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

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

Authors :
Singh-Taylor A
Molet J
Jiang S
Korosi A
Bolton JL
Noam Y
Simeone K
Cope J
Chen Y
Mortazavi A
Baram TZ
Source :
Molecular psychiatry [Mol Psychiatry] 2018 Mar; Vol. 23 (3), pp. 648-657. Date of Electronic Publication: 2017 Jan 10.
Publication Year :
2018

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.

Details

Language :
English
ISSN :
1476-5578
Volume :
23
Issue :
3
Database :
MEDLINE
Journal :
Molecular psychiatry
Publication Type :
Academic Journal
Accession number :
28070121
Full Text :
https://doi.org/10.1038/mp.2016.240