Dopaminergic regulation of vestibulo-cerebellar circuits through unipolar brush cells
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
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.
Reviewing Editor
- Megan R Carey, Champalimaud Foundation, Portugal
Ethics
Animal experimentation: All experiments were performed under the guidelines set by Northwestern University Institutional Animal Care and Use Committee (approved protocol IS00002086) .
Version history
- Preprint posted: March 27, 2021 (view preprint)
- Received: January 8, 2022
- Accepted: April 26, 2022
- Accepted Manuscript published: April 27, 2022 (version 1)
- 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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