Dopaminergic regulation of vestibulo-cerebellar circuits through unipolar brush cells

  1. Jose Ernesto Canton-Josh
  2. Joanna Qin
  3. Joseph Salvo
  4. Yevgenia Kozorovitskiy  Is a corresponding author
  1. Northwestern University, United States

Abstract

While multiple monoamines modulate cerebellar output, the mechanistic details of dopaminergic signaling in the cerebellum remain poorly understood. We show that Drd1 dopamine receptors are expressed in unipolar brush cells (UBCs) of the mouse cerebellar vermis. Drd1 activation increases UBC firing rate and postsynaptic NMDA receptor-mediated currents. Using anatomical tracing and in situ hybridization, we test three hypotheses about the source of cerebellar dopamine. We exclude midbrain dopaminergic nuclei and tyrosine hydroxylase-positive Purkinje cells as potential sources, supporting the possibility of dopaminergic co-release from locus coeruleus (LC) axons. Using an optical dopamine sensor GRABDA, electrical stimulation, and optogenetic activation of LC fibers in the acute slice, we find evidence for monoamine release onto Drd1-expressing UBCs. Altogether, we propose that the LC regulates cerebellar cortex activity by co-releasing dopamine onto UBCs to modulate their response to cerebellar inputs. Purkinje neurons directly inhibit these Drd1-positive UBCs, forming a dopamine-sensitive recurrent vestibulo-cerebellar circuit.

Data availability

A preprint of this manuscript has been updated on Biorxiv. Source data for each figure are provided.

Article and author information

Author details

  1. Jose Ernesto Canton-Josh

    Department of Neurobiology, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Joanna Qin

    Department of Neurobiology, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Joseph Salvo

    Department of Neurobiology, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yevgenia Kozorovitskiy

    Department of Neurobiology, Northwestern University, Evanston, United States
    For correspondence
    Yevgenia.Kozorovitskiy@northwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3710-1484

Funding

National Institute of Neurological Disorders and Stroke (R01NS107539)

  • Yevgenia Kozorovitskiy

National Institute of Mental Health (R01MH117111)

  • Yevgenia Kozorovitskiy

Rita Allen Foundation (Rita Allen Scholar Award)

  • Yevgenia Kozorovitskiy

Kinship Foundation (Searle Scholar Award)

  • Yevgenia Kozorovitskiy

National Institute of Neurological Disorders and Stroke (T32NS041234)

  • Jose Ernesto Canton-Josh

National Institute of Neurological Disorders and Stroke (F31NS120736)

  • Jose Ernesto Canton-Josh

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were performed under the guidelines set by Northwestern University Institutional Animal Care and Use Committee (approved protocol IS00002086) .

Reviewing Editor

  1. Megan R Carey, Champalimaud Foundation, Portugal

Publication history

  1. Preprint posted: March 27, 2021 (view preprint)
  2. Received: January 8, 2022
  3. Accepted: April 26, 2022
  4. Accepted Manuscript published: April 27, 2022 (version 1)
  5. Version of Record published: May 13, 2022 (version 2)

Copyright

© 2022, Canton-Josh et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jose Ernesto Canton-Josh
  2. Joanna Qin
  3. Joseph Salvo
  4. Yevgenia Kozorovitskiy
(2022)
Dopaminergic regulation of vestibulo-cerebellar circuits through unipolar brush cells
eLife 11:e76912.
https://doi.org/10.7554/eLife.76912

Further reading

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    Background:

    Associations between attention-deficit/hyperactivity disorder (ADHD) and brain morphology have been reported, although with several inconsistencies. These may partly stem from confounding bias, which could distort associations and limit generalizability. We examined how associations between brain morphology and ADHD symptoms change with adjustments for potential confounders typically overlooked in the literature (aim 1), and for the intelligence quotient (IQ) and head motion, which are generally corrected for but play ambiguous roles (aim 2).

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    Funding:

    Authors are supported by an NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200 to HT) for HT, LDA, SL, and the Sophia Foundation S18-20, and Erasmus University and Erasmus MC Fellowship for RLM.