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We found that molecular layer interneurons (MLIs), whose inhibition of PCs powerfully opposes climbing-fiber-mediated excitation, serve this function. Optogenetically suppressing the activity of floccular MLIs in mice during the vestibulo-ocular reflex (VOR) induces a learned increase in gain despite the absence of performance errors. Suppressing MLIs when the VOR is mistakenly underperformed reveled that their inhibitory output is necessary to orchestrate gain-increase learning by conditionally permitting climbing fibers to instruct plasticity induction during ipsiversive head turns. Ablation of an MLI circuit for PC disinhibition prevents gain-increase learning during VOR performance errors which was rescued by re-imposing PC disinhibition through MLI activity suppression. Our findings point to a decisive role for MLIs in gating climbing-fiber-mediated learning through their context-dependent inhibition of PCs.<\/jats:p>","DOI":"10.1101\/2023.08.04.552059","type":"posted-content","created":{"date-parts":[[2023,8,5]],"date-time":"2023-08-05T04:20:20Z","timestamp":1691209220000},"source":"Crossref","is-referenced-by-count":15,"title":["Molecular layer disinhibition unlocks climbing-fiber-instructed motor learning in the cerebellum"],"prefix":"10.64898","author":[{"given":"Ke","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Gaffield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garrett G.","family":"Gross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don B.","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason M.","family":"Christie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023080808150876000_2023.08.04.552059v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/0025-5564(71)90051-4"},{"key":"2023080808150876000_2023.08.04.552059v1.2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0179347"},{"key":"2023080808150876000_2023.08.04.552059v1.3","doi-asserted-by":"crossref","first-page":"3020","DOI":"10.1016\/j.celrep.2020.02.009","article-title":"Microcircuit Rules Governing Impact of Single Interneurons on Purkinje Cell Output In Vivo","volume":"30","year":"2020","journal-title":"Cell reports"},{"key":"2023080808150876000_2023.08.04.552059v1.4","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1091-17.2017"},{"key":"2023080808150876000_2023.08.04.552059v1.5","doi-asserted-by":"publisher","DOI":"10.1113\/JP271518"},{"key":"2023080808150876000_2023.08.04.552059v1.6","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1038\/s41467-021-22405-8","article-title":"Autonomous Purkinje cell activation instructs bidirectional motor learning through evoked dendritic calcium signaling","volume":"12","year":"2021","journal-title":"Nature communications"},{"key":"2023080808150876000_2023.08.04.552059v1.7","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.27.070203.144238"},{"key":"2023080808150876000_2023.08.04.552059v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.08.026"},{"key":"2023080808150876000_2023.08.04.552059v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.08.023"},{"key":"2023080808150876000_2023.08.04.552059v1.10","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.15-04-02777.1995"},{"key":"2023080808150876000_2023.08.04.552059v1.11","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/s41467-017-00312-1","article-title":"Serial processing of kinematic signals by cerebellar circuitry during voluntary whisking","volume":"8","year":"2017","journal-title":"Nature communications"},{"key":"2023080808150876000_2023.08.04.552059v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2718"},{"key":"2023080808150876000_2023.08.04.552059v1.13","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0559-08.2008"},{"key":"2023080808150876000_2023.08.04.552059v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(98)01310-1"},{"key":"2023080808150876000_2023.08.04.552059v1.15","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1350-11.2011"},{"key":"2023080808150876000_2023.08.04.552059v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(85)91136-9"},{"key":"2023080808150876000_2023.08.04.552059v1.17","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1152\/jn.00715.2020","article-title":"Population calcium responses of Purkinje cells in the oculomotor cerebellum driven by nonvisual input","volume":"126","year":"2021","journal-title":"Journal of neurophysiology"},{"key":"2023080808150876000_2023.08.04.552059v1.18","first-page":"706","article-title":"Calcium as a trigger for cerebellar long-term synaptic depression. 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