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Escape behavior is the critical output of rapid sensorimotor processing in the brain that allows animals to sense danger and avoid it. The circuit structures and mechanisms that underlie escape are still under investigation. Drosophila larvae are an advantageous system for studying the neuromuscular circuitry of escape behavior. When threatened with harmful mechanical touch, heat, or light, larvae perform C-shaped bending and lateral rolling, followed by rapid forward crawling. The sensory input and neural circuitry that promotes escape in the larva have been extensively characterized, but we do not understand how bending and rolling motor programs are generated by the larval neuromuscular system. This work identifies the movement patterns, muscle activities, and motor circuit features that drive escape behavior. High-speed imaging approaches reveal that larvae select between four distinct, interchangeable patterns of escape rolling, and that each pattern consists of synchronous rotations of every segment as the larva rotates. Investigating electron microscopic reconstructions of premotor and motor neurons elucidates premotor to motor connectivity patterns that could underlie sequential muscle activity that circumnavigates the larva and propels synchronous rotation along the whole body. Volumetric Swept Confocally-Aligned Planar Excitation (SCAPE) microscopy uncovers that, unlike larval crawling, a well-studied form of larval locomotion that is driven by bilaterally symmetric peristaltic waves of muscle activity, the muscle activity during bending and rolling occurs in a circumferential sequence that is synchronous along the larva’s segments. Muscles neighboring the dorsal and ventral midlines of the larva demonstrate left-right symmetric activity during rolling, and ventral muscles appear to drive the propulsion. Shifts in magnitude of left-right symmetric activity in midline muscles allow the larva to transition from initial escape bending into escape rolling. Preliminary computational predictions of PMN activities confirm the likely necessity of strong ventral muscle coactivity for driving escape. Probing specific PMNs during rolling demonstrates robustness of circuits controlling escape and requires further investigation, alongside the role that sensory feedback could play in this behavior. Altogether, these data reveal a new circuit organization and motor activity pattern that underlie the coordination of muscles during an escape sequence. Future work could reveal circuit components necessary for escape, including the mechanistic basis for action selection, behavioral maintenance, and behavioral flexibility.

Though all the cells of the same cell type in a tissue of a multicellular organism may appear interchangeable, this is not always the case. Throughout an organism’s lifespan, they will encounter many insults that lead to damage or mutation of cells, introducing heterogeneity into otherwise near homogeneous tissues. In the case deleterious heterogeneities, such as cells with decreased ability to grow, it benefits the organism to have fitness sensing mechanisms that can detect these cells and eliminate them. Cell competition was first identified as a mechanism that eliminates slower growing cells possessing ribosomal protein mutations in mosaic tissues with normally growing cells. Since its discovery, cell competition has been found to be induced by numerous genetic differences, including instances where the wild-type cells are eliminated by faster growing cells overexpressing the growth factor Myc, termed Myc super-competition. Though cell competition is primary viewed as a local cell-to-cell signaling event that determines fitness and eliminates less-fit cells, in this dissertation I identify a novel function of the steroid hormone ecdysone as a systemic, restrictive regulator of Myc super-competition in Drosophila. I find that Dilp8-Lgr3 signaling in the central nervous system represses ecdysone biosynthesis to systemically maintain a low-ecdysone, permissible environment for Myc super-competition. In further work that has begun probing how the level of systemic ecdysone prevents neighboring cell populations from undergoing Myc super-competition, I have found that the level of Myc in cells interacts with ecdysone through a variety of mechanisms, including being able to upregulate Dilp8 and downregulate the ecdysone receptor complex. This work lays the foundation for further work to investigate the mechanism by which ecdysone regulates Myc super-competition.

An alternative complementary approach was used to verify the antinociceptive effect of 4 CMMs aqueous extracts in a Drosophila adult model. Drosophila adults were subjected to CMM treatments and then placed on an in-house-designed heating device for noxious heat stimulation. Their behavioral outputs were quantified and expressed as heat avoidance index (AI) for revealing the degree of antinociceptive effect of CMMs. By comparing the AI value of non-CMM treated control group with CMM-treated groups at temperature challenge 32°C, it was found that an AI value of 0.2 was obtained for non-CMM-treated control group whereas CMMs-treated groups showed AI values ranged from 0.33 to 0.4. The increase of AI value in those CMM-treated groups means that Drosophila adults became more susceptible to noxious heat stimulation. This indicates that those identified CMMs by the larvae model possess strong and versatile antinoceiceptive activities in Drosophila adults. / In addition, reverse transcription PCR (RT PCR) analysis was performed to study the effects of CMMs on the mRNA expression of three nociceptive-related genes painless, nompC and CG4536. These three genes all belong to the Transient Receptor Potential (TRP) families and have been shown to be involved in heat response. The results indicate that the gene expression level for nompC was significantly down-regulated with fold changes ranging from 0.2 to 0.7 upon 2 hrs treatment of three aqueous CMM extracts Citrus aurantium, Angelica dahurica and Vitex trifolia. However, there is no significant difference in gene expression level for painless and CG4536. / In this study, it has been demonstrated that Drosophila are feasible to use for screening CMMs with antinociceptive activity. While the data of the relative gene expression level for those target genes observed in this study may also serve as biomarkers for providing more evidence to investigate drugs have antinociceptive effects. In the future, such information paves the way for further development in the study of antinociceptive drugs. / Nociception is the reception of signals in the central nervous system (CNS) triggered by specialized sensory receptors which received stimuli such as electrical, thermal, mechanical, or chemical and response to escape from danger. Similar to humans, the fruitfly Drosophila display evolutionarily conserved nociceptive response that makes it suitable for in vivo nociceptive study. In this study, Drosophila larvae were used as initial screening model to investigate the antinociceptive effect that was caused by 61 randomly selected Chinese Medicinal Materials (CMMs). Upon noxious heat stimulation, 73% of larvae in the control group produced a stereotypical rolling behavior within 1 s. Among those tested CMMs, the results indicated that 4 aqueous CMMs extracts from Citrus aurantium L. (family: Rutaceae), Angelica dahurica (Fish. ex Hoffm.) Benth. et Hook (family: Umbelliferae), Vitex trifolia L. var. simplicifolia Cham. (family: Verbenaceae) and Panax notoginseng (Burk.) F. H. Chen (family: Araliaceae) were found to have strong antinociceptive effect on Drosophila larvae since less than 40% of the larvae have produced stereotypical rolling behavior within 1 s upon noxious heat stimulation. / "September 2007." / Advisers: Ming Liang Song; Ho Yin Edwin Chan. / Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4768. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 134-139). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

We are interested in understanding the molecular mechanisms that govern synaptic growth and plasticity. Recent evidence from several laboratories suggests that small GTPases play an important role in the promotion of neurite outgrowth; however, their role in the control of synaptic growth and functional plasticity is not well understood. The goal of this thesis is to investigate the role of small GTPases (including Rac, Rho and Cdc42) in the regulation of synaptic growth in vivo, using the Drosophila larval neuromuscular junction (NMJ) synapses as a model system. Our results show that presynaptic overexpression of Rac, but not of Rho or Cdc42, positively regulates both synaptic structure and function. Genetic loss of Rac leads to embryonic lethality, making it impossible to assess the full loss-of-function phenotype using conventional mutants. To circumvent this, we use the MARCM (Mosaic Analysis with a Repressible Cell Marker) technique to generate single motor neuron clones devoid of all genetic copies of Rac. Our data suggest that Rac activity is crucial for normal synaptic development. In support of this conclusion, we demonstrate that genetic removal of trio, a guanine nucleotide exchange factor (GEF) that is known to activate Rac, leads to a drastic reduction in the number of synaptic boutons. In addition, genetic removal of one copy of trio is sufficient to suppress the gain-of-function phenotype of Rac. Moreover, we demonstrate that partial removal of the fragile X mental retardation gene (dfmr1), a known suppressor of Rac, enhances the gain-of-function phenotype of Rac. Taken together, our findings support a model in which Rac signaling positively regulates synaptic growth and function at the Drosophila larval NMJ.

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