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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.
- 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.
- Subjects :
- Animals
Animals, Newborn metabolism
Animals, Newborn psychology
Chromatin metabolism
Epigenesis, Genetic genetics
Excitatory Amino Acid Agents metabolism
Female
Humans
Hypothalamus
Male
Neurons metabolism
RNA, Messenger metabolism
Rats
Rats, Sprague-Dawley
Repressor Proteins metabolism
Resilience, Psychological
Transcription Factors genetics
Transcription, Genetic
Corticotropin-Releasing Hormone genetics
Neuronal Plasticity genetics
Repressor Proteins genetics
Subjects
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