Letter | Published:

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

Abstract

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 characterized1,2,3,4,5,6,7,8. However, the fundamental question of whether 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 we use in vivo calcium imaging, optogenetics and pharmacological approaches to show that granule neuron activation in the anterior dorsal cerebellar vermis has a crucial role in a delay tactile startle learning paradigm in mice. Of note, using large-scale transcriptome and chromatin profiling, we show 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 anterior dorsal cerebellar vermis granule neurons in adult mice disrupts enhancer–promoter interactions, 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.

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Data availability

ChIP-seq, RNA-seq, DHS, Hi-C and PLAC-seq data are available in the Gene Expression Omnibus (GEO) database under the reference number GSE127995.

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Change history

  • 22 May 2019

    In this Letter, ‘≥’ should be ‘≤’ in the sentence: “Intra-chromosomal reads were further split into short-range reads (≥1 kb) and long-range reads (>1 kb)”. This error has been corrected online.

    An amendment to this paper has been published and can be accessed via a link at the top of the paper

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Acknowledgements

We thank members of the Bonni laboratory for helpful discussions and critical reading of the manuscript, Y. Tanabe for genotyping, and M. Muratani and Tsukuba i-Laboratory for sequencing. Supported by NIH grants NS041021 (A.B.) and U54DK107977 (M.H.), the Mathers Foundation (A.B.), Program to Disseminate Tenure Tracking System by MEXT (T.Y.) and JSPS KAKENHI Grant-in-Aid for Young Scientists 17H04981 (T.Y.).

Reviewer information

Nature thanks Timothy Ebner and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

T.Y., Y.Y., P.V. and A.B. designed the study and wrote the manuscript. T.Y., Y.Y., I.J., A.A. and M.H. performed RNA-seq, ChIP-seq, Hi-C, PLAC-seq and bioinformatics analyses. Y.Y., P.V., K.H.M., A.N.G., A.G., A.O. and T.E.H. performed mouse behavior, optogenetics, CRISPR genetics and in vivo imaging analyses.

Competing interests

The authors declare no competing interests.

Correspondence to Tomoko Yamada or Azad Bonni.

Extended data figures and tables

  1. Extended Data Fig. 1 Pharmacological inactivation of the ADCV and lobule VI in delay tactile startle conditioning.

    a, Mice were subjected to tactile stimulation of the tail using an air puff (n = 3 mice). b, The delay tactile startle conditioning paradigm as in Fig. 1c–e using a 300 ms inter-stimulus interval (ISI) (left) and the percentage of trials with a conditioned response (CR) (right, day 1 versus day 7, P = 1.8 × 10−5, two-tailed t-test, n = 5 mice). c, d, Cannula placement in the ADCV for drug delivery (c). Top, sagittal view; bottom, coronal view. Black or red/pink crosses indicate sites of saline or muscimol injections, respectively. Muscimol conjugated with the fluorophore BODIPY TMR-X injected one day after the last day of delay tactile startle conditioning was used to identify the location of the cannula tip. A representative injection site is shown (d, n = 38 mice). e, Mice injected with saline or muscimol in the ADCV were tested on the DigiGait system (n = 5 mice). f, g, Cannula placement in lobule VI for drug delivery (f). The percentage of conditioned responses during delay tactile startle conditioning (g, top) and unconditioned responses (g, bottom) upon muscimol-dependent neuronal inactivation in lobule VI (n = 8 mice). In all panels, data show mean and shading or error bars denote s.e.m.

  2. Extended Data Fig. 2 Optogenetic inactivation and stimulation of the ADCV and lobule VI in delay tactile startle conditioning.

    a, Day 5 backward conditioned responses of control mice subjected to delay tactile startle conditioning and optical stimulation in the ADCV as in Fig. 1i (Ai40 control +ADCV laser, n = 9 mice), Ai40-GC mice subjected to delay tactile startle conditioning in the absence of optical stimulation (Ai40-GC + no laser, n = 6 mice), or Ai40-GC mice subjected to delay tactile startle conditioning and optogenetic silencing of lobule VI during the CS (Ai40-GC +L. VI laser, n = 7 mice). b, Acute sagittal cerebellar slices were prepared from mice expressing channelrhodopsin in granule neurons (Ai32-GC mice). Granule neuron action potentials were recorded in response to 100 ms optogenetic stimuli each composed of a 50 Hz train of 10 ms pulses (blue squares). A representative membrane potential trace for a granule neuron (left, n = 2 neurons) and the relationship between the intensity of optostimulation of granule neurons and action potential firing (right, n = 4 neurons). c, Mice expressing channelrhodopsin in granule neurons (Ai32-GC mice) were subjected to optostimulation of the granule neuron pathway in the ADCV as the CS in the absence of the US (n = 3 mice). d, Control mice were subjected to optical stimulation in the ADCV as the CS together with the US (n = 3 mice). e, Mice expressing channelrhodopsin in granule neurons (Ai32-GC mice) were subjected to three days of delay tactile startle conditioning using optostimulation of lobule VI as the CS (backward conditioned responses in naive versus day 3, P = 6.1 × 10−11, two-tailed t-test, n = 6 mice). In all panels, data show mean and error bars denote s.e.m.

  3. Extended Data Fig. 3 In vivo imaging of granule neuron coding during delay tactile startle conditioning.

    a, Sagittal sections from the cerebellum of mice expressing GCaMP6f in granule neurons (Ai95-GC) were subjected to immunohistochemistry using the GFP and Calbindin antibodies and the DNA dye Bisbenzimide (Hoechst) (n = 2 mice). Scale bar, 200 µm, 10× magnification (top); 50 µm, 40× magnification (bottom). IGL, internal granule layer; ML, molecular layer; PCL, Purkinje cell layer. b, In vivo two-photon calcium imaging of Ai95-GC mice subjected to delay tactile startle conditioning, followed by image registration and auto cell-segmentation. In a representative imaging session, the average mouse locomotion during ten training trials (top), segmented granule neuron somas (middle, left) and their calcium responses (middle, right), and population granule neuron responsivity (bottom) (n = 6 mice). c, Locomotion of Ai95-GC mice during delay tactile startle conditioning on day 1 and after training for 6–9 days (n = 6 mice). d, The percentage of granule neurons that are active in the ADCV during the CS period in tactile startle conditioning (*P = 0.031, ***P = 7.3 × 10−5, one-way ANOVA with Dunnett’s post hoc test, n = 5, 4, 4 mice for day 1, day 6–9 CR+, day 6–9 CR−). e, Population responsivity of granule neurons in lobule VI during the CS period in tactile startle conditioning (**P < 0.01, ***P < 0.001, two-way repeated measures ANOVA with Dunnett’s post hoc test, n = 5 mice). In all panels, data show mean and shading or error bars denote s.e.m.

  4. Extended Data Fig. 4 In vivo imaging of Purkinje cell dendrite coding during delay tactile startle conditioning.

    a, b, The AAV delivery approach to label Purkinje cells in the ADCV and lobule VI (a). Sagittal sections from the cerebellum of Pcp2-Cre mice injected with AAV9-Flex-GCaMP6f (AAV9-GCaMP6f-PC) were subjected to immunohistochemistry using the GFP antibody and Hoechst (b, n = 2 mice). Scale bars, 500 µm, 4× magnification (top); 50 µm, 40× magnification (bottom). c, In vivo two-photon calcium imaging of AAV9-GCaMP6f-PC mice subjected to 60 s of free wheel locomotion and 10 trials of delay tactile startle conditioning with randomized inter-trial intervals. In a representative imaging session, Purkinje cell dendrite calcium responses were analysed as in Extended Data Fig. 3b (n = 10 mice). d, Locomotion of AAV9–GCaMP6f–PC mice during delay tactile startle conditioning on day 1 and after training for 5–8 days (n = 10 mice). Data show mean and shading denotes s.e.m.

  5. Extended Data Fig. 5 Identification of cell type-enriched and sensorimotor experience-dependent gene modules in the cerebellum in mice.

    a, Gene modules identified in Fig. 3b were intersected with cerebellar cell type-specific TRAP-seq data and analysed as in Fig. 3c. b, Heat maps of gene module expression induced by sensorimotor stimulation as in Fig. 3a (n = 52 samples, log2 mean centred). c, Comparison of the log2 fold change in gene expression induced by free wheel locomotion compared to homecage control and the log2 fold change in gene expression upon treatment with the GABAA receptor agonist muscimol compared to saline control during free wheel locomotion in the ADCV of mice. Genes in the light cyan module induced by locomotion that were restored to homecage control expression levels upon silencing of the ADCV cortical activity with muscimol (reversal) fall on the dotted line. d, Sensorimotor stimulation-dependent gene modules analysed as in c. e, The average velocity of mice subjected to delay tactile startle conditioning (US + CS) or control (US) condition during inter-trial intervals (n = 4 mice). f, g, Gene expression in the ADCV or lobule VI of mice subjected to delay tactile startle conditioning (US + CS) or control (US) condition (n = 4 mice). In all panels, data show mean and error bars denote s.e.m.

  6. Extended Data Fig. 6 Optostimulation of granule neurons potentiates CS pathway-regulated gene modules.

    a, UCSC genome browser tracks of chromatin-bound (Chrom-seq) and nucleocytoplasmic (NucCyto-seq) RNA at the Fosl2 locus upon optostimulation of granule neurons in the ADCV in mice. The chromatin-bound fraction contained immature unspliced RNA and the nucleocytoplasmic fraction contained spliced mature RNA. bd, Comparisons of the log2 fold change in chromatin-bound RNA and the log2 fold change in nucleocytoplasmic RNA upon optostimulation of granule neurons together with the log2 fold change in total RNA upon sensorimotor stimulation in the ADCV in mice (n = 4, 4, 18 mice for chromatin, nucleocytoplasmic, total RNA). Data show mean ± s.e.m. e, Pulse chase analyses were performed by optogenetically stimulating granule neurons in the ADCV for 10 min and returning mice to their homecage for 10, 50 or 140 min. The ADCV of optostimulated or unstimulated control mice was then subjected to RNA-seq using the chromatin-bound (nascent) or nucleocytoplasmic (mature) fractions. fi, Time course of chromatin-bound (nascent) or nucleocytoplasmic (mature) RNA expression following optostimulation of granule neurons as in e (n = 2 mice).

  7. Extended Data Fig. 7 Optostimulation of the CS pathway regulates uaRNA and eRNA expression.

    a, b, Heat maps of significantly differentially expressed (DE) uaRNA and eRNA from chrom-seq or nuc-cyto-seq (two-sided P value from negative binomial distribution with Benjamini–Hochberg post hoc test, n = 4 mice, false discovery rate (FDR) < 0.05, log2 mean centred). c, Comparison of the log2 fold change in mRNA expression and the log2 fold change in uaRNA and eRNA expression at light cyan, midnight blue, and brown gene modules upon optostimulation of granule neurons (n = 83, 67, 342 transcript–uaRNA pairs and n = 66, 63, 366 transcript–eRNA pairs for light cyan, midnight blue, brown). The Pearson correlation coefficient (corr) is shown.

  8. Extended Data Fig. 8 Optostimulation of the CS pathway regulates histone modification and histone variant abundance at gene promoters and enhancers.

    ac, Comparison of the log2 fold change in gene expression and the log2 fold change in H3K27ac (a), H2A.z (b), or H3K4me3 (c) read density at the TSSs of granule neuron-enriched gene modules upon optostimulation of granule neurons in the ADCV in mice (n = 85, 355 transcripts for midnight blue, brown). The Pearson correlation coefficient (corr) is shown. d, The profile of the histone marks H3K27ac, H2A.z, H3K4me3, and H3K27me3 surrounding the TSSs of genes whose expression was upregulated (left, mRNA fold change >1, log2), not changed (middle, −0.05< mRNA fold change <0.05, log2), or downregulated (right, mRNA fold change <−1, log2) upon optostimulation of granule neurons (n = 2, 3, 2, 2 biological replicates for H3K27ac, H2A.z, H3K4me3, H3K27me3). e, f, Comparison of the log2 fold change in mRNA or eRNA and the log2 fold change in H3K27ac (top) or H2A.z (bottom) levels at the enhancers of granule neuron-enriched CS-regulated gene modules (e, n = 266, 256, 1,510 enhancers for light cyan, midnight blue, brown). The Pearson correlation coefficient (corr) is shown. The profile of H3K27ac and H2A.z surrounding enhancers with eRNA levels that were upregulated (left, mRNA fold change >1, log2), not changed (middle, −0.05 < mRNA fold change < 0.05, log2) or downregulated (right, mRNA fold change < −1, log2) upon optostimulation of granule neurons (f, n = 2, 3 biological replicates for H3K27ac, H2A.z). In all panels, data show mean.

  9. Extended Data Fig. 9 Transcription factors enriched at CS pathway regulated genes.

    a, Transcription factor binding motifs enriched at enhancers or promoters with upregulated (fold change >1 or >0.585, log2) or downregulated (fold change <−1 or <−0.585, log2) H3K27ac levels upon optostimulation of granule neurons (n = 1,379, 419 enhancers for FC > 1, FC < −1; n = 290, 166 promoters for FC > 0.585, FC < −0.585). b, Transcription factor binding motifs enriched at enhancers or promoters of granule neuron CS pathway activated gene modules (n = 364, 288, 1,139 enhancers and n = 37, 38, 69 promoters for light cyan, midnight blue, brown). In all panels, Fisher’s exact test with Benjamini post hoc test. NS, no significant motifs identified.

  10. Extended Data Fig. 10 Chromatin architecture in the cerebellum.

    a, Features of genomic loci interacting with promoters in the adult cerebellum. MAPS analyses of PLAC-seq data identified promoter-centric interactions enriched for regulatory regions of the genome marked by occupancy of CTCF or H3K27ac. b, c, PLAC-seq analyses of the number of home-specific and opto-specific interactions (b, P = 4.7 × 10−5, chi-square test, n = 2 biological replicates) or changes in interaction frequency (c, **P = 0.0045, ***P = 0.00026, two-sided Wilcoxon signed rank test, n = 83, 49 enhancer–promoter pairs for FC > 0.585, FC < −0.585) between promoters and enhancers harbouring upregulated (blue, fold change >0.585 or >1, log2) or downregulated (green, fold change <−0.585, log2) H3K27ac levels upon optostimulation of granule neurons. Box plots show median, quartiles (box) and range (whiskers). d, Features of frequently interacting regions (FIREs) in the adult cerebellum. e, The number of home-specific and opto-specific FIREs within 200 kb of TSSs harbouring upregulated (blue, fold change >0.585 or >1, log2) or downregulated (green, fold change <−0.585, log2) H3K27ac levels upon optostimulation of granule neurons (P = 8.8 × 10−7, chi-square test, n = 3 biological replicates). f, The profile of H3K27ac surrounding the distal (left) or proximal (right) enhancers of genes indicated in Fig. 4d (n = 2 biological replicates). Data show mean. g, h, A representative image of a granule neuron labelled with DNA FISH probes targeting the Nr4a3 (green) or Gapdh (red) gene together with Hoechst (g, n = 416 nuclei). The dotted line indicates the nucleus. The co-localization of the Nr4a3 and Gapdh genes upon optostimulation (h, n = 2 mice). Data show mean. i, Bins along chromosomes upon optostimulation of granule neurons (n = 24,046 bins). The Pearson correlation coefficient (corr) is shown. j, PLAC-seq analyses of inter-chromosomal normalized interaction frequency between genomic loci at 100 kb resolution harbouring upregulated (blue, fold change >0.585, log2) or downregulated (green, fold change <−0.585, log2) H3K27ac levels as in Fig. 4j. k, Sagittal sections from the cerebellum of Cas9-EGFP-GC mice infected with AAV9-gRNA-mCherry as in Fig. 5f and subjected to immunohistochemistry using the GFP and DsRed antibodies and DAPI (n = 4 mice). Scale bar, 100 µm. l, The ADCV of conditional CRISPR Rad21-knockout or control mice analysed as in Fig. 5j (n = 2, 2, 5, 5 mice for home-control, home-Rad21-cKO, US + CS control, US + CS Rad21-cKO). Data show mean and error bars denote s.e.m.

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Fig. 1: The ADCV plays a crucial role in delay tactile startle conditioning.
Fig. 2: Transformation of mossy fibre–granule neuron and climbing fibre–Purkinje cell neural coding in the anterior cerebellum during motor learning in mice.
Fig. 3: Sensorimotor stimulation triggers epigenetic regulation of cell type-enriched gene modules in the cerebellum in vivo.
Fig. 4: Activation of granule neuron CS pathway promotes enhancer–promoter interactions and compartmentalization in vivo.
Fig. 5: The core cohesin subunit Rad21 is required for activity-dependent transcription and motor learning in mice.
Extended Data Fig. 1: Pharmacological inactivation of the ADCV and lobule VI in delay tactile startle conditioning.
Extended Data Fig. 2: Optogenetic inactivation and stimulation of the ADCV and lobule VI in delay tactile startle conditioning.
Extended Data Fig. 3: In vivo imaging of granule neuron coding during delay tactile startle conditioning.
Extended Data Fig. 4: In vivo imaging of Purkinje cell dendrite coding during delay tactile startle conditioning.
Extended Data Fig. 5: Identification of cell type-enriched and sensorimotor experience-dependent gene modules in the cerebellum in mice.
Extended Data Fig. 6: Optostimulation of granule neurons potentiates CS pathway-regulated gene modules.
Extended Data Fig. 7: Optostimulation of the CS pathway regulates uaRNA and eRNA expression.
Extended Data Fig. 8: Optostimulation of the CS pathway regulates histone modification and histone variant abundance at gene promoters and enhancers.
Extended Data Fig. 9: Transcription factors enriched at CS pathway regulated genes.
Extended Data Fig. 10: Chromatin architecture in the cerebellum.

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