CoChat
Sign Up
Cited by 255Motor Control and AdaptationMemory and Neural MechanismsNeuroscience and Neuropharmacology Research

Predictive and reactive reward signals conveyed by climbing fiber inputs to cerebellar Purkinje cells

Open access
Kostadinov, Dimitar, Beau, Maxime, Blanco-Pozo, Marta, Häusser, Michael·2019·Nature Neuroscience
DOI 10.1038/s41593-019-0381-8PMC PMC7612392
Open this paper in CoChat — free account

Abstract

There is increasing evidence for a cerebellar contribution to cognitive processing, but the specific input pathways conveying this information remain unclear. We probed the role of climbing fiber inputs to Purkinje cells in generating and evaluating predictions about associations between motor actions, sensory stimuli and reward. We trained mice to perform a visuomotor integration task to receive a reward and interleaved cued and random rewards between task trials. Using two-photon calcium imaging and Neuropixels probe recordings of Purkinje cell activity, we show that climbing fibers signal reward expectation, delivery and omission. These signals map onto cerebellar microzones, with reward delivery activating some microzones and suppressing others, and with reward omission activating both reward-activated and reward-suppressed microzones. Moreover, responses to predictable rewards are progressively suppressed during learning. Our findings elucidate a specific input pathway for cerebellar contributions to reward signaling and provide a mechanistic link between cerebellar activity and the creation and evaluation of predictions.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41593-019-0381-8

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Cerebellar responses are related to reward expectation, regardless of its valence, contrary to striatal and prefrontal responses.

    “Contrary to the striatal and prefrontal responses, cerebellar responses would be related to reward expectation, regardless of its valence (Kostadinov et al., 2019).”

    From The Forward Model: A Unifying Theory for the Role of the Cerebellum in Motor Control and Sense of Agency (2021) · cites this paper as Kostadinov et al., 2019

    The Results (‘Predictability modulates reward-related sensory responses’; page unavailable) show that reward expectation modulates Purkinje-cell responses. The Discussion (‘Relationship with reward signals elsewhere in the brain’; page unavailable) reports increased climbing-fiber activity after reward omission as well as responses to reward delivery. These findings support a relationship to reward expectation, but the paper does not establish that responses are independent of valence or make the claimed comparison with striatal and prefrontal responses. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 71 · Cited by 255

Research works printed but not linked: 60

  1. [1]Wolpert DM Miall RC Kawato M Internal models in the cerebellum Trends Cogn Sci 1998 2 338 347 21227230
  2. [2]Kawato M Furukawa K Suzuki R A hierarchical neural-network model for control and learning of voluntary movement Biol Cybern 1987 57 169 185 3676355
  3. [3]Medina JF The multiple roles of Purkinje cells in sensori-motor calibration: to predict, teach and command Curr Opin Neurobiol 2011 21 616 622 21684147 PMC3957422
  4. [6]Ito M Cerebellar long-term depression: characterization, signal transduction, and functional roles Physiol Rev 2001 81 1143 1195 11427694
  5. [7]Apps R Garwicz M Anatomical and physiological foundations of cerebellar information processing Nat Rev Neurosci 2005 6 297 311 15803161
  6. [8]Sugihara I Shinoda Y Molecular, topographic, and functional organization of the cerebellar cortex: a study with combined aldolase C and olivocerebellar labeling J Neurosci 2004 24 8771 8785 15470143 PMC6729951
  7. [9]Mathy A Encoding of oscillations by axonal bursts in inferior olive neurons Neuron 2009 62 388 399 19447094 PMC2777250
  8. [10]Llinas R Baker R Sotelo C Electrotonic coupling between neurons in cat inferior olive J Neurophysiol 1974 37 560 571 4827022
  9. [11]Tang T Blenkinsop TA Lang EJ Complex spike synchrony dependent modulation of rat deep cerebellar nuclear activity eLife 2019 8 e40101 30624204 PMC6326725
  10. [12]Welsh JP Lang EJ Suglhara I Llinás R Dynamic organization of motor control within the olivocerebellar system Nature 1995 374 453 457 7700354
  11. [13]Ozden I Dombeck DA Hoogland TM Tank DW Wang SS Widespread state-dependent shifts in cerebellar activity in locomoting mice PLoS One 2012 7 e42650 22880068 PMC3411825
  12. [14]Ghosh KK Miniaturized integration of a fluorescence microscope Nat Methods 2011 8 871 878 21909102 PMC3810311
  13. [16]De Gruijl JR Hoogland TM De Zeeuw CI Behavioral correlates of complex spike synchrony in cerebellar microzones J Neurosci 2014 34 8937 8947 24990915 PMC6608251
  14. [17]Hoogland TM De Gruijl JR Witter L Canto CB De Zeeuw CI Role of synchronous activation of cerebellar purkinje cell ensembles in multi-joint movement control Curr Biol 2015 25 1157 1165 25843032 PMC4425462
  15. [18]Najafi F Giovannucci A Wang SS Medina JF Coding of stimulus strength via analog calcium signals in Purkinje cell dendrites of awake mice eLife 2014 3 e03663 25205669 PMC4158287
  16. [19]Mukamel EA Nimmerjahn A Schnitzer MJ Automated analysis of cellular signals from large-scale calcium imaging data Neuron 2009 63 747 760 19778505 PMC3282191
  17. [21]Medina JF Lisberger SG Links from complex spikes to local plasticity and motor learning in the cerebellum of awake-behaving monkeys Nat Neurosci 2008 11 1185 1192 18806784 PMC2577564
  18. [22]Yang Y Lisberger SG Purkinje-cell plasticity and cerebellar motor learning are graded by complex-spike duration Nature 2014 510 529 532 24814344 PMC4132823
  19. [23]Strick PL Dum RP Fiez JA Cerebellum and nonmotor function Annu Rev Neurosci 2009 32 413 434 19555291
  20. [24]Rochefort C Cerebellum shapes hippocampal spatial code Science 2011 334 385 389 22021859
  21. [25]Stoodley CJ Schmahmann JD Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies Neuroimage 2009 44 489 501 18835452
  22. [26]Wagner MJ Kim TH Savall J Schnitzer MJ Luo L Cerebellar granule cells encode the expectation of reward Nature 2017 544 96 100 28321129 PMC5532014
  23. [27]Lee KH Circuit mechanisms underlying motor memory formation in the cerebellum Neuron 2015 86 529 540 25843404 PMC4417109
  24. [28]Ozden I Sullivan MR Lee HM Wang SS Reliable coding emerges from coactivation of climbing fibers in microbands of cerebellar Purkinje neurons J Neurosci 2009 29 10463 10473 19710300 PMC2783593
  25. [29]Kitamura K Häusser M Dendritic calcium signaling triggered by spontaneous and sensory-evoked climbing fiber input to cerebellar Purkinje cells in vivo J Neurosci 2011 31 10847 10858 21795537 PMC3758548
  26. [30]Schultz SR Kitamura K Post-Uiterweer A Krupic J Häusser M Spatial pattern coding of sensory information by climbing fiber-evoked calcium signals in networks of neighboring cerebellar Purkinje cells J Neurosci 2009 29 8005 8015 19553440 PMC6666035
  27. [31]Gaffield MA Bonnan A Christie JM Conversion of graded presynaptic climbing fiber activity into graded postsynaptic Ca2+ signals by Purkinje cell dendrites Neuron 2019 10.1016/j.neuron.2019.03.010 PMC6533163 30928170 · DOI
  28. [34]Rowan MJM Graded control of climbing-fiber-mediated plasticity and learning by inhibition in the cerebellum Neuron 2018 99 999 1015 e6 30122378 PMC6206434
  29. [35]Ivry RB Keele SW Timing functions of the cerebellum J Cogn Neurosci 1989 1 136 152 23968462
  30. [36]Lang EJ The roles of the olivocerebellar pathway in motor learning and motor control. A consensus paper Cerebellum 2017 16 230 252 27193702 PMC5116294
  31. [37]Ten Brinke MM Boele HJ De Zeeuw CI Conditioned climbing fiber responses in cerebellar cortex and nuclei Neurosci Lett 2019 688 26 36 29689340
  32. [38]Giovannucci A Cerebellar granule cells acquire a widespread predictive feedback signal during motor learning Nat Neurosci 2017 20 727 734 28319608 PMC5704905
  33. [40]Schultz W Dayan P Montague PR A neural substrate of prediction and reward Science 1997 275 1593 1599 9054347
  34. [41]Watabe-Uchida M Eshel N Uchida N Neural circuitry of reward prediction error Annu Rev Neurosci 2017 40 373 394 28441114 PMC6721851
  35. [42]Turecek J NMDA receptor activation strengthens weak electrical coupling in mammalian brain Neuron 2014 81 1375 1388 24656255 PMC4266555
  36. [43]Mathy A Clark BA Häusser M Synaptically induced long-term modulation of electrical coupling in the inferior olive Neuron 2014 81 1290 1296 24656251 PMC3988996
  37. [44]Lefler Y Yarom Y Uusisaari MY Cerebellar inhibitory input to the inferior olive decreases electrical coupling and blocks subthreshold oscillations Neuron 2014 81 1389 1400 24656256
  38. [45]Miyazaki K Miyazaki KW Doya K Activation of dorsal raphe serotonin neurons underlies waiting for delayed rewards J Neurosci 2011 31 469 479 21228157 PMC6623450
  39. [46]Garden DLF Rinaldi A Nolan MF Active integration of glutamatergic input to the inferior olive generates bidirectional postsynaptic potentials J Physiol 2017 595 1239 1251 27767209 PMC5309349
  40. [47]Carta I Chen CH Schott AL Dorizan S Khodakhah K Cerebellar modulation of the reward circuitry and social behavior Science 2019 363 eaav0581 30655412 PMC6711161
  41. [48]Gao Z A cortico-cerebellar loop for motor planning Nature 2018 563 113 116 30333626 PMC6212318
  42. [49]Chabrol FP Blot A Mrsic-Flogel TD Cerebellar contribution to preparatory activity in motor neocortex biorXiv 2018 10.1101/335703 PMC6693889 31201123 · DOI
  43. [51]Zhang XM Highly restricted expression of Cre recombinase in cerebellar Purkinje cells Genesis 2004 40 45 51 15354293
  44. [52]Chen TW Ultrasensitive fluorescent proteins for imaging neuronal activity Nature 2013 499 295 300 23868258 PMC3777791
  45. [53]Aronov D Tank DW Engagement of neural circuits underlying 2D spatial navigation in a rodent virtual reality system Neuron 2014 84 442 456 25374363 PMC4454359
  46. [54]Burgess CP High-yield methods for accurate two-alternative visual psychophysics in head-fixed mice Cell Rep 2017 20 2513 2524 28877482 PMC5603732
  47. [55]Slotnick B A simple 2-transistor touch or lick detector circuit J Exp Anal Behav 2009 91 253 255 19794837 PMC2648519
  48. [57]Pachitariu M Suite2p: beyond 10,000 neurons with standard two-photon microscopy Preprint at biorXiv 2017 10.1101/061507 · DOI
  49. [58]Deneux T Accurate spike estimation from noisy calcium signals for ultrafast three-dimensional imaging of large neuronal populations in vivo Nat Commun 2016 7 12190 27432255 PMC4960309
  50. [59]Ozden I Lee HM Sullivan MR Wang SS Identification and clustering of event patterns from in vivo multiphoton optical recordings of neuronal ensembles J Neurophysiol 2008 100 495 503 18497355 PMC2493472
  51. [60]Tsutsumi S Structure-function relationships between aldolase C/zebrin II expression and complex spike synchrony in the cerebellum J Neurosci 2015 35 843 852 25589776 PMC6605375
  52. [61]Ramirez JE Stell BM Calcium imaging reveals coordinated simple spike pauses in populations of cerebellar Purkinje cells Cell Rep 2016 17 3125 3132 28009283
  53. [62]Streng ML Popa LS Ebner TJ Climbing fibers control Purkinje cell representations of behavior J Neurosci 2017 37 1997 2009 28077726 PMC5338751
  54. [63]Watson BO Yuste R Packer AM PackIO and EphysViewer: software tools for acquisition and analysis of neuroscience data Preprint at biorXiv 2016 10.1101/054080 · DOI
  55. [64]Pachitariu M Steinmetz NA Kadir SN Carandini M Harris KD Fast and accurate spike sorting of high-channel count probes with Kilosort Adv Neural Inf Process Syst 2016 29 4448 4456
  56. [65]Armstrong DM Rawson JA Activity patterns of cerebellar cortical neurones and climbing fibre afferents in the awake cat J Physiol 1979 289 425 448 458677 PMC1281378
  57. [66]Gao H Solages Cd Lena C Tetrode recordings in the cerebellar cortex J Physiol Paris 2012 106 128 136 22057014
  58. [67]Dong H-W The Allen Reference Atlas: A Digital Color Brain Atlas of the C57Bl/6J Male Mouse 2008 Wiley
  59. [68]Oh SW A mesoscale connectome of the mouse brain Nature 2014 508 207 214 24695228 PMC5102064
  60. [69]Shamash P Carandini M Harris K Steinmetz N A tool for analyzing electrode tracks from slice histology Preprint at biorXiv 2018 10.1101/447995 · DOI

Authors
Kostadinov, D., Beau, M., Blanco-Pozo, M., & Häusser, M.
Affiliations
  • University College London (GB)
  • University of Oxford (GB)
Corresponding author
  • Kostadinov, Dimitar
  • Häusser, Michael
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2019-04-29
Volume
22
Issue
6
Pages
950-962
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-019-0381-8
PMC
PMC7612392
OpenAlex
W2942648114
Cited by
255
References
71
Citations by year
2026: 29 · 2025: 39 · 2024: 41 · 2023: 38 · 2022: 27 · 2021: 32 · 2020: 36 · 2019: 13
FWCI
15.70
Type
journal article
Language
en
Update notices
correction (2020-01-24)
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
Funders
Wellcome Trust (695709, 201225, 201225/Z/16/Z)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Motor Control and Adaptation
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
cerebellum, Purkinje cells, climbing fibers, reward signaling, reward anticipation, reward omission, reward prediction, visual-motor integration, prediction error, learning
MeSH terms
Animals, Behavior, Animal, Male, Motor Activity, Neural Pathways, Purkinje Cells, Reward, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review