Dopaminergic regulation of vestibulo-cerebellar circuits through unipolar brush cells

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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 GRAB_DA, 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.

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

Article and author information

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Jose Ernesto Canton-Josh

Department of Neurobiology, Northwestern University, Evanston, United States

Competing interests
The authors declare that no competing interests exist.
Joanna Qin

Department of Neurobiology, Northwestern University, Evanston, United States

Competing interests
The authors declare that no competing interests exist.
Joseph Salvo

Department of Neurobiology, Northwestern University, Evanston, United States

Competing interests
The authors declare that no competing interests exist.
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.

"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) .

Copyright

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.