UCLA

Sensorimotor learning is the process by which motor skills are gradually refined to reach a target goal via sensory feedback. This process requires the basal ganglia, a set of predominantly inhibitory forebrain nuclei that form interconnected loops with the cortex and thalamus, modulate and evaluate motor patterns, and receive dopaminergic modulatory inputs. However, there is still much that remains unknown about the neurogenetic mechanisms by which motor learning takes place in the basal ganglia. The zebra finch (Taeniopygia guttata) is a well-established model organism in behavioral neuroscience due to the male courtship song, which is acquired by young birds during development who copy an adult male tutor. The song-linked region of the zebra finch basal ganglia, Area X, has a strong degree of gene expression overlap with human striatal regions dedicated to vocal learning. Furthermore, optimal song learning requires singing-dependent regulation of the transcription factor gene FoxP2 within Area X; the human analogue, FOXP2, is strongly associated with speech learning and fluency. Previous work has identified behaviorally linked gene expression modules within Area X that correlate with the amount of singing and with the degree of learning; however, Area X contains numerous neuronal and non-neuronal cell types, and it is unknown which specific basal ganglia cell type(s) express these genes. To address this, single-cell RNA sequencing was used to characterize the cell-type-specific transcriptome of Area X of juvenile and adult male zebra finches. Additionally, this experiment examined the cell-type-specific effects of 2 hours of singing, a behavioral paradigm that is known to significantly downregulate FoxP2 at the bulk level, on the cell-type-specific transcriptome by comparing between singing and non-singing sibling pairs. I collected tissue from 16 individuals across 4 conditions, generated single-cell suspensions, performed 10X library preparation and sequencing, and analyzed the data to generate an integrated clustering analysis showing shared clusters representing distinct basal ganglia cell types and identifying cluster-specific cell type markers. Differential expression analysis between conditions shows broad upregulation of gene expression in juveniles compared to adults, across all cell types. Gene Set Enrichment Analysis by cluster between behavioral conditions identifies a subpopulation of medium spiny neurons, marked by expression of ARPP21, that differentially express genes from a singing-linked module identified at the bulk level. This identifies ARPP21-expressing medium spiny neurons as playing an important role in plasticity relating to motor learning. Overall, this work utilizes a well-established animal model for motor learning, the zebra finch song system, to investigate sensorimotor learning-linked changes in the transcriptomes of basal ganglia cell types. This work has translational relevance for better understanding neurogenetic mechanisms underlying sensorimotor skill learning within the basal ganglia. This includes the potential to provide insights into vocal learning, which may be disrupted in a variety of speech and language disorders. In particular, speech deficits are a common feature of autism spectrum disorder (ASD). Research on mechanisms underlying zebra finch vocal song learning may point to novel therapeutic approaches for addressing speech and language deficits in humans.