NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience

A. Singh-Taylor, J. Molet, S. Jiang, A. Korosi, J. L. Bolton, Y. Noam, Kristina A. Simeone, J. Cope, Y. Chen, A. Mortazavi, T. Z. Baram

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Resilience to stress-related emotional disorders is governed in part by early-life experiences. Here we demonstrate experience-dependent re-programming of stress-sensitive hypothalamic neurons, which takes place through modification of neuronal gene expression via epigenetic mechanisms. Specifically, we found that augmented maternal care reduced glutamatergic synapses onto stress-sensitive hypothalamic neurons and repressed expression of the stress-responsive gene, Crh. In hypothalamus in vitro, reduced glutamatergic neurotransmission recapitulated the repressive effects of augmented maternal care on Crh, and this required recruitment of the transcriptional repressor repressor element-1 silencing transcription factor/neuron restrictive silencing factor (NRSF). Increased NRSF binding to chromatin was accompanied by sequential repressive epigenetic changes which outlasted NRSF binding. chromatin immunoprecipitation-seq analyses of NRSF targets identified gene networks that, in addition to Crh, likely contributed to the augmented care-induced phenotype, including diminished depression-like and anxiety-like behaviors. Together, we believe these findings provide the first causal link between enriched neonatal experience, synaptic refinement and induction of epigenetic processes within specific neurons. They uncover a novel mechanistic pathway from neonatal environment to emotional resilience.Molecular Psychiatry advance online publication, 10 January 2017; doi:10.1038/mp.2016.240.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - Jan 10 2017

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Epigenomics
Neurons
Transcriptional Silencer Elements
Genetic Epigenesis
Mothers
Gene Regulatory Networks
Chromatin Immunoprecipitation
Psychological Stress
Synaptic Transmission
Synapses
Hypothalamus
Chromatin
Psychiatry
Publications
Transcription Factors
Anxiety
Depression
Phenotype
Gene Expression
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

Cite this

NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience. / Singh-Taylor, A.; Molet, J.; Jiang, S.; Korosi, A.; Bolton, J. L.; Noam, Y.; Simeone, Kristina A.; Cope, J.; Chen, Y.; Mortazavi, A.; Baram, T. Z.

In: Molecular Psychiatry, 10.01.2017.

Research output: Contribution to journalArticle

Singh-Taylor, A. ; Molet, J. ; Jiang, S. ; Korosi, A. ; Bolton, J. L. ; Noam, Y. ; Simeone, Kristina A. ; Cope, J. ; Chen, Y. ; Mortazavi, A. ; Baram, T. Z. / NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience. In: Molecular Psychiatry. 2017.
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