GSE161498
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. Overall design: Gene expression was profiled in dorsal hippocampi from 8-week-old male rats that were subjected to either control rearing conditions (n=4) or ELA (n=5), and did not undergo behavioral testing.