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Local synaptic inhibition mediates cerebellar granule cell pattern separation and enables learned sensorimotor associations

Nature Neuroscience volume 27, pages 689–701 (2024)Cite this article

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Abstract

The cerebellar cortex has a key role in generating predictive sensorimotor associations. To do so, the granule cell layer is thought to establish unique sensorimotor representations for learning. However, how this is achieved and how granule cell population responses contribute to behavior have remained unclear. To address these questions, we have used in vivo calcium imaging and granule cell-specific pharmacological manipulation of synaptic inhibition in awake, behaving mice. These experiments indicate that inhibition sparsens and thresholds sensory responses, limiting overlap between sensory ensembles and preventing spiking in many granule cells that receive excitatory input. Moreover, inhibition can be recruited in a stimulus-specific manner to powerfully decorrelate multisensory ensembles. Consistent with these results, granule cell inhibition is required for accurate cerebellum-dependent sensorimotor behavior. These data thus reveal key mechanisms for granule cell layer pattern separation beyond those envisioned by classical models.

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Fig. 1: Local synaptic inhibition sparsens and thresholds cerebellar granule cell sensory responses.
Fig. 2: Synaptic inhibition restricts the number of granule cells recruited by sensory input.
Fig. 3: Cerebellar granule cells exhibit stimulus feature preferences that are not abolished by blocking synaptic inhibition.
Fig. 4: Synaptic inhibition facilitates pattern separation for auditory and somatosensory responsive granule cell ensembles.
Fig. 5: Coincident stimuli create unique granule cell ensembles.
Fig. 6: Cerebellar granule cells respond with temporal variability to auditory stimuli.
Fig. 7: Local synaptic inhibition is necessary for the expression of a sensorimotor association.

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Data availability

Due to the large size of these datasets, data that support the findings of this study are available from the corresponding author upon request.

Code availability

Codes that support the findings of this study are available at

https://github.com/Glickfeld-And-Hull-Laboratories/ImagingCode-Glickfeld-Hull/tree/master/court/Manuscripts/Fleming_NatureNeurosci.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (NIH) (institutes: NINDS (5R01NS096289 and R01NS112917 to C.H., 1F31NS113742 to E.A.F. and R01-NS107472 to M.R.T.), NIMH (RF1-MH117055 and DP2-MH1194025 to M.R.T.), NIDA (R61-DA051530 to M.R.T.) and NEI (EY031396 to G.D.F.)). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper. We thank S. Lisberger, L. Glickfeld, J. Pearson and N. Calakos for input throughout the project; J. Medina and S. Heiney for input specific to eyelid conditioning experiments; J. Medina and W. Regehr for comments on the paper; and B. Shields for technical assistance with DART reagents.

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Authors and Affiliations

  1. Department of Neurobiology, Duke University Medical School, Durham, NC, USA

    Elizabeth A. Fleming, Greg D. Field, Michael R. Tadross & Court Hull

  2. Stein Eye Institute, Department of Ophthalmology, University of California, Los Angeles, CA, USA

    Greg D. Field

  3. Department of Biomedical Engineering, Duke University, Durham, NC, USA

    Michael R. Tadross

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Contributions

E.A.F. performed surgeries, conducted experiments and analyzed data. G.D.F. performed decoding analyses. M.R.T. provided DART reagents and consulted on their use. C.H. and E.A.F. designed experiments, made figures and wrote the paper. All authors read and edited the paper.

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Correspondence to Court Hull.

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Supplementary Figs. 1–20 and Table 1.

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Example field of view of granule cell activity.

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Fleming, E.A., Field, G.D., Tadross, M.R. et al. Local synaptic inhibition mediates cerebellar granule cell pattern separation and enables learned sensorimotor associations. Nat Neurosci 27, 689–701 (2024). https://doi.org/10.1038/s41593-023-01565-4

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