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Description
Specific dendritic morphologies are a hallmark of neuronal identity, circuit assembly, and behaviorally relevant function. Despite the importance of dendrites in brain health and disease, the functional consequences of dendritic shape remain largely unknown. This dissertation addresses two fundamental and interrelated aspects of dendrite neurobiology. First, by utilizing the genetic power of Drosophila melanogaster, these studies assess the developmental mechanisms underlying single neuron morphology, and subsequently investigate the functional and behavioral consequences resulting from developmental irregularity. Significant insights into the molecular mechanisms that contribute to dendrite development come from studies of Down syndrome cell adhesion molecule (Dscam). While these findings have been garnered primarily from sensory neurons whose arbors innervate a two-dimensional plane, it is likely that the principles apply in three-dimensional central neurons that provide the structural substrate for synaptic input and neural circuit formation. As such, this dissertation supports the hypothesis that neuron type impacts the realization of Dscam function. In fact, in Drosophila motoneurons, Dscam serves a previously unknown cell-autonomous function in dendrite growth. Dscam manipulations produced a range of dendritic phenotypes with alteration in branch number and length. Subsequent experiments exploited the dendritic alterations produced by Dscam manipulations in order to correlate dendritic structure with the suggested function of these neurons. These data indicate that basic motoneuron function and behavior are maintained even in the absence of all adult dendrites within the same neuron. By contrast, dendrites are required for adjusting motoneuron responses to specific challenging behavioral requirements. Here, I establish a direct link between dendritic structure and neuronal function at the level of the single cell, thus defining the structural substrates necessary for conferring various aspects of functional motor output. Taken together, information gathered from these studies can inform the quest in deciphering how complex cell morphologies and networks form and are precisely linked to their function.
ContributorsHutchinson, Katie Marie (Author) / Duch, Carsten (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Newfeld, Stuart (Committee member) / Smith, Brian (Committee member) / Orchinik, Miles (Committee member) / Arizona State University (Publisher)
Created2013
Description
Olfaction is an important sensory modality for behavior since odors inform animals of the presence of food, potential mates, and predators. The fruit fly, Drosophila melanogaster, is a favorable model organism for the investigation of the biophysical mechanisms that contribute to olfaction because its olfactory system is anatomically similar to but simpler than that of vertebrates. In the Drosophila olfactory system, sensory transduction takes place in olfactory receptor neurons housed in the antennae and maxillary palps on the front of the head. The first stage of olfactory processing resides in the antennal lobe, where the structural unit is the glomerulus. There are at least three classes of neurons in the antennal lobe - excitatory projection neurons, excitatory local neurons, and inhibitory local neurons. The arborizations of the local neurons are confined to the antennal lobe, and output from the antennal lobe is carried by projection neurons to higher regions of the brain. Different views exist of how circuits of the Drosophila antennal lobe translate input from the olfactory receptor neurons into projection neuron output. We construct a conductance based neuronal network model of the Drosophila antennal lobe with the aim of understanding possible mechanisms within the antennal lobe that account for the variety of projection neuron activity observed in experimental data. We explore possible outputs obtained from olfactory receptor neuron input that mimic experimental recordings under different connectivity paradigms. First, we develop realistic minimal cell models for the excitatory local neurons, inhibitory local neurons, and projections neurons based on experimental data for Drosophila channel kinetics, and explore the firing characteristics and mathematical structure of these models. We then investigate possible interglomerular and intraglomerular connectivity patterns in the Drosophila antennal lobe, where olfactory receptor neuron input to the antennal lobe is modeled with Poisson spike trains, and synaptic connections within the antennal lobe are mediated by chemical synapses and gap junctions as described in the Drosophila antennal lobe literature. Our simulation results show that inhibitory local neurons spread inhibition among all glomeruli, where projection neuron responses are decreased relatively uniformly for connections of synaptic strengths that are homogeneous. Also, in the case of homogeneous excitatory synaptic connections, the excitatory local neuron network facilitates odor detection in the presence of weak stimuli. Excitatory local neurons can spread excitation from projection neurons that receive more input from olfactory receptor neurons to projection neurons that receive less input from olfactory receptor neurons. For the parameter values for the network models associated with these results, eLNs decrease the ability of the network to discriminate among single odors.
ContributorsLuli, Dori (Author) / Crook, Sharon (Thesis advisor) / Baer, Steven (Committee member) / Castillo-Chavez, Carlos (Committee member) / Smith, Brian (Committee member) / Arizona State University (Publisher)
Created2013
Description
Cell morphology and the distribution of voltage gated ion channels play a major role in determining a neuron's firing behavior, resulting in the specific processing of spatiotemporal synaptic input patterns. Although many studies have provided insight into the computational properties arising from neuronal structure as well as from channel kinetics, no comprehensive theory exists which explains how the interaction of these features shapes neuronal excitability. In this study computational models based on the identified Drosophila motoneuron (MN) 5 are developed to investigate the role of voltage gated ion channels, the impact of their densities and the effects of structural features.
First, a spatially collapsed model is used to develop voltage gated ion channels to study the excitability of the model neuron. Changing the channel densities reproduces different in situ observed firing patterns and induces a switch from resonator to integrator properties. Second, morphologically realistic multicompartment models are studied to investigate the passive properties of MN5. The passive electrical parameters fall in a range that is commonly observed in neurons, MN5 is spatially not compact, but for the single subtrees synaptic efficacy is location independent. Further, different subtrees are electrically independent from each other. Third, a continuum approach is used to formulate a new cable theoretic model to study the output in a dendritic cable with many subtrees, both analytically and computationally. The model is validated, by comparing it to a corresponding model with discrete branches. Further, the approach is demonstrated using MN5 and used to investigate spatially distributions of voltage gated ion channels.
First, a spatially collapsed model is used to develop voltage gated ion channels to study the excitability of the model neuron. Changing the channel densities reproduces different in situ observed firing patterns and induces a switch from resonator to integrator properties. Second, morphologically realistic multicompartment models are studied to investigate the passive properties of MN5. The passive electrical parameters fall in a range that is commonly observed in neurons, MN5 is spatially not compact, but for the single subtrees synaptic efficacy is location independent. Further, different subtrees are electrically independent from each other. Third, a continuum approach is used to formulate a new cable theoretic model to study the output in a dendritic cable with many subtrees, both analytically and computationally. The model is validated, by comparing it to a corresponding model with discrete branches. Further, the approach is demonstrated using MN5 and used to investigate spatially distributions of voltage gated ion channels.
ContributorsBerger, Sandra (Author) / Crook, Sharon (Thesis advisor) / Baer, Steven (Committee member) / Hamm, Thomas (Committee member) / Smith, Brian (Committee member) / Arizona State University (Publisher)
Created2014
Description
Dendrites are the structures of a neuron specialized to receive input signals and to provide the substrate for the formation of synaptic contacts with other cells. The goal of this work is to study the activity-dependent mechanisms underlying dendritic growth in a single-cell model. For this, the individually identifiable adult motoneuron, MN5, in Drosophila melanogaster was used. This dissertation presents the following results. First, the natural variability of morphological parameters of the MN5 dendritic tree in control flies is not larger than 15%, making MN5 a suitable model for quantitative morphological analysis. Second, three-dimensional topological analyses reveals that different parts of the MN5 dendritic tree innervate spatially separated areas (termed "isoneuronal tiling"). Third, genetic manipulation of the MN5 excitability reveals that both increased and decreased activity lead to dendritic overgrowth; whereas decreased excitability promoted branch elongation, increased excitability enhanced dendritic branching. Next, testing the activity-regulated transcription factor AP-1 for its role in MN5 dendritic development reveals that neural activity enhanced AP-1 transcriptional activity, and that AP-1 expression lead to opposite dendrite fates depending on its expression timing during development. Whereas overexpression of AP-1 at early stages results in loss of dendrites, AP-1 overexpression after the expression of acetylcholine receptors and the formation of all primary dendrites in MN5 causes overgrowth. Fourth, MN5 has been used to examine dendritic development resulting from the expression of the human gene MeCP2, a transcriptional regulator involved in the neurodevelopmental disease Rett syndrome. Targeted expression of full-length human MeCP2 in MN5 causes impaired dendritic growth, showing for the first time the cellular consequences of MeCP2 expression in Drosophila neurons. This dendritic phenotype requires the methyl-binding domain of MeCP2 and the chromatin remodeling protein Osa. In summary, this work has fully established MN5 as a single-neuron model to study mechanisms underlying dendrite development, maintenance and degeneration, and to test the behavioral consequences resulting from dendritic growth misregulation. Furthermore, this thesis provides quantitative description of isoneuronal tiling of a central neuron, offers novel insight into activity- and AP-1 dependent developmental plasticity, and finally, it establishes Drosophila MN5 as a model to study some specific aspects of human diseases.
ContributorsVonhoff, Fernando Jaime (Author) / Duch, Carsten J (Thesis advisor) / Smith, Brian H. (Committee member) / Vu, Eric (Committee member) / Crook, Sharon (Committee member) / Arizona State University (Publisher)
Created2012
Description
We examined the evolutionary morphological responses of Drosophila melanogaster that had evolved at constant cold (16°), constant hot (25°C), and fluctuating (16° and 25°C). Flies that were exposed to the constant low mean temperature developed larger thorax, wing, and cell sizes than those exposed to constant high mean temperatures. Males and females both responded similarly to thermal treatments in average wing and cell size. The resulting cell area for a given wing size in thermal fluctuating populations remains unclear and remains a subject for future research.
ContributorsAdrian, Gregory John (Author) / Angilletta, Michael (Thesis director) / Harrison, Jon (Committee member) / Rusch, Travis (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2015-05
Description
Virtually all animals require relatively predictable developmental schedules in order to fulfill the cycle of life. Cell death and severe inflammation alter steroid hormone production and can disrupt the timing of developmental transitions such as puberty. In the fruit fly, Drosophila melanogaster, injury to wing precursor tissues has been shown to result in decreased steroid hormone levels and delay development. The effects of damage to other tissues have not yet been explored. Here, the larval salivary glands were damaged in order to observe how injuring these specific tissues affect the timing of developmental transitions. Damage was induced by tissue-specific, temperature sensitive activation of cell death genes. The results indicated that death to salivary gland cells accelerates the Drosophila time to adult eclosion and that the observed acceleration of development is age-dependent. Insight into the effects of injury on development in Drosophila can potentially lead to information about development in other organisms, including humans, following injury or chronic inflammation.
ContributorsRippere, Alicia Leann (Author) / Hackney, Jennifer (Thesis director) / Marshall, Pamela (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor)
Created2015-05
Description
Fruit flies show a strong attraction to fruit odors. Most fruit odors, including strawberry scent, are complex multimolecular mixtures comprised of many chemically distinct constituents. How animals are able to process these mixtures and derive behaviorally relevant information is largely unknown. A new procedure was created to test odor preference for Heisenberg canton-s strain of Drosophila melanogaster. 30 flies were cold anesthetized at 4.2°C for 30 minutes and then placed in a testing arena. After acclimating for 45 minutes, the flies were exposed to two sources of air, one with ripe strawberry odor and one with only humidified air. Images were captured every minute for an hour and a preference index was calculated for every 10th image. The Drosophila had a positive average preference for the strawberry odor. Five out of six trials showed a general increase in odor preference over the course of the trial. While there was a generally positive trend for average preference over time, there was not a significant increase in average odor preference from time 1 to time 60. The data indicates that Drosophila show a preference for strawberry odor over humidified air, and we propose to extend this test to investigate how Drosophila process and react to complex odors and their chemical constituents.
ContributorsSteinmetz, Kyle J (Author) / Smith, Brian (Thesis director) / Jernigan, Chris (Committee member) / School of Life Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
Animals are thought to die at high temperatures because proteins and cell membranes lose their structural integrity. Alternatively, a newer hypothesis (the oxygen and capacity limitation of thermal tolerance, or OCLTT) states that death occurs because oxygen supply becomes limited at high temperatures. Consequently, animals exposed to hypoxia are more sensitive to heating than those exposed to normoxia or hyperoxia. We hypothesized that animals raised in hypoxia would acclimate to the low oxygen supply, thereby making them less sensitive to heating. Such acclimation would be expressed as greater heat tolerance and better flight performance in individuals raised at lower oxygen concentrations. We raised flies (Drosophila melanogaster) from eggs to adults under oxygen concentrations ranging from 10% to 31% and measured two aspects of thermal tolerance: 1) the time required for flies to lose motor function at 39.5°C at normoxia (21%), referred to as knock-down time, and 2) flight performance at 37°, 39°, or 41°C and 12%, 21%, or 31% oxygen. Contrary to our prediction, flies from all treatments had the same knock-down time. However, flight performance at hypoxia was greatest for flies raised in hypoxia, but flight performance at normoxia and hyperoxia was greatest for flies raised at hyperoxia. Thus, flight performance acclimated to oxygen supply during development, but heat tolerance did not. Our data does not support the OCLTT hypothesis, but instead supports the beneficial acclimation hypothesis, which proposes that acclimation improves the function of an organism during environmental change.
ContributorsShiehzadegan, Shayan (Co-author) / VadenBrooks, John (Co-author) / Le, Jackie (Co-author) / Smith, Colton (Co-author) / Shiehzadegan, Shima (Co-author) / Angilletta, Michael (Co-author, Thesis director) / VandenBrooks, John (Committee member) / Klok, C. J. (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
The goal of this project was to design and create a genetic construct that would allow for <br/>tumor growth to be induced in the center of the wing imaginal disc of Drosophila larvae, the <br/>R85E08 domain, using a heat shock. The resulting transgene would be combined with other <br/>transgenes in a single fly that would allow for simultaneous expression of the oncogene and, in <br/>the surrounding cells, other genes of interest. This system would help establish Drosophila as a <br/>more versatile and reliable model organism for cancer research. Furthermore, pilot studies were <br/>performed, using elements of the final proposed system, to determine if tumor growth is possible <br/>in the center of the disc, which oncogene produces the best results, and if oncogene expression <br/>induced later in development causes tumor growth. Three different candidate genes were <br/>investigated: RasV12, PvrACT, and Avli.
ContributorsSt Peter, John Daniel (Author) / Harris, Rob (Thesis director) / Varsani, Arvind (Committee member) / School of Molecular Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Edward B. Lewis studied embryonic development in Drosophila, including the discovery of the cis-trans test for recessive genes, and the identification of the bithorax complex and its role in development in Drosophila. He shared the 1995 Nobel Prize in Physiology or Medicine with Christiane Nüsslein-Volhard and Eric F. Wieschaus for work on genetic control of early embryonic development.
ContributorsNavis, Adam R. (Author) / Arizona State University. School of Life Sciences. Center for Biology and Society. Embryo Project Encyclopedia. (Publisher) / Arizona Board of Regents (Publisher)
Created2007-11-11