Life Sciences Commons^™

Towards A New Role Of Mitochondrial Hydrogen Peroxide In Synaptic Function, Cliyahnelle Z. Alexander

Student Theses and Dissertations

Aerobic metabolism is known to generate damaging ROS, particularly hydrogen peroxide. Reactive oxygen species (ROS) are highly reactive molecules containing oxygen that have the potential to cause damage to cells and tissues in the body. ROS are highly reactive atoms or molecules that rapidly interact with other molecules within a cell. Intracellular accumulation can result in oxidative damage, dysfunction, and cell death. Due to the limitations of H₂O₂ (hydrogen peroxide) detectors, other impacts of ROS exposure may have been missed. HyPer7, a genetically encoded sensor, measures hydrogen peroxide emissions precisely and sensitively, even at sublethal levels, during …

Methamphetamine-Induced Dna Double-Stranded Breaks: The Impact Of The Dopamine Transporter And Insights Into The Mechanisms Of Dna Damage In Mouse Neuro 2a Cells, Lizette Couto

Dissertations, Theses, and Capstone Projects

Methamphetamine (METH) abuse remains a global health concern, with emerging evidence highlighting its genotoxic potential. In the central nervous system METH enters dopaminergic cells primarily through the dopamine transporter (DAT), which controls the dynamics of dopamine (DA) neurotransmission by driving the reuptake of extracellular DA into the presynaptic neuronal cell. Additional effects of METH on the storage of DA in synaptic vesicles lead to the dysregulated cytosolic accumulation of DA. Previous studies have shown that after METH disrupts intracellular vesicular stores of DA, the excess DA in the cytosol is rapidly oxidized. This generates an abundance of reactive oxygen species …

The Role Of Glutamate In The Medial Prefrontal Cortex In The Acquistion And Expression Of Conditioned Approach, Rudolf Nisanov

Dissertations, Theses, and Capstone Projects

A series of experiments were conducted to assess the role of glutamatergic stimulation in the dorsal and ventral regions of the medial prefrontal cortex (mPFC) in both the acquisition and expression of reward-related learning using a Pavlovian conditioning paradigm, the conditioned-approach paradigm. Rats with surgically implanted cannulas were exposed to Pavlovian conditioning sessions that occurred on three alternative days (acquisition) or seven consecutive days (expression). These 60-min conditioning sessions consisted of 30 pairings of light (CS) and food pellets (US) presented under a random time schedule. After a two-day break, rats underwent a session with no CS or US and …

Characterization Of Pathological Tau Mutants, Charles J. Mcdonald

Dissertations, Theses, and Capstone Projects

Tau is a protein expressed exclusively in glia and neurons in the central nervous system and implicated in several neurogenerative diseases called “tauopathies”. Among all the tauopathies, one third is characterized by the presence of genetic mutations leading to the synthesis of tau proteins with single amino acid substitutions at specific locations and affecting protein function. While most of the initial studies have emphasize the functional role of tau as modulator of the axonal cytoskeleton, it has recently been well accepted that tau is also an intrinsically disordered protein that tends to form membraneless organelles called coacervates, due to a …

Validating A New In Vivo Model To Study Als, Izabela J. Cimachowska

Student Theses and Dissertations

Buildup of oxidative stress and mitochondrial dysfunction are well known characteristics of both sporadic and hereditary amyotrophic lateral sclerosis (ALS). While both forms of the disease seem to arise from common cellular dysfunction, the genetic disease is studied to a much greater extent. Engineering novel animal models of the sporadic form of the disease is crucial for development of druggable targets to treat ALS and understand the underlying mechanisms. Interestingly, accumulation of oxidative stress by exacerbated emission of reactive oxygen species (ROS) from presynaptic mitochondria is a hallmark of both hereditary and sporadic ALS. Previous work by our laboratory showed …

Clustered Protocadherins Ubiquitination And Phosphorylation Regulates Surface Expression, Albert Ptashnik

Dissertations, Theses, and Capstone Projects

Clustered protocadherins (Pcdhs) are a family of 60 adhesion-like molecules forming a neural barcode. In vertebrate neurons, 60 Pcdhs are coded by a large gene cluster. Numerous axons in the cluster are coding for the different extracellular, transmembrane, variable portion of the cytoplasmic and constant cytoplasmic domains where their expression is controlled epigenetically. These proteins mediate interactions between axons, dendrites, and glial cells during neural development. Yet, Pcdhs are not strictly adhesion molecules. In the amacrine cells of the retina, Pcdhs promote avoidance of the same cell dendrites, where in the cortex Pcdhs promote interactions between dendrites and astrocytes. In …

Mechanism Of Tau Propagation: Putative Therapeutic Approaches, Viktoriya Morozova

Dissertations, Theses, and Capstone Projects

One of the characteristics of Alzheimer’s disease and associated tauopathies is the accumulation and aggregation of hyperphosphorylated tau protein. The biological activity of tau is to bind to tubulin and promote its assembly into microtubules with subsequent stabilization of the latter. When tau gets hyperphosphorylated it cannot bind to tubulin and carry on its function, instead, it binds to normal tau and sequesters it from microtubules leading to disruption of microtubular assembly and ultimately to the death of neurons. Our lab had previously shown that tau phosphorylation sites 199, 212, 231, and 262, combined with the FTDP-17 mutation R406W (Pathological …

Role Of Nuclear Lamins In Oligodendrocyte Lineage Cells, Camila Yattah

Dissertations, Theses, and Capstone Projects

Differentiation of oligodendrocytes from progenitor cells is a highly regulated process characterized by a series of molecular changes, resulting in nuclear and morphological features unique to the mature oligodendrocyte state. Heterochromatin formation starting at the nuclear periphery, as well as increased nuclear rigidity are characteristically observed. The nuclear periphery is characterized by the presence of the nuclear lamina and it has been implicated in higher-order genome organization in cells. Lamins are the protein components of the nuclear lamina, and their expression is dependent upon the cell differentiation stage of the cells. While Lamin B1 (LMNB1) expression is high in progenitors …

Novel Therapeutic Strategies For Alzheimer’S Disease: Prostaglandin D2 Signaling And Its Human Polymorphisms As Well As A Polypharmacological Approach, Charles H. Wallace

Dissertations, Theses, and Capstone Projects

Alzheimer’s disease (AD) is an age related neurodegenerative disease with pathology that includes amyloid plaques, neurofibrillary tangles and non-resolving neuroinflammation. Non-resolving neuroinflammation lasts the entire course of the disease and has deleterious effects and is often thought to accelerate AD pathology. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) have commonly been used as therapeutics to treat pain, inflammation and vascular. NSAIDs work by altering the cyclooxygenase (COX) mediated biosynthesis of prostaglandins which are lipid mediators that have many physiological functions, for example nociception, inflammation and vasodilation. Epidemiological studies support the notion that NSAIDs could be used to treat AD. Yet, clinical trials using …

Development And Characterization Of A Novel, Genetically- Encoded Sensor To Image Sonic Hedgehog Signaling In Functional Circuits, Sonia Bernal

Dissertations, Theses, and Capstone Projects

Dynamic neurotransmitter and neuromodulator signaling in functional circuits is the neural substrate of animal behavior and cognition. The study of said circuits requires tools with sufficient spatiotemporal dynamics that can probe complex signaling patterns and decode their functional relevance by coupling the signal to behavioral output, ideally in awake, behaving animals. Much is known about the role of classical neurotransmitters such as dopamine in behavior, but a wide variety of peptides and small molecules also regulate neuronal transmission. One of these is Shh, whose presence has been observed in a variety of brain regions known to modulate movement, perception, and …

Role Of The G Protein Beta Gamma Subunits In Serotonin Transporter Dynamics, Nora Awadallah

Dissertations, Theses, and Capstone Projects

Serotonin is a vital neurotransmitter and hormone with significant roles in almost every organ system. In the central nervous system, serotonin mediates physiological functions that in turn guide behavior and mood. Here, serotonin is released from serotonergic neurons and exerts its effects through serotonin receptors. Regulation of serotonin neurotransmission is important for the maintenance of its physiological functions; thus, extracellular serotonin must be sequestered to limit the intensity and duration of serotonin transmission. Disproportionate transmission is strongly linked with neurological and psychiatric ailments.

Extracellular serotonin levels are primarily mediated by the serotonin transporter (SERT), a critically important plasma membrane protein …

Genetic Circadian Mosaics And The Clock Network’S Contributions To Sleep, Lukasz Widziszewski

Dissertations, Theses, and Capstone Projects

Circadian rhythms are physiological and behavioral changes which follow a 24-hour cycle. Drosophila Melanogaster’s circadian clock neuronal network (CCNN) has been identified and several subpopulations have been characterized based on previous studies; the classifications of subpopulations of neurons within the CCNN are based on a return of anticipatory locomotor activity preceding the two daily light transitions (Lights on = dawn/Lights off = dusk). The neurons responsible for the return of anticipatory morning locomotor activity have been referred to as the M-cells, the group of neurons known to rescue evening anticipatory locomotor activity have been termed the E-cells. In this …

Withdrawal From Voluntary Oral Methamphetamine Reveals Female Specific Susceptibilities To Behavioral Deficits And Neurochemical Perpetuators Of Neurotoxicity And Drug Seeking Behavior, Nicoletta K. Memos

Dissertations, Theses, and Capstone Projects

MA is a potent, highly addictive psychomotor stimulant known to produce neurotoxic effects on the brain leading to neurological impairments^1-6 characterized by neurodegeneration of dopaminergic fibers, cell bodies and pathways, as well as brain regions such as the hippocampus, frontal cortex, and midbrain^1,5.

In MA addiction, women are more vulnerable to the behavioral and cognitive effects of MA compared to men. Adult human literature reveals gender differences in usage patterns and women demonstrate increased vulnerability to the neurotoxic effects and health effects of MA use. Women begin drug use at an earlier age, escalate drug use quicker, …

Novel Strategies For Glutamate Clearance In The Glia-Deprived Synaptic Hub Of C. Elegans, Joyce Chan

Dissertations, Theses, and Capstone Projects

As the major excitatory neurotransmitter in the mammalian brain, Glutamate (Glu) is critical for normal neuronal physiology. Disruption in Glu clearance results in hyper-stimulation of glutamatergic circuits, potentially leading to excitotoxic neurodegeneration. The canonical model of brain connectivity describes glutamatergic synapses as well insulated and enveloped by glia. These glia express Glu Transporters (GluTs) which work to clear Glu following synaptic activity. However, critical areas of the brain such as the mammalian hippocampus display poor synaptic isolation, which may result in Glu spillover between adjacent synapses and subsequent loss of circuit specificity. How accurate signal transmission is achieved in these …

Importin-Mediated Pathological Tau Nuclear Translocation Causes Disruption Of The Nuclear Lamina, Tdp-43 Mislocalization And Cell Death, Robert F. Candia, Leah S. Cohen, Viktoriya Morozova, Christopher Corbo, Alejandra D. Alonso

Publications and Research

Tau is a cytosolic protein that has also been observed in the nucleus, where it has multiple proposed functions that are regulated by phosphorylation. However, the mechanism underlying the nuclear import of tau is unclear, as is the contribution of nuclear tau to the pathology of tauopathies. We have previously generated a pathological form of tau, PH-tau (pseudophosphorylation mutants S199E, T212E, T231E, and S262E) that mimics AD pathological behavior in cells, Drosophila, and a mouse model. Here, we demonstrated that PH-tau translocates into the nucleus of transiently transfected HEK-293 cells, but wildtype tau does not. We identified a putative …

Investigation Of Notch Signaling In Cone Fate Specification In Vertebrate Retina, Xueqing Chen

Dissertations, Theses, and Capstone Projects

In the vertebrate retina, cone photoreceptors are crucial for high acuity color vision. Several retinal diseases lead to loss of cones and there is a need to identify the normal developmental genesis of these cells to inform the development of stem cell-based therapies. Cone genesis has previously been shown to be repressed by Notch signaling, however, the mechanism by which Notch signaling controls cone fate determination is still unclear. It has been identified that cone photoreceptors are formed from multipotent retinal progenitor cells (RPCs) that first generate genetically-defined, restricted RPCs with limited mitotic and fate potential to preferentially form cones …

Estrogen Modulation Of Vta Dopamine Neuron Physiology And Behavioral Responsivity To Variable Social Stressors, Mary R. Shanley

Dissertations, Theses, and Capstone Projects

The behavioral output of different animals, or even the same animal in different contexts, is remarkably variable in response to the same external stimulus. This behavioral diversity is due to the complex integration of external and internal stimuli, through both neuronal and hormonal signals that selects the best behavioral response. By their nature as long-distance signaling molecules, hormones play a critical role in communicating information about internal states across the organism. Many hormones produced in the periphery target the central nervous system to modulate animal behavior, selecting for behaviors that are appropriate over behaviors that are maladaptive in that specific …

Sites Of Circadian Clock Neuron Plasticity Mediate Sensory Integration And Entrainment, Maria P. Fernand, Hannah L. Pettibone, Joseph T. Bogart, Casey J. Roell, Charles E. Davey, Ausra Pranevicius, Khang V. Huynh, Sara M. Lennox, Boyan Kostadinov, Orie T. Shafer

Publications and Research

Networks of circadian timekeeping in the brain display marked daily changes in neuronal morphology. In Drosophila melanogaster, the striking daily structural remodeling of the dorsal medial termini of the small ventral lateral neurons has long been hypothesized to mediate endogenous circadian timekeeping. To test this model, we have specifically abrogated these sites of daily neuronal remodeling through the reprogramming of neural development and assessed the effects on circadian timekeeping and clock outputs. Remarkably, the loss of these sites has no measurable effects on endogenous circadian timekeeping or on any of the major output functions of the small ventral lateral neurons. …

Targeting Ampa Receptor Modulation During Early Life Adversity: A Mediator For Threat Associated Memories, Roseanna M. Zanca

Dissertations, Theses, and Capstone Projects

Early life adversity (ELA) is the exposure to a single or to multiple traumatic events before the age of 18 that go beyond the child’s coping. These adverse events are often exacerbated during adolescence particularly when cognitive performance is compromised. Adolescents who experienced ELA may show symptoms of post-traumatic stress disorder (PTSD), while not vividly recalling the early life trauma. These individuals show atypical connectivity between prefrontal-amygdala and hippocampus, all of which is associated with an increased risk of experiencing a traumatic event again later in life. While clinical research has increasingly stressed the importance in addressing the long-lasting consequences …

Mitochondrial Distribution Of Glycine Receptors In Motor Neuron Cell Lines, Katsiaryna Milashevich

Student Theses and Dissertations

Although non-essential, glycine plays an important role in major metabolic reactions and is most known for its anti-inflammatory effects. An accumulation of contemporary research has shown that glycine is able to stabilize membrane potential using glycine receptors at the cellular level and to protect mitochondrial function directly, whether it is from inflammation, heavy metal poisoning, or ischemia-induced neuroinflammation. In this research, the existence of a hypothetical mitochondrial glycine receptor is examined. Immunofluorescence imaging was used to examine the presence of the glycine receptor subunits alpha 1 and alpha 2 in both non- differentiated and differentiated neuroblastoma cell lines. The preliminary …

Third Harmonic Generation: A Method For Visualizing Myelin In The Murine Cerebral Cortex, Michael Redlich

Dissertations, Theses, and Capstone Projects

Here we present the use of Third Harmonic Generation (THG) for the label-free imaging of myelinated axons in the murine cerebral cortex. Myelin plays an important role in the processes of learning and disease. However, much of the myelin biology research thus far has focused on white matter tracts where myelin is more visible. Much is still unknown, particularly with regard to myelin in gray matter. First, we engage in THG microscopy using an optical parametric oscillator pumped by a titanium-sapphire laser to demonstrate the utility of the technique for imaging myelin in vivo. Second, we investigate the use of …

Cloning And Characterization Of The Vasopressin-Oxytocin Neuropeptide Signaling System In The Vocal Control System Of The Zebra Finch (Taeniopygia Guttata), Emily R. Tortora

Dissertations and Theses

Vasopressin (VP) and Oxytocin (OT) are neuropeptides produced in the hypothalamus and expressed in the cerebrum and pituitary gland of the brain. Studies of VP and OT have long demonstrated their influence on social behaviors in mammals. Comparative analyses of these neuropeptides and in-depth analyses in non-mammalian species may reveal the specific mechanistic roles these hormones play in social behavioral functioning. The acquisition of complex behavioral patterns involves sensory-motor functions. How social interactions modulate sensory-motor mechanisms that promote complex behavior acquisition and maintenance can be well study in vocal learning birds. Here, in addition to reviewing the pertinent literature, I …

Functions Of Fibroblast Growth Factor Homologous Factor 2 In Excitable Tissues, Christopher Marra

Dissertations, Theses, and Capstone Projects

Purpose: Fibroblast Growth Factor Homologous Factors (FHFs) are a group of proteins known to associate with and modulate voltage-gated sodium channels (Na_v) in excitable cells. The four FHF genes are differentially expressed in specific cell-types, with FHF2 expressed prominently in the hippocampus, cerebral cortex, heart and dorsal root ganglia. Due to previous unavailability of an Fhf2 knockout mouse, this gene’s functions have been understudied in comparison to other those encoding other FHFs. The purpose of this research has been to better understand the normal physiological functions of FHF2 at the cellular and system levels in the heart, sensory …

Rehabilitative Movement Approaches And Dance Interventions In Parkinson’S Disease, Cecilia Fontanesi

Dissertations, Theses, and Capstone Projects

The scope of this work is to address the functional deficits and symptoms experienced by those living with Parkinson’s Disease through movement interventions.

Chapter 1 offers a brief overview of current pharmacotherapy and rehabilitation approaches in Parkinson’s, focusing on dance in particular as a movement intervention that may be particularly suited to this population.

Chapter 2 focuses on brain plasticity and motor learning in PD, reporting the effects of rTMS applied after the acquisition of a motor skill. In this study, adaptation tested in patients with PD was comparable in the sham and TMS sessions, while retention indices tested on …

Employing High Probability Gene Choice Elements To Understand Singular Odorant Receptor Expression, Raena Mina

Dissertations, Theses, and Capstone Projects

The ability to detect odorous chemicals in the environment is the oldest of the senses necessary for survival, from escaping danger, finding mates, to locating food. It is said that humans can identify and discriminate up to a trillion different odor mixtures. For chemoreception to have such a high discriminatory power, would require a diverse population of cells dedicated for odor detection. These detector cells are the olfactory sensory neurons (OSNs), which express odorant receptors (ORs) that bind to chemical odors in the environment. In order to increase specificity and sensitivity, an essential property in olfaction is for each OSN …

Expression Analyses Of Hippocampal And Cortical Proteins In A Rat Model For Alzheimer’S Disease, Rangon Islam

Theses and Dissertations

Currently, Alzheimer’s disease (AD) has no cure. Using a rat AD model, we identified aberrantly expressed proteins during pre-pathology as potential biomarkers. The expression of certain biomarkers was reversed by diazoxide, a repurposed hypertension drug. These results suggest that drug repurposing at an early stage of AD has therapeutic potential.

Tamalin/Gras-1 Connects Glutamate Receptor Activity To The Insulin/Igf Signaling Cascade To Regulate Neuroprotection In A Nematode Model Of Excitotoxicity, Ayesha Chowdhury

Dissertations, Theses, and Capstone Projects

Brain ischemia is a major cause of debilitation and death in the United States. Excitotoxicity, a condition that arises from the accumulation of glutamate (Glu) in the synapse that leads to overactivation of Glu receptors (GluRs), is the major mechanism of neuronal damage in brain ischemia / stroke. Although it is commonly acknowledged that over activation of GluRs leads to neurodegeneration, it has been recently shown that even during excitotoxicity Glu has a concurrent important role in regulating neuroprotection. GluR-activated transcription factors seem to mediate this neuroprotection, but it remains unclear which signaling cascades and transcription factors are regulated by …

Understanding How Sequence Differences Among Glutamate Transporters Might Contribute To Their Differential Function In Glutamate Clearance In C. Elegans, Irving Estevez

Dissertations and Theses

In the nervous system, high circuit resolution requires efficient post-signaling clearance of the neurotransmitter. Glutamate-mediated neurotransmission involves the release of glutamate (Glu) into the synaptic cleft by the presynaptic cell and binding to glutamate receptors (GluR) on the postsynaptic cell, leading to activation of a signal transduction cascade. Neurotransmission is eventually terminated by Glu uptake via glutamate transporters (GluT). Inefficient Glu clearance is detrimental to precise rapid signaling, can lead to blurring of circuit resolution by inadvertent Glu spillover to nearby circuits, and may even be neurotoxic. While classical views depict synapses as insulated by glia, recent technological advances show …

Effects Of Weak Electric Fields On Long-Term Synaptic Plasticity, Gregory Kronberg

Dissertations and Theses

Transcranial direct current stimulation (tDCS) is a technique where a weak direct electrical current is applied to the scalp with the goal of stimulating the brain. There is tremendous interest in the use of tDCS for treating brain disorders and improving brain function. However, the effects of tDCS have been highly variable across studies, leading to a debate over its efficacy. A major challenge is therefore to design tDCS protocols that yield predictable effects, which will require a better understanding of its basic mechanisms of action. One commonly discussed mechanism is that tDCS may alter synaptic plasticity, but the biophysics …

A Kinesin Adapter Directly Mediates Dendritic Mrna Localization During Neural Development In Mice, Hao Wu, Jing Zhou, Tianhui Zhu, Ivan Cohen, Jason Dictenberg

Publications and Research

Motor protein-based active transport is essential for mRNA localization and local translation in animal cells, yet how mRNA granules interact with motor proteins remains poorly understood. Using an unbiased yeast two–hybrid screen for interactions between murine RNA-binding proteins (RBPs) and motor proteins, here we identified protein interaction with APP tail-1 (PAT1) as a potential direct adapter between zipcode-binding protein 1 (ZBP1, a β-actin RBP) and the kinesin-I motor complex. The amino acid sequence of mouse PAT1 is similar to that of the kinesin light chain (KLC), and we found that PAT1 binds to KLC directly. Studying PAT1 in mouse …