title: NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience.
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.
authors.affiliation: Department of Pediatrics and Anatomy/Neurobiology, University of California-Irvine, Irvine, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Singh-Taylor
authors.affiliation: Department of Pediatrics and Anatomy/Neurobiology, University of California-Irvine, Irvine, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Molet
authors.affiliation: Department of Developmental and Cell Biology, University of California-Irvine, Irvine, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Korosi
authors.affiliation: Department of Pediatrics and Anatomy/Neurobiology, University of California-Irvine, Irvine, CA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Bolton
authors.affiliation: Department of Pediatrics and Anatomy/Neurobiology, University of California-Irvine, Irvine, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Noam
authors.affiliation: Department of Pharmacology, Creighton University, Omaha, NE, USA.
authors.forename: K
authors.initials: K
authors.lastname: Simeone
authors.affiliation: Department of Pediatrics and Anatomy/Neurobiology, University of California-Irvine, Irvine, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cope
authors.affiliation: Department of Pediatrics and Anatomy/Neurobiology, University of California-Irvine, Irvine, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Developmental and Cell Biology, University of California-Irvine, Irvine, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mortazavi
authors.affiliation: Department of Pediatrics and Anatomy/Neurobiology, University of California-Irvine, Irvine, CA, USA.|Department of Neurology, University of California-Irvine, Irvine, CA, USA.
authors.forename: T Z
authors.initials: TZ
authors.lastname: Baram
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism / Q000523:psychology; D002843:Chromatin / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D018683:Excitatory Amino Acid Agents / Q000378:metabolism; D005260:Female; D006801:Humans; D007031:Hypothalamus; D008297:Male; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D055500:Resilience, Psychological; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D000099229:RE1-Silencing Transcription Factor
chemical_list: D002843:Chromatin; D003346:Corticotropin-Releasing Hormone; D018683:Excitatory Amino Acid Agents; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor