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ABSTRACT: There has been recent interest in the possibility that epigenetic mechanisms might contribute to the transgenerational transmission of stress-induced vulnerability. Here, we focused on possible paternal transmission with the social defeat stress paradigm.
Adult male mice exposed to chronic social defeat stress or control nondefeated mice were bred with normal female mice, and their offspring were assessed behaviorally for depressive- and anxiety-like measures. Plasma levels of corticosterone and vascular endothelial growth factor were also assayed. To directly assess the role of epigenetic mechanisms, we used in vitro fertilization (IVF); behavioral assessments were conducted on offspring of mice from IVF-control and IVF-defeated fathers.
We show that both male and female offspring from defeated fathers exhibit increased measures of several depression- and anxiety-like behaviors. The male offspring of defeated fathers also display increased baseline plasma levels of corticosterone and decreased levels of vascular endothelial growth factor. However, most of these behavioral changes were not observed when offspring were generated through IVF.
These results suggest that, although behavioral adaptations that occur after chronic social defeat stress can be transmitted from the father to his male and female F1 progeny, only very subtle changes might be transmitted epigenetically under the conditions tested.
Biological psychiatry 06/2011; 70(5):408-14. · 8.93 Impact Factor
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ABSTRACT: The molecular mechanisms underlying stress- and drug-induced neuronal adaptations are incompletely understood. One molecule implicated in such adaptations is ΔFosB, a transcription factor that accumulates in the rodent nucleus accumbens (NAc), a key brain reward region, in response to either chronic stress or repeated exposure to drugs of abuse. The upstream transcriptional mechanisms controlling ΔFosB induction by these environmental stimuli remain elusive. Here, we identify the activity-dependent transcription factor, serum response factor (SRF), as a novel upstream mediator of stress-, but not cocaine-, induced ΔFosB. SRF is downregulated in NAc of both depressed human patients and in mice chronically exposed to social defeat stress. This downregulation of SRF is absent in resilient animals. Through the use of inducible mutagenesis, we show that stress-mediated induction of ΔFosB, which occurs predominantly in resilient mice, is dependent on SRF expression in this brain region. Furthermore, NAc-specific genetic deletion of SRF promotes a variety of prodepressant- and proanxiety-like phenotypes and renders animals more sensitive to the deleterious effects of chronic stress. In contrast, we demonstrate that SRF does not play a role in ΔFosB accumulation in NAc in response to chronic cocaine exposure. Furthermore, NAc-specific knock-out of SRF has no effect on cocaine-induced behaviors, indicating that chronic social defeat stress and repeated cocaine exposure regulate ΔFosB accumulation and behavioral sensitivity through independent mechanisms.
Journal of Neuroscience 10/2010; 30(43):14585-92. · 7.11 Impact Factor
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Quincey LaPlant,
Vincent Vialou,
Herbert E Covington,
Dani Dumitriu,
Jian Feng,
Brandon L Warren,
Ian Maze,
David M Dietz, Emily L Watts,
Sergio D Iñiguez, [......],
Amelia J Eisch,
Carlos A Bolaños,
Mohamed Kabbaj,
Guanghua Xiao,
Rachael L Neve,
Yasmin L Hurd,
Ronald S Oosting,
Gouping Fan,
John H Morrison,
Eric J Nestler
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ABSTRACT: Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli.
Nature Neuroscience 09/2010; 13(9):1137-43. · 15.53 Impact Factor
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Vincent Vialou,
Alfred J Robison,
Quincey C Laplant,
Herbert E Covington,
David M Dietz,
Yoshinori N Ohnishi,
Ezekiell Mouzon,
Augustus J Rush, Emily L Watts,
Deanna L Wallace, [......],
Yoko H Ohnishi,
Michel A Steiner,
Brandon L Warren,
Vaishnav Krishnan,
Carlos A Bolaños,
Rachael L Neve,
Subroto Ghose,
Olivier Berton,
Carol A Tamminga,
Eric J Nestler
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ABSTRACT: In contrast with the many studies of stress effects on the brain, relatively little is known about the molecular mechanisms of resilience, the ability of some individuals to escape the deleterious effects of stress. We found that the transcription factor DeltaFosB mediates an essential mechanism of resilience in mice. Induction of DeltaFosB in the nucleus accumbens, an important brain reward-associated region, in response to chronic social defeat stress was both necessary and sufficient for resilience. DeltaFosB induction was also required for the standard antidepressant fluoxetine to reverse behavioral pathology induced by social defeat. DeltaFosB produced these effects through induction of the GluR2 AMPA glutamate receptor subunit, which decreased the responsiveness of nucleus accumbens neurons to glutamate, and through other synaptic proteins. Together, these findings establish a previously unknown molecular pathway underlying both resilience and antidepressant action.
Nature Neuroscience 06/2010; 13(6):745-52. · 15.53 Impact Factor
