Reduction of DNMT3a and RORA in the nucleus accumbens plays a causal role in post-traumatic stress disorder-like behavior: reversal by combinatorial epigenetic therapy

Warhaftig, Gal; Zifman, Noa; Sokolik, Chaya Mushka; Massart, Renaud; Gabay, Orshay; Sapozhnikov, Daniel M.; Vaisheva, Farida; Lictenstein, Yehuda; Confortti, Noa; Ahdoot, Hadas; Jacob, Avi; Bareli, Tzofnat; Szyf, Moshe; Yadid, Gal

doi:10.1038/s41380-021-01178-y

Cited by 9 publications

(2 citation statements)

References 131 publications

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“…A growing body of data indicates that NAc, a rewarding hub [44] in the brain, plays an important role in several aversive learning behaviors [45–47]. A recent study supports the causal role of reduction of DNA methyltransferase DNMT3a in NAc of rats in PTSD‐like behavior induced by predatory‐associated “trauma” (cat scent) [48]. The present study improved our understanding of the role of TET3‐dependent DNA demethylation in NAc in fear generalization.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of Tet3 in nucleus accumbens enhances fear generalization and anxiety‐like behaviors in mice

et al. 2022

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Stress-induced neuroepigenetic programming gains growing more and more interest in the studies of the etiology of posttraumatic stress disorder (PTSD). However, seldom attention is focused on DNA demethylation in fear memory generalization, which is the core characteristic of PTSD. Here, we show that ten-eleven translocation protein 3 (TET3), the most abundant DNA demethylation enzyme of the TET family in neurons, senses environmental stress and bridges neuroplasticity with behavioral adaptation during fear generalization. Foot shock strength dependently induces fear generalization and TET3 expression in nucleus accumbens (NAc) in mice. Inhibition of DNA demethylation by infusing demethyltransferase inhibitors or AAV-Tet3-shRNA virus in NAc enhances the fear generalization and anxiety-like behavior. Furthermore, TET3 knockdown impairs the dendritic spine density, PSD length, and thickness of neurons, decreases DNA hydroxymethylation (5hmC), reduces the expression of synaptic plasticity-related genes including Homer1, Cdkn1a, Cdh8, Vamp8, Reln, Bdnf, while surprisingly increases immune-related genes Stat1, B2m, H2-Q7, H2-M2, C3, Cd68 shown by RNA-seq. Notably, knockdown of TET3 in NAc activates microglia and CD39-P2Y12R signaling pathway, and inhibition of CD39 reverses the effects of TET3 knockdown on the fear memory generalization and anxiety. Overexpression of TET3 by Crispr-dSaCas9 virus delivery to activate endogenous Tet3 in NAc increases dendritic spine density of neurons in NAc and reverses fear memory generalization and anxiety-like behavior in mice. These results suggest that TET3 modulates fear generalization and anxiety via regulating synaptic plasticity and CD39 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Deficiency of Tet3 in nucleus accumbens enhances fear generalization and anxiety‐like behaviors in mice

et al. 2022

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“…A team led by Moshe Szyf and Gal Yadid recently investigated a rat model of PTSD in which they identified changes in DNA methylation associated with susceptibility or resilience to stress responses upon exposure to a predator odor. [26] Results suggested a pattern of diffuse hypomethylation in susceptible animals, along with reduced expression of one of the two main proteins responsible for methylating DNA in mammalian brains (DNMT3A). They then directly increased the expression of this protein and found that it partially blocked the emergence of PTSD-like behaviors in their model.…”

Section: • Mediation Of Epigenetic Reprogramming Through Dna Methylationmentioning

confidence: 98%

Can you remember silence? Epigenetic memory and reversibility as a site of intervention

2023

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Just over 20 years ago, molecular biologists Leonie Ringrose and Renato Paro published an article with a provocative title, "Remembering Silence", in BioEssays. The article focused on how epigenetic elements could return to their silent state, operationally defined as their epigenetic status before their modulation by experimental or environmental factors. Though Ringrose and Paro's article was on fruit flies and factors affecting embryological growth, the article asked a question of considerable importance to rapidly expanding research in neuroepigenetics on the correlation between trauma and neuropsychiatric risk: If you experience a traumatic event and, as a result, acquire an epigenetic trait that is considered pathological, can you free yourself of that trait? Ultimately, we are interested in how a return to silence is envisioned in neuroepigenetics research, how interventions purported to bring about that silence might function, and what this might mean for people who live in the aftermath of trauma.

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Epigenetic Processes as Mediators of the Impact of the Social Environment

Szyf

2024

Epigenetics in Biological Communication

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Reduction of DNMT3a and RORA in the nucleus accumbens plays a causal role in post-traumatic stress disorder-like behavior: reversal by combinatorial epigenetic therapy

Cited by 9 publications

References 131 publications

Deficiency of Tet3 in nucleus accumbens enhances fear generalization and anxiety‐like behaviors in mice

Deficiency of Tet3 in nucleus accumbens enhances fear generalization and anxiety‐like behaviors in mice

Can you remember silence? Epigenetic memory and reversibility as a site of intervention

Epigenetic Processes as Mediators of the Impact of the Social Environment

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