Dopaminergic regulation of vestibulo-cerebellar circuits through unipolar brush cells

SUMMARY While multiple monoamines modulate cerebellar output, the mechanistic details of dopaminergic signaling in the cerebellum remain poorly understood. Here we show that Drd1 dopamine receptors are expressed in unipolar brush cells (UBCs) of the cerebellar vermis. Drd1 activation increases UBC firing rate and postsynaptic NMDA receptor-mediated currents. Using anatomical tracing and in situ hybridization, we tested 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.