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- Creators: Arizona State University
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
Methyl-CpG binding protein 2 (MECP2) is a widely abundant, multifunctional regulator of gene expression with highest levels of expression in mature neurons. In humans, both loss- and gain-of-function mutations of MECP2 cause mental retardation and motor dysfunction classified as either Rett Syndrome (RTT, loss-of-function) or MECP2 Duplication Syndrome (MDS, gain-of-function). At the cellular level, MECP2 mutations cause both synaptic and dendritic defects. Despite identification of MECP2 as a cause for RTT nearly 16 years ago, little progress has been made in identifying effective treatments. Investigating major cellular and molecular targets of MECP2 in model systems can help elucidate how mutation of this single gene leads to nervous system and behavioral defects, which can ultimately lead to novel therapeutic strategies for RTT and MDS. In the work presented here, I use the fruit fly, Drosophila melanogaster, as a model system to study specific cellular and molecular functions of MECP2 in neurons. First, I show that targeted expression of human MECP2 in Drosophila flight motoneurons causes impaired dendritic growth and flight behavioral performance. These effects are not caused by a general toxic effect of MECP2 overexpression in Drosophila neurons, but are critically dependent on the methyl-binding domain of MECP2. This study shows for the first time cellular consequences of MECP2 gain-of-function in Drosophila neurons. Second, I use RNA-Seq to identify KIBRA, a gene associated with learning and memory in humans, as a novel target of MECP2 involved in the dendritic growth phenotype. I confirm bidirectional regulation of Kibra by Mecp2 in mouse, highlighting the translational utility of the Drosophila model. Finally, I use this system to identify a novel role for the C-terminus in regulating the function of MECP in apoptosis and verify this finding in mammalian cell culture. In summary, this work has established Drosophila as a translational model to study the cellular effects of MECP2 gain-of-function in neurons, and provides insight into the function of MECP2 in dendritic growth and apoptosis.
ContributorsWilliams, Alison (Author) / Duch, Carsten (Thesis advisor) / Orchinik, Miles (Committee member) / Gallitano, Amelia (Committee member) / Huentelman, Matthew (Committee member) / Narayanan, Vinodh (Committee member) / Newfeld, Stuart (Committee member) / Arizona State University (Publisher)
Created2015