Access to abstract permanently restricted to Ball State community only / Access to thesis permanently restricted to Ball State community only / Department of Biology

Seizure activity is the primary symptom in a common but very serious neurological disorder known as epilepsy. Brain glycogen is utilized for neuronal function, prompting us to investigate the role of brain glycogen during seizure activity in mouse models. Seizures were induced with Pentylenetetrazole (PTZ) in both wild-type mice and mice lacking brain glycogen (MGSKO/GSL30 mice). A time course of brain glycogen utilization after onset of seizure activity revealed a reduction of brain glycogen in wild-type mice. The glycogen synthase activity ratio increased after onset of seizure activity, while the glycogen phosphorylase activity ratio remained constant. Brain and blood glucose levels increased after seizure onset in wild-type mice. Despite lacking brain glycogen, MGSKO/GSL30 mice exhibited acute seizure activity. No differences were observed in seizure intensity, onset time, and duration between genotypes. These findings suggest that brain glycogen is important, but not required for PTZ-induced acute seizure activity in mice. / Access to thesis permanently restricted to Ball State community only / Department of Biology

Thesis (M.S.)--University of Hawaii at Manoa, 2007. / Includes bibliographical references (leaves 45-55). / i, 92 leaves, bound ill. 29 cm

The brain evolved to control behavior, and locomotion is among the behaviors most critical to animal survival. The neural mechanisms of skilled locomotion have been studied for decades, yet recently developed technologies offer the opportunity to shine new light on this long studied behavior. I leveraged these technologies to develop a system for studying the behavioral strategies and neural mechanisms of skilled locomotion in mice. In Chapter 2, I use detailed 3D kinematic tracking and behavioral modelling to describe a rapid sensorimotor decision that determines the kinematic strategies used by mice to step over obstacles. Despite the whisker dependency of this behavior, performance is minimally affected by manipulations of whisker sensory cortex, whereas motor cortex manipulations impair but did not prevent obstacle clearance. Neither cortical manipulation substantially impacts the sensorimotor decision. In Chapter 3, we turn to the cerebellum. The cerebellum is thought to contribute to the coordination of movement, as evinced by the locomotor deficits that are a hallmark of cerebellar ataxia. However, much cerebellar research has focused on simple behaviors involving single body parts. Furthermore, the recent discovery of reward signals in the cerebellar cortex has drawn attention to its potential non-motor functions, but whether such signals exist in the output of the cerebellum is unknown. We conducted an electrophysiological survey of the deep cerebellar nuclei to characterize the signals communicated by the cerebellum to downstream structures. Preliminary analyses from this ongoing work suggest that cerebellar output is dominated by orofacial and locomotor signals, whereas reward related modulations are largely accounted for by the behavioral correlates of reward delivery. Collectively, these results demonstrate that quantitative whole body analyses of ethologically inspired behaviors can enhance our understanding of the neural control of sensorimotor behaviors.

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Cells in transitional states are found in multiple biological systems and sit at the crossroadof important events, such as development and regeneration. These cells are enigmatic due to their mixed identities, transient gene expression signature, and harboring key regulators of cell-fate switch. Despite their importance, it is challenging to understand the regulation of these transitional states in developmental systems, where dynamic tissue interactions lead to morphogenetic changes that rapidly generate new compartments and boundaries. One paradigm for the study of these states is the developing murine lung. During lung morphogenesis, distal epithelial progenitors in growing buds undergo dramatic changes in fate and cytoarchitecture as they transition into airway progenitors. Lineage studies in mice show that distal epithelial cells identified by expression of Id2 or Sox9 expand to form the future alveolar compartment but also give rise to the Sox2 epithelial tubules that form the bronchial tree. Formation of these distinct and well-balanced compartments labeled by Sox9 or Sox2 is a key event during formation of the bronchial tree overall preceding the appearance of defined differentiated epithelial cell phenotypes. Cells undergoing transition are at the most plastic state as they are being subjected to signals that allow them to progressively initiate a distinct program while repressing their initial program. A variety of studies have investigated the overall gene expression signatures associated with the distal and proximal identity of these compartments as they expand. But it remains unclear what characterizes the epithelial cells that lie in the transition between Sox9-Sox2 fates, their regulation, and impact in the developing lung. Although studies in mice have identified signals such as the Hippo-Yap as regulators of this transition, the identity of these cells and their phenotypic features and behavior remain elusive. We have developed a system to identify and characterize cells undergoing transition from the Sox9 to the Sox2 compartments in the developing murine lung epithelium. Using an unbiased single cell genomic approach and bioinformatic analysis, we identified markers to isolate the cells during the period when branching morphogenesis is most active and most representative of the transitional cell state. The analyses revealed a previously uncharacterized population of NKX2- 1/ICAM1 double-positive epithelial progenitors with an expression signature distinct from all others in the lung. Surprisingly, their signature showed extensive overlap with that of transitional cells reported in the adult murine alveolar epithelium undergoing repair after severe injury. Analysis of human fetal lungs showed that this signature was largely conserved, labeling transitional cells at the sites of segregation of Sox9 and Sox2 fates in the developing distal epithelium. Functional analysis in lung explant cultures and organoids showed that these cells are remarkably plastic and respond to morphogenetic cues by changing their domain and abundance, reflecting dynamic changes in proximal-distal cell fate. Progression of NKX2-1/ICAM1 throughout these transitional states was regulated by balanced activation of signals such as Fgf, Tgfβ, Hippo-Yap, p53, and AP1. Moreover, analysis of additional injury models in the adult lung identified cells undergoing a similar transitional cell state during repopulation of the airway epithelium after severe injury. These observations broaden the understanding of these transitional states and suggest they may be relevant in the development of regenerative strategies for managing pulmonary conditions.