Sensory experience remodels genome architecture in neural circuit to drive motor learning

Neuronal activity-dependent transcription couples sensory experience to adaptive responses of the brain including learning and memory. Mechanisms of activity-dependent gene expression including alterations of the epigenome have been characterized. However, the fundamental question of whether and how sensory experience remodels chromatin architecture in the adult brain in vivo to induce neural code transformations and learning and memory remains to be addressed. Here, in vivo calcium imaging, optogenetics, and pharmacological approaches reveal that granule neuron activation in the anterior dorsal cerebellar vermis (ADCV) plays a crucial role in a novel delay tactile startle learning paradigm in mice. Strikingly, using large-scale transcriptome and chromatin profiling, we have discovered that activation of the motor learning-linked granule neuron circuit reorganizes neuronal chromatin including through long-distance enhancer-promoter and transcriptionally active compartment interactions to orchestrate distinct granule neuron gene expression modules. Conditional CRISPR knockout of the chromatin architecture regulator Cohesin in ADCV granule neurons in adult mice disrupts activity-dependent transcription and motor learning. These findings define how sensory experience patterns chromatin architecture and neural circuit coding in the brain to drive motor learning. Overall design: Two to four replicates of the histone modifications (H3K27ac, H3K27me3, and H3K4me3), histone variant (H2A.z), transcriptional regulator (CTCF), in situ chromosome conformation capture (HiC), and proximity ligation assisted ChIP (PLAC) from ADCV of 6-8 weeks old mice subjected to optogenetic stimulation or the homecage control were examined using libraries prepared with the NEBNext Ultra™ II DNA Library Prep Kit. Two to five replicates of chromatin-bound RNA, nucleocytoplasmic RNA, or total RNA were extracted from ADCV, lobule VI, or total cerebella of 6-8 weeks old mice subjected to optogenetic stimulation, pharmacological treatment, sensorimotor stimulation, or control conditions using Trizol and the NEBNext rRNA Depletion Kit were examined using libraries prepared with the NEBNext Ultra™ Directional RNA Library Prep Kit. Two replicates of DNase hypersensitive sites from total cerebella of P22 mice were examined using libraries prepared with the Illumina DNA Sample Prep Kit. All samples were sequenced on the Illumina NextSeq 500 platform, except for DHS samples that were sequenced on the Illumina HiSeq 2000 platform.