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Astrocytic Regulation Of Seizure-Like Behavior, Sukhee Cho Dec 2017

Astrocytic Regulation Of Seizure-Like Behavior, Sukhee Cho

GSBS Dissertations and Theses

Astrocytes are emerging as important regulators of neural circuit function and behavior in the healthy and diseased nervous system. In a screen for astrocyte molecules that modulate neuronal hyperexcitability we identified multiple components of focal adhesion complexes (FAs) as potent suppressors of genetically- or pharmacologically-induced seizure-like activity. Depletion of astrocytic Tensin, b-integrin, Talin, Focal adhesion kinase (FAK), or matrix metalloproteinase 1 (Mmp1), which degrades extracellular matrix to activate b-integrin receptors, resulted in enhanced recovery from, or resistance to seizure activity. Reciprocally, promoting FA signaling by overexpression of Mmp1 in astrocytes led to enhanced-seizure severity. Blockade of FA signaling in astrocytes ...


The Drosophila Homolog Of The Intellectual Disability Gene Acsl4 Acts In Glia To Regulate Morphology And Neuronal Activity: A Dissertation, Caitlin M. Quigley Jul 2016

The Drosophila Homolog Of The Intellectual Disability Gene Acsl4 Acts In Glia To Regulate Morphology And Neuronal Activity: A Dissertation, Caitlin M. Quigley

GSBS Dissertations and Theses

Recent developments in neurobiology make it clear that glia play fundamental and active roles, in the adult and in development. Many hereditary cognitive disorders have been linked to developmental defects, and in at least two cases, Rett Syndrome and Fragile X Mental Retardation, glia are important in pathogenesis. However, most studies of developmental disorders, in particular intellectual disability, focus on neuronal defects. An example is intellectual disability caused by mutations in ACSL4, a metabolic enzyme that conjugates long-chain fatty acids to Coenzyme A (CoA). Depleting ACSL4 in neurons is associated with defects in dendritic spines, a finding replicated in patient ...


Functional Characterization Of Novel Pfn1 Mutations Causative For Familial Amyotrophic Lateral Sclerosis: A Dissertation, Chi-Hong Wu Dec 2015

Functional Characterization Of Novel Pfn1 Mutations Causative For Familial Amyotrophic Lateral Sclerosis: A Dissertation, Chi-Hong Wu

GSBS Dissertations and Theses

Amyotrophic lateral sclerosis (ALS) is a progressive adult neurodegenerative disease that causes death of both upper and lower motor neurons. Approximately 90 percent of ALS cases are sporadic (SALS), and 10 percent are inherited (FALS). Mutations in the PFN1 gene have been identified as causative for one percent of FALS. PFN1 is a small actin-binding protein that promotes actin polymerization, but how ALS-linked PFN1 mutations affect its cognate functions or acquire gain-of-function toxicity remains largely unknown.

To elucidate the contribution of ALS-linked PFN1 mutations to neurodegeneration, we have characterized these mutants in both mammalian cultured cells and Drosophila models. In ...


Transposition Driven Genomic Heterogeneity In The Drosophila Brain: A Dissertation, Paola N. Perrat Jun 2012

Transposition Driven Genomic Heterogeneity In The Drosophila Brain: A Dissertation, Paola N. Perrat

GSBS Dissertations and Theses

In the Drosophila brain, memories are processed and stored in two mirrorsymmetrical structures composed of approximately 5,000 neurons called Mushroom Bodies (MB). Depending on their axonal extensions, neurons in the MB can be further classified into three different subgroups: αβ, α’β’ and γ. In addition to the morphological differences between these groups of neurons, there is evidence of functional differences too. For example, it has been previously shown that while neurotransmission from α’β’ neurons is required for consolidation of olfactory memory, output from αβ neurons is required for its later retrieval. To gain insight into the functional ...


Role Of Glia In Sculpting Synaptic Connections At The Drosophila Neuromuscular Junction: A Dissertation, Yuly F. Fuentes Medel Jan 2012

Role Of Glia In Sculpting Synaptic Connections At The Drosophila Neuromuscular Junction: A Dissertation, Yuly F. Fuentes Medel

GSBS Dissertations and Theses

Emerging evidence in both vertebrates and invertebrates is redefining glia as active players in the development and integrity of the nervous system. The formation of functional neuronal circuits requires the precise addition of new synapses. Mounting evidence implicates glial function in synapse remodeling and formation. However, the precise molecular mechanisms governing these functions are poorly understood. My thesis work begins to define the molecular mechanisms by which glia communicate with neurons at the Drosophila neuromuscular junction (NMJ).

During development glia play a critical role in remodeling neuronal circuits in the CNS. In order to understand how glia remodel synapses, I ...


Autoregulatory And Paracrine Control Of Synaptic And Behavioral Plasticity By Dual Modes Of Octopaminergic Signaling: A Dissertation, Alex C. Koon Oct 2011

Autoregulatory And Paracrine Control Of Synaptic And Behavioral Plasticity By Dual Modes Of Octopaminergic Signaling: A Dissertation, Alex C. Koon

GSBS Dissertations and Theses

Synaptic plasticity—the ability of a synapse to change—is fundamental to basic brain function and behavioral adaptation. Studying the mechanisms of synaptic plasticity benefits our understanding of the formation of neuronal connections and circuitry, which has great implications in the field of learning and memory and the studies of numerous human diseases.

The Drosophila larval neuromuscular junction (NMJ) system is a powerful system for studying synaptic plasticity. The NMJ consists of at least two different types of motorneurons innervating the body wall muscles. Type I motorneurons controls muscle contraction using glutamate as the neurotransmitter, while type II are modulatory ...


Molecular Mechanisms Of Pirna Biogenesis And Function In Drosophila: A Dissertation, Chengjian Li Apr 2011

Molecular Mechanisms Of Pirna Biogenesis And Function In Drosophila: A Dissertation, Chengjian Li

GSBS Dissertations and Theses

In the Drosophila germ line, PIWI-interacting RNAs (piRNAs) ensure genomic stability by silencing endogenous selfish genetic elements such as retrotransposons and repetitive sequences.

We examined the genetic requirements for the biogenesis and function of piRNAs in both female and male germ line. We found that piRNAs function through the PIWI, rather than the AGO, family Argonaute proteins, and the production of piRNAs requires neither microRNA (miRNA) nor small interfering RNA (siRNA) pathway machinery. These findings allowed the discovery of the third conserved small RNA silencing pathway, which is distinct from both the miRNA and RNAi pathways in its mechanisms of ...


Axon Death Prevented: WldS And Other Neuroprotective Molecules: A Dissertation, Michelle A. Avery Dec 2010

Axon Death Prevented: WldS And Other Neuroprotective Molecules: A Dissertation, Michelle A. Avery

GSBS Dissertations and Theses

A common feature of many neuropathies is axon degeneration. While the reasons for degeneration differ greatly, the process of degeneration itself is similar in most cases. Axon degeneration after axotomy is termed ‘Wallerian degeneration,’ whereby injured axons rapidly fragment and disappear after a short period of latency (Waller, 1850). Wallerian degeneration was thought to be a passive process until the discovery of the Wallerian degeneration slow (Wlds) mouse mutant. In these mice, axons survive and function for weeks after nerve transection. Furthermore, when the full-length protein is inserted into mouse models of disease with an axon degeneration phenotype (such ...


A Glia-Mediated Feedback Mechanism For The Termination Of Drosophila Visual Response: A Dissertation, Peiyi Guo Sep 2010

A Glia-Mediated Feedback Mechanism For The Termination Of Drosophila Visual Response: A Dissertation, Peiyi Guo

GSBS Dissertations and Theses

High temporal resolution of vision relies on the rapid kinetics of the photoresponse in the light-sensing photoreceptor neurons. It is well known that the rapid recovery of photoreceptor membrane potential at the end of light stimulation depends on timely deactivation of the visual transduction cascade within photoreceptors. Whether any extrinsic factor contributes to the termination speed of the photoresponse is unknown.

In this thesis, using Drosophilaas a model system, I show that a feedback circuit mediated by both neurons and glia in the visual neuropile lamina is required for rapid repolarization of the photoreceptor at the end of the ...


Molecular Mechanisms Of Neurite Complexity In The Drosophila Brain: A Dissertation, Lei Shi Jun 2010

Molecular Mechanisms Of Neurite Complexity In The Drosophila Brain: A Dissertation, Lei Shi

GSBS Dissertations and Theses

Development of functional neural circuits involves a series of complicated steps, including neurogenesis and neuronal morphogenesis. To understand the molecular mechasnims of neurite complexity, especially neurite branching/arborization, the Drosophila brain, especially MBNs (mushroom body neurons) and PNs (projection neurons) in olfactory circuitry, was used in this dissertation work as the model system to study how two molecules, Dscam and Kr-h1 affect neurite complexity in the Drosophilabrain.

For the Drosophila Dscam, through alternative splicing it could encode up to 152,064 distinct immunoglobulin/fibronectin type cell adhesion molecules. Each Dscam isoform is derived from one of the 19,008 ...


Endogenous Small Rnas In The Drosophila Soma: A Dissertation, Megha Ghildiyal Mar 2010

Endogenous Small Rnas In The Drosophila Soma: A Dissertation, Megha Ghildiyal

GSBS Dissertations and Theses

Since the discovery in 1993 of the first small silencing RNA, a dizzying number of small RNAs have been identified, including microRNAs (miRNAs), small interfering RNAs (siRNAs) and Piwi-interacting RNAs (piRNAs). These classes differ in their biogenesis, modes of target regulation and in the biological pathways they regulate.

Historically, siRNAs were believed to arise only from exogenous double-stranded RNA triggers in organisms lacking RNA-dependent RNA polymerases. However, the discovery of endogenous siRNAs in flies expanded the biological significance of siRNAs beyond viral defense. By high throughput sequencing we identified Drosophila endosiRNAs as 21 nt small RNAs, bearing a 2´-O ...


Maintenance Of Visual Sensitivity In The Drosophila Eye: A Dissertation, Lina Ni Jan 2010

Maintenance Of Visual Sensitivity In The Drosophila Eye: A Dissertation, Lina Ni

GSBS Dissertations and Theses

High visual sensitivity is a common but important characteristic of animal eyes. It is especially critical for night vision. In animal eyes, photoreceptors are the first to receive the incoming rays of light and they convert the light signals to electrical signals before passing the information to interneurons in the eye and finally to the brain.

To function in dim light conditions, photoreceptors have developed high sensitivities to light. It is reported that both mammalian rod photoreceptors and Drosophilaphotoreceptors can detect single photons.

The high sensitivities of photoreceptors largely depend on a high content of rhodopsin, a light-stimulated G ...


Neural Circuit Analyses Of The Olfactory System In Drosophila: Input To Output: A Dissertation, Shamik Dasgupta Sep 2009

Neural Circuit Analyses Of The Olfactory System In Drosophila: Input To Output: A Dissertation, Shamik Dasgupta

GSBS Dissertations and Theses

This thesis focuses on several aspects of olfactory processing in Drosophila. In chapter I and II, I will discuss how odorants are encoded in the brain. In both insects and mammals, olfactory receptor neurons (ORNs) expressing the same odorant receptor gene converge onto the same glomerulus. This topographical organization segregates incoming odor information into combinatorial maps. One prominent theory suggests that insects and mammals discriminate odors based on these distinct combinatorial spatial codes. I tested the combinatorial coding hypothesis by engineering flies that have only one class of functional ORNs and therefore cannot support combinatorial maps. These files can be ...


Dna Damage-Induced Apoptosis In The Presence And Absence Of The Tumor Suppressor P53: A Dissertation, Laura Michelle Mcnamee Oct 2008

Dna Damage-Induced Apoptosis In The Presence And Absence Of The Tumor Suppressor P53: A Dissertation, Laura Michelle Mcnamee

GSBS Dissertations and Theses

A key regulator of DNA damage-induced apoptosis is the tumor suppressor gene, p53. p53 is a transcription factor that upregulates genes involved in cell cycle arrest, apoptosis, and senescence. How p53 decides to activate one of these responses in response to DNA damage is largely unanswered. Many have hypothesized it is due to interaction with various signaling pathways and post-translational modification. The p53 tumor suppressor can be modified by SUMO-1 in mammalian cells, but the functional consequences of this modification are unclear. Conjugation to SUMO is a reversible post-translational modification that regulates several transcription factors involved in cell proliferation, differentiation ...


Molecular And Neuronal Analysis Of Circadian Photoresponses In Drosophila: A Dissertation, Alejandro D. Murad Oct 2007

Molecular And Neuronal Analysis Of Circadian Photoresponses In Drosophila: A Dissertation, Alejandro D. Murad

GSBS Dissertations and Theses

Most organisms, from cyanobacteria to humans are equipped with circadian clocks. These endogenous and self-sustained pacemakers allow organisms to adapt their physiology and behavior to daily environmental variations, and to anticipate them. The circadian clock is synchronized by environmental cues (i.e. light and temperature fluctuations).

The fruit fly, Drosophila melanogaster, is well established as a model for the study of circadian rhythms. Molecular mechanisms of the Drosophilacircadian clock are conserved in mammals. Using genetic screens, several essential clock proteins (PER, TIM, CLK, CYC, DBT, SGG and CK-II) were identified in flies. Homologs of most of these proteins are ...


Neural Diversity In The Drosophila Olfactory Circuitry: A Dissertation, Sen-Lin Lai Jul 2007

Neural Diversity In The Drosophila Olfactory Circuitry: A Dissertation, Sen-Lin Lai

GSBS Dissertations and Theses

Different neurons and glial cells in the Drosophila olfactory circuitry have distinct functions in olfaction. The mechanisms to generate most of diverse neurons and glial cells in the olfactory circuitry remain unclear due to the incomprehensive study of cell lineages. To facilitate the analyses of cell lineages and neural diversity, two independent binary transcription systems were introduced into Drosophila to drive two different transgenes in different cells. A technique called ‘dual-expression-control MARCM’ (mosaic analysis with a repressible cell marker) was created by incorporating a GAL80-suppresible transcription factor LexA::GAD (GAL4 activation domain) into the MARCM. This technique allows the induction ...


Molecular And Behavioral Analysis Of Drosophila Circadian Photoreception And Circadian Thermoreception: A Dissertation, Ania Busza May 2007

Molecular And Behavioral Analysis Of Drosophila Circadian Photoreception And Circadian Thermoreception: A Dissertation, Ania Busza

GSBS Dissertations and Theses

Circadian clocks are biological timekeepers that help maintain an organism’s behavior and physiological state optimally timed to the Earth’s day/night cycle. To do this, these internal pacemakers must accurately keep track of time. Equally importantly, they must be able to adjust their oscillations in response to external time cues to remain properly synchronized with the environment, and correctly anticipate environmental changes. When the internal clock is offset from its surrounding day/night cycle, clinically relevant disruptions develop, ranging from inconveniences such as jet-lag to more severe problems such as sleep disorders or mood disorders. In this work ...


Snail Protein Family In Drosophila Neurogenesis: A Dissertation, Shovon I. Ashraf Sep 2001

Snail Protein Family In Drosophila Neurogenesis: A Dissertation, Shovon I. Ashraf

GSBS Dissertations and Theses

The Snail protein functions as a transcriptional regulator to establish early mesodermal cell fate in Drosophila. Later, in germ band-extended embryos, Snail is considered a pan-neural protein based on its extensive expression in neuroblasts. The evidence presented in thesis links snail expression and function in CNS. Cloning and functional characterization of a novel snail homologue, in Drosophila, are also described here. Cloning of this gene, worniu (Chinese for snail), revealed that the neural function of snail is masked by this and another closely related gene escargot. Both Escargot and Worniu contain zinc finger domains that are highly homologous to that ...


Analysis Of The Mechanism Of Ras Activation: Mapping Of Important Functional Domains Of The Son Of Sevenless Protein, Linda Sue Mccollam-Guilani Feb 1998

Analysis Of The Mechanism Of Ras Activation: Mapping Of Important Functional Domains Of The Son Of Sevenless Protein, Linda Sue Mccollam-Guilani

GSBS Dissertations and Theses

The questions outlined in this thesis dissertation were proposed in order to provide insight regarding the mechanism by which the Drosophila Son of sevenless (dSOS) protein activates Ras. Ras proteins are GTP-binding proteins which bind guanine nucleotides very tightly and cycle between the inactive GDP-bound state and the active GTP-bound state. To address the mechanism by which the dSOS proteins activates Ras, a structure-function analysis of the dSOS protein was performed using truncation and deletion mutants of dSOS. In vivo Ras activation experiments using transiently transfected cells revealed that the NH2-terminal domain of dSOS is required in order ...