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1 / Yanyan Jiang

Synapses must continuously maintain stable function in order for neuronal circuits and higher-order systems to properly function. By necessity, tight regulation of molecules necessary for appropriate neurotransmission coupled with homeostatic forms of plasticity function to stabilize synaptic output. The Drosophila melanogaster larval neuromuscular junction (NMJ) is an excellent model synapse for investigating both homeostatic synaptic plasticity (HSP) and neurotransmission machinery. At the NMJ, post-synaptic impairments to neurotransmitter sensitivity (decreased quantal size) initiate HSP. A retrograde, muscle-to-nerve signal instructs the presynaptic neuron to increase neurotransmitter release (quantal content) to compensate for the post-synaptic impairment and maintain synaptic output. HSP can be separated into temporally distinct induction and maintenance phases, depending on the nature of the impairment. Acute blockade of glutamate receptors initiates rapid forms of HSP that restore synaptic output within minutes. Loss-of-function mutations in a gene encoding a glutamate receptor result in reduced quantal size, and as a result, expression of HSP over the lifespan of that animal. However, it is unclear whether these temporal phases are distinct processes with overlapping machinery, or whether both phases are part of a common process with temporal distinct signaling requirements. Here we show that, in addition to being molecularly distinct, the temporal phases are functionally distinct. We provide evidence that the long-term maintenance of HSP requires continuous inositol trisphosphate receptor (IP3R) and Ryanodine receptor (RyR) activities, but neither are necessary for the rapid induction phase of HSP. In addition, we investigated how mutations associated with Familial Hemiplegic Migraine Type 1 (FHM1) impact synapse function and seizure behavior. We show that flies expressing this mutant channel are susceptible to seizures. Further, neurons expressing a transgene for cacophony containing the FHM1 mutations R192Q and S218L in the analogous locations showed significant hyper-excitability. Concurrent knockdown of the gene Multiple inositol polyphosphate phosphatase 2 (Mipp2) attenuated hyper-excitable phenotypes. Additionally, Mipp2 knockdown or LiCl treatment, both of which should attenuate downstream IP3R signaling, mitigated susceptibility to seizures in adults. Together these results contribute to our understanding both of both the pathophysiology of migraine and seizures.

The physiological responses involved in mediating adaptive change due to varying environmental conditions or social interactions are complex and involve integration of numerous signaling pathways. With Drosophila melanogaster, I can investigate the responses to varied environmental and social stimuli through quantification of signaling activity, stress resistance, and changes in gene expression and behavior. My work focuses on investigating signaling pathways that adult insects use to regulate homeostasis. The steroid hormone 20- hydroxyecdysone (ecdysone) and its receptor (EcR/USP) are vital during arthropod development for coordinating molting and metamorphosis. However, recent adult studies in Drosophila melanogaster indicate that the hormone and receptor influence many processes. I characterized the wild-type expression patterns and activity of ecdysone receptors in individual tissues during early adult life. I found that receptor components EcR and usp were expressed in numerous adult tissues, but receptor activation varied depending on tissue type and adult age. EcR/USP activity did not detectably change in response to environmental stimuli but is reduced when a constitutively inactive ecdysone receptor is present. The current state of our understanding of this signaling system is reviewed with reference to my findings. I discuss future directions focusing on identifying locations of hormone synthesis, metabolism, and storage, isoform-specific roles of EcR, and functional roles of gene repression and activation to link hormone receptor activity with physiological responses. Adult physiology is also regulated by interactions between adipose tissue and the central nervous system. Genes expressed in the insect fat body are involved in regulating nutrient homeostasis, stress resistance, immunity, reproduction, and behavior. Of particular interest is female-specific independent of transformer (fit). Several studies indicate that fat body expression of fit may influence responses to environmental change by altering adult behavior or physiology. Our lab created fit mutants that I used to assess the effects of these mutations on adult Drosophila physiology and behavior. I found that fit mutant adults survive longer without food, have increased nutrient levels, are more active, and feed extensively. My findings indicate that the fat-biased gene fit influences multiple aspects of adult physiology that affect appetite modulation, metabolism, and behavior.

Abstract The synaptic input received by neurons in cortical circuits is in constant flux. From both environmental sensory changes and learning mechanisms that modify synaptic strengths, the excitatory and inhibitory signals received by a post-synaptic cell vary on a continuum of time scales. These variable inputs inherent in different sensory environments, as well as inputs changed by Hebbian learning mechanisms (which have been shown to destabilize the activity of neural circuits) serve to limit the input ranges over which a neural network can effectively operate. To avoid circuit behavior which is either quiescent or epileptic, there are a variety of homeostatic mechanisms in place to maintain proper levels of circuit activity. This article provides a basic overview of the biological mechanisms, and consider the advantages and disadvantages of homeostasis on a theoretical level. / text

Sterols serve two important biological functions in animals - they act as cellular membrane components, and as the precursor to steroid hormones. Insects require a dietary source of sterol because they cannot synthesize sterols de novo. Cholesterol is the most common sterol in plant-feeding insects, but because plants contain very little cholesterol, plant-feeding insects must convert plant sterols into cholesterol. In this dissertation I investigate the effect of common and novel plant sterols and steroids found in a transgenic tobacco line on several caterpillar species. I also explore the metabolism of these sterols and steroids, and use a microarray approach to identify genes involved in sterol use and metabolism in plant-feeding insects. I also study cholesterol homeostasis using a grasshopper species. Modified tobacco plants containing a novel sterol profile negatively affected performance three different caterpillar species, especially in the second generation. Insects reared on modified plants contained less total sterols and cholesterol than those on control plants having normal sterol profile. Similar results were found using artificial diets containing atypical steroids, e.g., cholestanol and cholestan-3-one, identified in the tobacco plants that were fed to my experimental caterpillars. More importantly, the sterol/steroid ratio, but not their absolute amount in the diets, determined the negative effects. Caterpillar species could convert stigmasterol, a common plant sterol, into cholesterol. They could also convert cholestan-3-one into cholestanol and epicholestanol, although this ability varied among different species. A microarray study, that focused on gene expression in midgut tissue, indicated that stigmasterol, cholestanol and cholestan-3-one could induce different gene expression level, and that cholestan-3-one caused a the largest pool of genes to be regulated. The genes possibly involved in the metabolism of stigmasterol and cholestan-3-one were reported. These findings are important in directing further research on the potential application of plant sterol modification to control pests in agricultural systems. Insect herbivores could behaviorally regulate the intake of several nutrients, but they could not regulate their sterol intake. They did, however, practice cholesterol homeostasis, by postingestively regulating tissue sterol levels, even when feeding on diets with high cholesterol content. Collectively, the results from this dissertation provide unique insight into cholesterol regulation, which is difficult to achieve in mammals that are capable of synthesizing their own sterols.

This thesis investigates hair cell (He) homeostasis and the compression wave cochlear amplifier. In the first part of the thesis, an accurate physiological treatment of a generic HC is conducted using a nonlinear distributed parameter physical model. This model includes the major ionic species (sodium, potassium and chlorine), defining the active cellular homeostatic properties. This model is used for transient response analysis. Resting state and transient responses of the HC model are in excellent agreement with the experimental literature. HCs in this model are most simply classified as instantaneous nonlinear transduction devices (i. e. their homeostatic mechanisms are not significantly frequency selective). A compression wave cochlear amplifier (CW-CA) is defined and modelled for the first time in the second part of the thesis. It is a physiological model that addresses three main elements present in the peripheral hearing circuit: cochlear mechanics, HC nonlinearity, and neurology. The actual physiological feedback mechanism of the CW-CA is realistic. A passive travelling wave (or other mechanical) vibration is the input to the system. Whilst the travelling wave wiggles the Organ of Corti, the compression wave pulsates it. The CW-CA is an alternative to the physiologically ill-defined locally active travelling wave cochlear feedback amplifier proposed by others. The new CW-CA model results in a cycle-by-cycle amplifier with nonlinear response. It is capable of assuming an infinite number of different operating states. The stable and first few amplitude-limited unstable states are significant in describing the operation of the peripheral hearing system. The CW-CA model can explain a large number of hearing phenomena. Several of these are investigated by means of a system analysis for both the stable and unstable cases. The system is studied and the tone, two-tone suppression and distortion product responses are found to align well with published results. Explanations for various mechanical, HC and neurological phenomena are discussed and presented. For example, previously poorly understood phenomena such as otoacoustic emissions and neural spontaneous rates are accounted for.

v, 137 leaves : ill., (part col.) ; 26 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.1974) from the Dept. of Zoology, University of Adelaide

Thesis (Ph.D. 1974) from the Dept. of Zoology, University of Adelaide.

Thesis (Ph. D.)--University of Missouri-Columbia, 2004. / Last two leaves of Table of Contents misnumbered v, vi instead of x, xi. Typescript. Vita. Includes bibliographical references. Also available on the Internet.