Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 153-160).

The medial ganglionic eminence (MGE) is a progenitor domain in the subpallium that produces both locally-projecting interneurons which undergo tangential migration in structures such as the cortex as well as long-range projection neurons that occupy subcortical nuclei. Very little is known about the transcriptional mechanisms specifying the migratory behavior and axonal projection patterns of these two broad classes of MGE-derived neurons. In this study, I identify St18 as a novel transcriptional determinant specifying projection neuron fate in the MGE lineage. St18 is transiently expressed in the MGE subventricular zone (SVZ) and mantle, and I assessed its function using an ES cell-based model of MGE development. Induction of St18 is sufficient to direct ES-derived MGE neurons to adopt a projection neuron-like identity as defined by migration and morphology. Through gene expression analysis I identified a downstream effector of St18, Cbx7, which is a component of Polycomb repressor complex 1. I find that Cbx7 is essential for projection neuron-like migration and is not involved in St18-mediated projection neuron-like morphology. Using genetic loss-of-function in mice, I find that St18 is required for the production of globus pallidus pars externa (GPe) prototypic projection neurons. Single cell RNA sequencing revealed that St18 regulates MGE output of specific neuronal populations: in the absence of St18, I observe a large expansion of cortical interneurons at the expense of putative GPe neurons. I also find that, following St18 genetic loss of function, mouse walk cycles are disrupted downstream of a loss of a critical neuronal projection from the GPe to the sub thalamic nucleus (STN). These results characterize a novel transcriptional determinant that directs GPe prototypic projection neuron identity within the MGE lineage. Further, I have identified a downstream target of St18, Cbx7, which regulates only the migratory behavior of long-range projection neurons, suggesting that specific features of MGE projection neuron identity may be governed in a compartmentalized fashion by distinct transcriptional modules downstream of St18. I’ve also demonstrated the role of the GPe PV+ prototypic neurons in the production and maintenance of mouse locomotor gait.

Thesis (Ph. D.)--University of Oregon, 2008. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 281-287). Also available online in Scholars' Bank; and in ProQuest, free to University of Oregon users.

This thesis documents three main projects performed during my PhD. Chapter 3 describes a published project in which detailed behavioral analysis based on machine learning approaches for pose-estimation were used to characterize a novel sensorimotor transformation in which mice use whisker information to rapidly modify their gait in order to rapidly avoid an obstacle in their path (Warren et al., 2021). I contributed to designing experiments, data collection and analysis related to this project spanning roughly from Aug. 2018 to Aug. 2019. Appendix 1 describes a follow-up study in which I performed multi-site silicon probe recordings and anatomical reconstruction of recording sites across the deep cerebellar nuclei in head-fixed mice performing the same obstacle avoidance behavior mentioned above. Data collection for this project spanned roughly from May 2019 to Jan. 2021. This data was initially analyzed in collaboration with Richard Warren and is currently being analyzed in collaboration with Ramin Kajeh in Dr. Larry Abbott’s group. Finally, Chapter 2 reports on the major independent work undertaken as part of my thesis, spanning from Sept. 2021 to present. As such, the Introduction relates solely to Chapter 2. The goal of this ongoing project is to extend the Sawtell laboratory studies of the mechanisms for sensory prediction and cancellation in the cerebellum-like circuitry of the electrosensory lobe (ELL) of electric fish to a cerebellum-like circuit in mammals, the dorsal cochlear nucleus (DCN) in the auditory brainstem. In particular, my work provides initial insights into the function of the cartwheel cell (CWC), a previously enigmatic cell type that occupies a similar place in the circuitry of the dorsal cochlear nucleus as the Purkinje cell of the cerebellum and the medium ganglion (MG) cell of the ELL. We have demonstrated that CWCs convey tonotopically-specific signals that are well-suited for canceling self-generated auditory responses in fusiform cells (FCs), the principal output cells in the DCN. Additionally, our findings reveal that the two characteristic types of spikes observed in CWCs—the axonal simple spikes (comparable to simple spikes in Purkinje cells and narrow spikes in MG cells) and dendritic complex spikes (similar to complex spikes in Purkinje cells and broad spikes in MG cells)—are distinctly modulated by both self-generated behavior and external acoustic stimuli, suggesting that these two types of spikes serve separate functional roles in the processing of the cancellation signal, as well as auditory information, within the DCN circuitry. This finding is consistent with the reported distinct functions of narrow and broad spikes in MG cells within the circuitry of the ELL, suggesting an evolutionarily conserved role of Purkinje-like cells in cerebellum-like circuits.