IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-57080-6.html
   My bibliography  Save this article

Cerebellar output neurons can impair non-motor behaviors by altering development of extracerebellar connectivity

Author

Listed:
  • Andrew S. Lee

    (Sloan Kettering Institute
    Weill Cornell Graduate School of Medical Sciences)

  • Tanzil M. Arefin

    (New York University Grossman School of Medicine
    University of Rochester Medical Center)

  • Alina Gubanova

    (Sloan Kettering Institute)

  • Daniel N. Stephen

    (Sloan Kettering Institute)

  • Yu Liu

    (University of Minnesota Medical School
    University of Minnesota)

  • Zhimin Lao

    (Sloan Kettering Institute)

  • Anjana Krishnamurthy

    (Sloan Kettering Institute
    Weill Cornell Graduate School of Medical Sciences)

  • Natalia V. De Marco García

    (Weill Cornell Graduate School of Medical Sciences
    Weill Cornell Medicine)

  • Detlef H. Heck

    (University of Minnesota Medical School
    University of Minnesota)

  • Jiangyang Zhang

    (New York University Grossman School of Medicine)

  • Anjali M. Rajadhyaksha

    (Weill Cornell Graduate School of Medical Sciences
    Weill Cornell Medicine
    Weill Cornell Medicine
    Temple University)

  • Alexandra L. Joyner

    (Sloan Kettering Institute
    Weill Cornell Graduate School of Medical Sciences
    Weill Cornell Graduate School of Medical Sciences)

Abstract

The capacity of the brain to compensate for insults during development depends on the type of cell loss, whereas the consequences of genetic mutations in the same neurons are difficult to predict. We reveal powerful compensation from outside the mouse cerebellum when the excitatory cerebellar output neurons are ablated embryonically and demonstrate that the main requirement for these neurons is for motor coordination and not basic learning and social behaviors. In contrast, loss of the homeobox transcription factors Engrailed1/2 (EN1/2) in the cerebellar excitatory lineage leads to additional deficits in adult learning and spatial working memory, despite half of the excitatory output neurons being intact. Diffusion MRI indicates increased thalamo-cortico-striatal connectivity in En1/2 mutants, showing that the remaining excitatory neurons lacking En1/2 exert adverse effects on extracerebellar circuits regulating motor learning and select non-motor behaviors. Thus, an absence of cerebellar output neurons is less disruptive than having cerebellar genetic mutations.

Suggested Citation

  • Andrew S. Lee & Tanzil M. Arefin & Alina Gubanova & Daniel N. Stephen & Yu Liu & Zhimin Lao & Anjana Krishnamurthy & Natalia V. De Marco García & Detlef H. Heck & Jiangyang Zhang & Anjali M. Rajadhyak, 2025. "Cerebellar output neurons can impair non-motor behaviors by altering development of extracerebellar connectivity," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57080-6
    DOI: 10.1038/s41467-025-57080-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-57080-6
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-57080-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Meike E. Heijden & Alejandro G. Rey Hipolito & Linda H. Kim & Dominic J. Kizek & Ross M. Perez & Tao Lin & Roy V. Sillitoe, 2023. "Glutamatergic cerebellar neurons differentially contribute to the acquisition of motor and social behaviors," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Jimena Laura Frontera & Hind Baba Aissa & Romain William Sala & Caroline Mailhes-Hamon & Ioana Antoaneta Georgescu & Clément Léna & Daniela Popa, 2020. "Bidirectional control of fear memories by cerebellar neurons projecting to the ventrolateral periaqueductal grey," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    3. Le Xiao & Caroline Bornmann & Laetitia Hatstatt-Burklé & Peter Scheiffele, 2018. "Regulation of striatal cells and goal-directed behavior by cerebellar outputs," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    4. Kim M. Gruver & Jenny W. Y. Jiao & Eviatar Fields & Sen Song & Per Jesper Sjöström & Alanna J. Watt, 2024. "Structured connectivity in the output of the cerebellar cortex," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Xiaolu Wang & Si-yang Yu & Zhong Ren & Chris I. De Zeeuw & Zhenyu Gao, 2020. "A FN-MdV pathway and its role in cerebellar multimodular control of sensorimotor behavior," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    6. Jimena L. Frontera & Romain W. Sala & Ioana A. Georgescu & Hind Baba Aissa & Marion N. d’Almeida & Daniela Popa & Clément Léna, 2023. "The cerebellum regulates fear extinction through thalamo-prefrontal cortex interactions in male mice," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Bérénice Coutant & Jimena Laura Frontera & Elodie Perrin & Adèle Combes & Thibault Tarpin & Fabien Menardy & Caroline Mailhes-Hamon & Sylvie Perez & Bertrand Degos & Laurent Venance & Clément Léna & D, 2022. "Cerebellar stimulation prevents Levodopa-induced dyskinesia in mice and normalizes activity in a motor network," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Adrien T. Stanley & Michael R. Post & Clay Lacefield & David Sulzer & Maria Concetta Miniaci, 2023. "Norepinephrine release in the cerebellum contributes to aversive learning," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Zhong Ren & Xiaolu Wang & Milen Angelov & Chris I. De Zeeuw & Zhenyu Gao, 2025. "Neuronal dynamics of cerebellum and medial prefrontal cortex in adaptive motor timing," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    4. Jimena L. Frontera & Romain W. Sala & Ioana A. Georgescu & Hind Baba Aissa & Marion N. d’Almeida & Daniela Popa & Clément Léna, 2023. "The cerebellum regulates fear extinction through thalamo-prefrontal cortex interactions in male mice," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57080-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.