The cerebellar cortical system is an extensively studied circuit which is critical for motor learning. While multiple monoamines, such as norepinephrine and serotonin, modulate cerebellar cortical output, the mechanistic details of dopaminergic signaling in the cerebellum remain poorly understood. Additionally, neuronal cell types residing within the cerebellum remain relatively under-characterized. Here I show that Drd1 dopamine receptors are expressed in unipolar brush cells (UBCs) of the cerebellar vermis. Drd1 activation increases UBC firing rate and postsynaptic N-Methyl-D-aspartate receptor-mediated currents. Using anatomical tracing and in situ hybridization to measure mRNA for dopamine receptors and release machinery, I tested three hypotheses about the source of cerebellar dopamine. I exclude the midbrain dopaminergic nuclei and tyrosine hydroxylase-positive Purkinje cells as potential sources, supporting the possibility of dopaminergic co-release from locus coeruleus (LC) axons, known to release norepinephrine. Using a fluorescent dopamine sensor GRABDA, electrical stimulation, and optogenetic activation of LC fibers in the acute brain slice preparation, I find evidence for monoamine release onto Drd1-expressing UBCs. Altogether, I propose that the LC regulates cerebellar cortex activity by co-releasing dopamine onto UBCs to modulate their response to cerebellar inputs.To gain insight into the function of UBCs within their local circuitry, I used the Drd1a-Cre transgenic mouse line to label a subpopulation of dopamine-sensing UBCs. I performed whole-cell recordings in the acute slice preparation, using optogenetics to interrogate the modulation of Purkinje cell activity by UBCs. I explored UBC connectivity using optogenetics and cell-type specific trans-synaptic viral tracing tools and discovered a direct inhibitory connection from Purkinje cells to Drd1-positive UBCs. Together these finding begin to describe a new dopamine-sensitive recurrent vestibulo-cerebellar circuit. A substantial proportion of my studies of cerebellar neuromodulation critically relied on diverse imaging approaches. Complementary to my main research program, I also collaborated with engineers of fluorescent proteins and microscopy experts to characterize a new near infra-red genetically encoded calcium indicator using light-sheet microscopy, which can be used in future cerebellar system studies.

Creator

• Canton-Josh, Jose Ernesto

DOI

• https://doi.org/10.21985/n2-6cad-tx37

Subject

• Neurosciences

Language

• en

Alternate Identifier

• http://dissertations.umi.com/northwestern:15996
• etdadmin_upload_896041

Keyword

• Cerebellum
• Dopamine
• Unipolar brush cells
• Light sheet microscope

Date created

• 2022-01-01

Resource type

• Dissertation

Rights statement

• In Copyright