{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:14:41Z","timestamp":1785420881079,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,3]]},"group-title":"Neuroscience","reference-count":42,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01 MH132710"],"award-info":[{"award-number":["R01 MH132710"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The cerebellar granule cell layer receives mossy fiber inputs from diverse brain regions, yet the principles governing how individual granule cells sample distinct types of inputs remain poorly understood. Using a volumetric correlated light and electron microscopy (vCLEM) dataset from an adult female mouse cerebellum, in which VGluT1-positive and VGluT1-negative mossy fiber terminals are molecularly distinguished, we reconstructed granule cell and mossy fiber connectivity to examine input selection rules. We constructed spatially constrained null models to simulate sampling during adulthood and development. Granule cell-centered analysis showed that granule cells shared less innervation from the same mossy fiber than expected by chance. Moreover, subpopulations of granule cells preferentially sample either VGluT1-positive or VGluT1-negative mossy fibers. In contrast, mossy fiber\u2013centered analysis showed that individual terminals distributed their outputs across granule cells in a pattern consistent with random sampling. However, sampling in the adult state was more selective than in developmental simulations. Together, our findings demonstrated structured, non-random sampling of cerebellar VGluT1-positive and VGluT1-negative mossy fiber inputs and provide a framework for understanding how granule cells integrate molecularly distinct inputs to support cerebellar computation.<\/jats:p>","DOI":"10.1101\/2025.10.02.679866","type":"posted-content","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T08:45:16Z","timestamp":1759481116000},"source":"Crossref","is-referenced-by-count":0,"title":["Structured Sampling of Molecularly Classified Mossy Fiber Inputs by Cerebellar Granule Cells"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1409-7419","authenticated-orcid":false,"given":"Xiaomeng","family":"Han","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif Sevde","family":"Meral","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0208-3212","authenticated-orcid":false,"given":"Jeff","family":"Lichtman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025100608551027000_2025.10.02.679866v1.1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/0025-5564(71)90051-4","article-title":"A Theory of Cerebellar Function","volume":"10","year":"1971","journal-title":"Bellman Prize in Mathematical Biosciences"},{"key":"2025100608551027000_2025.10.02.679866v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.901450403"},{"key":"2025100608551027000_2025.10.02.679866v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/cne.901790104"},{"key":"2025100608551027000_2025.10.02.679866v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2698"},{"key":"2025100608551027000_2025.10.02.679866v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.07.020"},{"issue":"6","key":"2025100608551027000_2025.10.02.679866v1.6","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/nmeth.3400","article-title":"Correlated Light and Electron Microscopy: Ultrastructure Lights Up!","volume":"12","year":"2015","journal-title":"Nature Methods"},{"issue":"1","key":"2025100608551027000_2025.10.02.679866v1.7","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1038\/s41467-017-01109-y","article-title":"Sparse Synaptic Connectivity Is Required for Decorrelation and Pattern Separation in Feedforward Networks","volume":"8","year":"2017","journal-title":"Nature Communications"},{"key":"2025100608551027000_2025.10.02.679866v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3974"},{"key":"2025100608551027000_2025.10.02.679866v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-00754-9"},{"issue":"1","key":"2025100608551027000_2025.10.02.679866v1.10","doi-asserted-by":"crossref","first-page":"17561","DOI":"10.1038\/s41598-018-35829-y","article-title":"Developmental Pattern and Structural Factors of Dendritic Survival in Cerebellar Granule Cells in Vivo","volume":"8","year":"2018","journal-title":"Scientific Reports"},{"key":"2025100608551027000_2025.10.02.679866v1.11","doi-asserted-by":"crossref","first-page":"30","DOI":"10.3389\/fncir.2019.00030","article-title":"Tracing of Afferent Connections in the Zebrafish Cerebellum Using Recombinant Rabies Virus","volume":"13","year":"2019","journal-title":"Frontiers in Neural Circuits"},{"key":"2025100608551027000_2025.10.02.679866v1.12","unstructured":"Eccles, John C. 2013. The Cerebellum as a Neuronal Machine. Berlin, Germany: Springer."},{"key":"2025100608551027000_2025.10.02.679866v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2003.11.005"},{"issue":"2","key":"2025100608551027000_2025.10.02.679866v1.14","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s00429-011-0339-4","article-title":"Parasagittal Compartmentation of Cerebellar Mossy Fibers as Revealed by the Patterned Expression of Vesicular Glutamate Transporters VGLUT1 and VGLUT2","volume":"217","year":"2012","journal-title":"Brain Structure & Function"},{"key":"2025100608551027000_2025.10.02.679866v1.15","doi-asserted-by":"publisher","DOI":"10.1002\/cne.902200402"},{"issue":"1","key":"2025100608551027000_2025.10.02.679866v1.16","doi-asserted-by":"crossref","first-page":"6648","DOI":"10.1038\/s41467-024-50411-z","article-title":"Multiplexed Volumetric CLEM Enabled by ScFvs Provides Insights into the Cytology of Cerebellar Cortex","volume":"15","year":"2024","journal-title":"Nature Communications"},{"key":"2025100608551027000_2025.10.02.679866v1.17","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/nmeth.2476","article-title":"Cellular-Resolution Connectomics: Challenges of Dense Neural Circuit Reconstruction","volume":"10","year":"2013","journal-title":"Nature Methods"},{"key":"2025100608551027000_2025.10.02.679866v1.18","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2008.06572.x"},{"key":"2025100608551027000_2025.10.02.679866v1.19","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.12916"},{"key":"2025100608551027000_2025.10.02.679866v1.20","doi-asserted-by":"crossref","first-page":"1236015","DOI":"10.3389\/fnmol.2023.1236015","article-title":"Regulation of Cerebellar Network Development by Granule Cells and Their Molecules","volume":"16","year":"2023","journal-title":"Frontiers in Molecular Neuroscience"},{"issue":"1","key":"2025100608551027000_2025.10.02.679866v1.21","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/s42003-023-04825-y","article-title":"Developmental Timing-Dependent Organization of Synaptic Connections between Mossy Fibers and Granule Cells in the Cerebellum","volume":"6","year":"2023","journal-title":"Communications Biology"},{"issue":"9","key":"2025100608551027000_2025.10.02.679866v1.22","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.cub.2017.03.029","article-title":"Sensorimotor Representations in Cerebellar Granule Cells in Larval Zebrafish Are Dense, Spatially Organized, and Non-Temporally Patterned","volume":"27","year":"2017","journal-title":"Current Biology: CB"},{"key":"2025100608551027000_2025.10.02.679866v1.23","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.15-02-01110.1995"},{"key":"2025100608551027000_2025.10.02.679866v1.24","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.18-04-01478.1998"},{"key":"2025100608551027000_2025.10.02.679866v1.25","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.15021.1"},{"key":"2025100608551027000_2025.10.02.679866v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2020.06.008"},{"key":"2025100608551027000_2025.10.02.679866v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.01.030"},{"key":"2025100608551027000_2025.10.02.679866v1.28","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1969.sp008820"},{"issue":"1","key":"2025100608551027000_2025.10.02.679866v1.29","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/s42003-020-0953-x","article-title":"Parameter Tuning Differentiates Granule Cell Subtypes Enriching Transmission Properties at the Cerebellum Input Stage","volume":"3","year":"2020","journal-title":"Communications Biology"},{"key":"2025100608551027000_2025.10.02.679866v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05471-w"},{"key":"2025100608551027000_2025.10.02.679866v1.31","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9861(20000619)422:1<55::AID-CNE4>3.0.CO;2-9"},{"key":"2025100608551027000_2025.10.02.679866v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(03)00568-2"},{"key":"2025100608551027000_2025.10.02.679866v1.33","unstructured":"Palay, S. L. , and V. Chan-Palay . 2012. Cerebellar Cortex: Cytology and Organization. Springer Science & Business Media."},{"key":"2025100608551027000_2025.10.02.679866v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s43586-022-00131-9"},{"issue":"12","key":"2025100608551027000_2025.10.02.679866v1.35","doi-asserted-by":"crossref","first-page":"109721","DOI":"10.1016\/j.celrep.2021.109721","article-title":"Homologous Organization of Cerebellar Pathways to Sensory, Motor, and Associative Forebrain","volume":"36","year":"2021","journal-title":"Cell Reports"},{"key":"2025100608551027000_2025.10.02.679866v1.36","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4695(199702)32:2<223::AID-NEU7>3.0.CO;2-A"},{"key":"2025100608551027000_2025.10.02.679866v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(94)90293-3"},{"issue":"1","key":"2025100608551027000_2025.10.02.679866v1.38","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s00018-014-1729-6","article-title":"Mechanisms of Developmental Neurite Pruning","volume":"72","year":"2015","journal-title":"Cellular and Molecular Life Sciences: CMLS"},{"key":"2025100608551027000_2025.10.02.679866v1.39","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-071714-033954"},{"issue":"1","key":"2025100608551027000_2025.10.02.679866v1.40","doi-asserted-by":"crossref","first-page":"16240","DOI":"10.1038\/s41598-017-15938-w","article-title":"Population-Scale Organization of Cerebellar Granule Neuron Signaling during a Visuomotor Behavior","volume":"7","year":"2017","journal-title":"Scientific Reports"},{"key":"2025100608551027000_2025.10.02.679866v1.41","doi-asserted-by":"crossref","unstructured":"Tavakoli, Mojtaba R. , Julia Lyudchik , Micha\u0142 Januszewski , Vitali Vistunou , Nathalie Agudelo Due\u00f1as , Jakob Vorlaufer , Christoph Sommer , et al. 2025. \u201cLight-Microscopy-Based Connectomic Reconstruction of Mammalian Brain Tissue.\u201d Nature, May, 1\u201313.","DOI":"10.1101\/2024.03.01.582884"},{"key":"2025100608551027000_2025.10.02.679866v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/S1364-6613(98)01210-8"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.02.679866","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:43:08Z","timestamp":1768470188000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.10.02.679866"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,3]]},"references-count":42,"URL":"https:\/\/doi.org\/10.1101\/2025.10.02.679866","relation":{},"subject":[],"published":{"date-parts":[[2025,10,3]]},"subtype":"preprint"}}