当前位置: X-MOL 学术Mol. Psychiatry › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience.
Molecular Psychiatry ( IF 11.0 ) Pub Date : 2018-03-01 , DOI: 10.1038/mp.2016.240
A Singh-Taylor , J Molet , S Jiang , A Korosi , J L Bolton , Y Noam , K Simeone , J Cope , Y Chen , A Mortazavi , T Z Baram

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.

中文翻译:

NRSF依赖的表观遗传机制通过新生儿的经验有助于对压力敏感神经元的编程,从而增强适应力。

对与压力有关的情绪障碍的适应能力部分受早期生活经验的支配。在这里,我们展示了应激敏感的下丘脑神经元的经验依赖型重编程,它是通过表观遗传机制通过修饰神经元基因表达而发生的。具体来说,我们发现增强的孕产妇保健减少了对应激敏感的下丘脑神经元的谷氨酸能突触,并抑制了应激反应基因Crh的表达。在体外下丘脑中,减少的谷氨酸能神经传递重现了加强产妇护理对Crh的抑制作用,这需要募集转录抑制因子1沉默转录因子/神经元限制性沉默因子(NRSF)。NRSF与染色质的结合增加,伴随着顺序性抑制表观遗传变化,从而使NRSF结合更持久。NRSF靶标的染色质免疫沉淀-seq分析确定了除Crh外还可能促进护理引起的表型增加的基因网络,包括抑郁症和焦虑症的行为减少。在一起,我们相信这些发现提供了丰富的新生儿经验,突触细化和特定神经元内表观遗传过程的诱导之间的第一个因果关系。他们发现了从新生儿环境到情绪复原的新颖机制。包括减少的抑郁症和焦虑症行为。在一起,我们相信这些发现提供了丰富的新生儿经验,突触细化和特定神经元内表观遗传过程的诱导之间的第一个因果关系。他们发现了从新生儿环境到情绪复原的新颖机制。包括减少的抑郁症和焦虑症行为。在一起,我们相信这些发现提供了丰富的新生儿经验,突触细化和特定神经元内表观遗传过程的诱导之间的第一个因果关系。他们发现了从新生儿环境到情绪复原的新颖机制。
更新日期:2018-02-21
down
wechat
bug