Unexpected Transcriptional Programs Contribute to Hippocampal Memory Deficits and Neuronal Stunting after Early-Life Adversity.
Unexpected Transcriptional Programs Contribute to Hippocampal Memory Deficits and Neuronal Stunting after Early-Life Adversity.
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DOI：
10.1016/j.celrep.2020.108511
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发表时间：
2020-12-15
期刊：
影响因子：
8.8
通讯作者：
Baram TZ
中科院分区：
文献类型：
--
作者：
Bolton JL;Schulmann A;Garcia-Curran MM;Regev L;Chen Y;Kamei N;Shao M;Singh-Taylor A;Jiang S;Noam Y;Molet J;Mortazavi A;Baram TZ
早期生活逆境（ELA）与终身记忆缺陷有关，但其机制尚不清楚。我们通过在模拟贫困环境中饲养大鼠幼崽来施加ELA，评估海马记忆，并探索基因表达、转录调控的变化以及随之而来的海马神经元结构的变化。ELA大鼠海马记忆较差，海马锥体神经元发育不良，与约140个差异表达基因相关。改变基因的上游调节因子包括糖皮质激素受体和转录因子神经元限制性沉默因子（NRSF/REST）。NRSF在ELA大鼠的记忆缺陷中起着至关重要的作用，因为在ELA后短暂阻断其功能可以恢复空间记忆并恢复海马锥体神经元的树突树突化。体外阻断NRSF功能增加了发育中的海马神经元的树突复杂性，表明NRSF抑制了参与神经元成熟的基因。这些发现确立了NRSF对ela诱导的转录编程的重要而惊人的贡献，这种转录编程破坏了海马的成熟和记忆功能。Bolton等人报道了早期生活逆境（ELA）后的持久记忆障碍与促进神经元成熟和神经传递的关键海马基因的大规模抑制有关。他们确定糖皮质激素受体（GR）和抑制性转录因子神经元限制性沉默因子（NRSF）作为候选的上游调节因子。暂时阻断NRSF染色质结合可恢复海马记忆和神经元结构。
Early-life adversity (ELA) is associated with lifelong memory deficits, yet the responsible mechanisms remain unclear. We impose ELA by rearing rat pups in simulated poverty, assess hippocampal memory, and probe changes in gene expression, their transcriptional regulation, and the consequent changes in hippocampal neuronal structure. ELA rats have poor hippocampal memory and stunted hippocampal pyramidal neurons associated with ~140 differentially expressed genes. Upstream regulators of the altered genes include glucocorticoid receptor and, unexpectedly, the transcription factor neuron-restrictive silencer factor (NRSF/REST). NRSF contributes critically to the memory deficits because blocking its function transiently following ELA rescues spatial memory and restores the dendritic arborization of hippocampal pyramidal neurons in ELA rats. Blocking NRSF function in vitro augments dendritic complexity of developing hippocampal neurons, suggesting that NRSF represses genes involved in neuronal maturation. These findings establish important, surprising contributions of NRSF to ELA-induced transcriptional programming that disrupts hippocampal maturation and memory function. Bolton et al. report enduring memory impairments after early-life adversity (ELA) associated with large-scale repression of key hippocampal genes contributing to neuronal maturation and neurotransmission. They identify glucocorticoid receptor (GR) and the repressive transcription factor neuron-restrictive silencer factor (NRSF) as candidate upstream regulators. Temporary block of NRSF chromatin-binding rescues hippocampal memory and neuronal structure.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
早期生活节目和神经发育障碍。
影响因子：
10.6
作者：
Bale, Tracy L.;Baram, Tallie Z.;Brown, Alan S.;Goldstein, Jill M.;Insel, Thomas R.;McCarthy, Margaret M.;Nemeroff, Charles B.;Reyes, Teresa M.;Simerly, Richard B.;Susser, Ezra S.;Nestler, Eric J.
通讯作者：
Nestler, Eric J.
影响因子：
4.8
作者：
Avishai-Eliner, S;Eghbal-Ahmadi, M;Baram, TZ
通讯作者：
Baram, TZ
影响因子：
3
作者：
Bolton, Jessica L.;Short, Annabel Katherine;Baram, Tallie Z.
通讯作者：
Baram, Tallie Z.
影响因子：
64.5
作者：
Ballas, N;Grunseich, C;Mandel, G
通讯作者：
Mandel, G