Involved in Cortisol Stress Reactivity and Predicts the Development of Post-Traumatic Stress Disorder (PTSD) After Military Deployment

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