Cell type-specific transcriptional programs in mouse prefrontal cortex during adolescence and addiction

Coordinated activity-induced transcriptional changes across multiple neuron subtypes of the prefrontal cortex (PFC) play a pivotal role in encoding and regulating major cognitive behaviors. Yet, the specific transcriptional programs in each neuron subtype remain unknown. Using single-cell RNA sequencing (scRNA-seq), here we comprehensively classified all unique cell subtypes in the PFC. We analyzed transcriptional dynamics of each cell subtype under a naturally adaptive and an induced condition. Adaptive changes during adolescence (between P21 and P60), a highly dynamic phase of postnatal neuroplasticity, profoundly impacted transcription in each neuron subtype, including cell type-specific regulation of genes implicated in major neuropsychiatric disorders. On the other hand, an induced plasticity evoked by chronic cocaine addiction resulted in progressive transcriptional changes in multiple neuron subtypes and became most pronounced upon prolonged drug withdrawal. Our findings lay a foundation for understanding cell type-specific postnatal transcriptional dynamics under normal PFC function and in neuropsychiatric disease states. To generate a comprehensive cell map of mouse PFC, we dissect this brain region from acute coronal sections of young (3 weeks) and adult mouse brains (8-10 weeks). After cell dissociation, single cells are captured with the 10X Chromium platform (10X Genomics), followed by cDNA synthesis, library preparation and high-throughput sequencing. Adult mice were subject to cocaine self-administration, samples were collected a three time points: Maintance, 48h after cocaine withdrawal and 15 days after cocaine withdrawal. A total of 6 saline-treated adult mice samples (2 in each time point), 6 cocaine-treated adult mice samples (2 in each time point) and 3 young mouse (P21) samples were sequenced and analyzed. Each sample represents mixed cell types (please refer to meta_data.csv).