Transcriptional effect of early-life adversity in adult hippocampus

Early-life adversity (ELA) is associated with lifelong memory deficits, yet the responsible mechanisms remain unclear. We imposed ELA by rearing rat pups in simulated poverty, assessed hippocampal memory, and probed changes in gene expression, their transcriptional regulation and the consequent changes in hippocampal neuronal structure. ELA rats had poor hippocampal memory and stunted hippocampal pyramidal neurons, associated with ~140 differentially expressed genes. Upstream regulators of the altered genes included glucocorticoid receptor and, unexpectedly, the transcription factor neuron-restrictive silencer factor (NRSF/REST). NRSF contributed critically to the memory deficits because blocking its function transiently following ELA rescued spatial memory and restored the dendritic arborization of hippocampal pyramidal neurons in ELA rats. Blocking NRSF function in vitro augmented 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.早期不良经历（Early-life adversity, ELA）与终身记忆缺陷密切相关，但其潜在作用机制仍不明确。本研究通过在模拟贫困环境中饲养幼鼠构建ELA模型，对大鼠海马体记忆功能进行评估，并探究了基因表达变化、其转录调控机制以及由此引发的海马神经元结构改变。结果显示，ELA模型大鼠存在海马体记忆缺陷与海马锥体神经元发育迟缓的问题，同时伴随约140个差异表达基因的表达异常。这些异常表达基因的上游调控因子包括糖皮质激素受体，以及此前未被预期的转录因子神经元限制性沉默因子（neuron-restrictive silencer factor, NRSF/REST）。NRSF在记忆缺陷的发生中发挥关键作用：在ELA建模后瞬时阻断其功能，可恢复ELA模型大鼠的空间记忆，并修复其海马锥体神经元的树突分支形态。体外实验中，阻断NRSF功能能够增强发育中海马神经元的树突复杂度，提示NRSF可抑制参与神经元成熟过程的相关基因表达。本研究证实，NRSF通过介导ELA诱导的转录编程破坏海马体成熟与记忆功能，这一贡献具有重要且出乎意料的研究意义。