Neuronal activation induces rapid transcription of immediate early genes (IEGs) and longer-term chromatin remodeling around secondary response genes (SRGs). Here, we use high-resolution chromosome-conformation-capture carbon-copy sequencing (5C-seq) to elucidate the extent to which long-range chromatin loops are altered during short- and long-term changes in neural activity. We find that more than 10% of loops surrounding select IEGs, SRGs, and synaptic genes are induced de novo during cortical neuron activation. IEGs Fos and Arc connect to activity-dependent enhancers via singular short-range loops that form within 20 min after stimulation, prior to peak messenger RNA levels. By contrast, the SRG Bdnf engages in both pre-existing and activity-inducible loops that form within 1–6 h. We also show that common single-nucleotide variants that are associated with autism and schizophrenia are colocalized with distinct classes of activity-dependent, looped enhancers. Our data link architectural complexity to transcriptional kinetics and reveal the rapid timescale by which higher-order chromatin architecture reconfigures during neuronal stimulation.

神经元激活诱导立即早期基因 (IEG) 的快速转录和次级反应基因 (SRG) 周围的长期染色质重塑。在这里，我们使用高分辨率染色体构象捕获碳拷贝测序（5C-seq）来阐明在神经活动的短期和长期变化期间长程染色质环改变的程度。我们发现，在皮层神经元激活过程中，超过 10% 的围绕选定 IEG、SRG 和突触基因的环是从头诱导的。 IEG Fos和Arc通过刺激后 20 分钟内、信使 RNA 水平达到峰值之前形成的单一短程环连接到活动依赖性增强子。相比之下，SRG Bdnf参与 1-6 小时内形成的预先存在的环路和活动诱导环路。我们还表明，与自闭症和精神分裂症相关的常见单核苷酸变异与不同类别的活性依赖性环状增强子共定位。我们的数据将结构复杂性与转录动力学联系起来，并揭示了高阶染色质结构在神经元刺激过程中重新配置的快速时间尺度。