Molecular and Cellular Neuroscience Commons^™

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 …

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 …

Transcriptional Mechanisms Of Neuroprotection In Excitotoxicity Driven Neurodegeneration In C. Elegans, Zelda Z. Mendelowitz

Dissertations, Theses, and Capstone Projects

Excitotoxicity is notorious for triggering neuronal cell death in both developmental and adult-onset neurodegenerative diseases. In excitotoxicity, excessive concentrations of Glutamate in the synapse overstimulate Glutamate Receptors (GluRs) on postsynaptic neurons. While GluR mediated degenerative mechanisms remain obscure, GluR activation was surprisingly found to also have a neuroprotective effect through activation of specific transcriptional programs. To identify evolutionarily conserved transcriptional programs in neuroprotection we use a C. elegans model of excitotoxic necrosis (glt-3;nuIs5). We have identified that non-canonical activation of the transcription factor CRH-1/CREB mediates neuroprotection in our excitotoxicity model. We found the Histone Acetyl Transferase, MYS-1/KAT6, and the neuronal …

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 …

Neural Stem Cells: Age-Dependent Outcomes During Viral Infections In The Central Nervous System, Manisha N. Chandwani

Electronic Theses and Dissertations

Viral infections in the central nervous system (CNS) are associated with neurodevelopmental and neurobehavioral deficits. The outcomes of viral infections can be driven by damage and death of neurons. Neural stem cells (NSCs) play key roles in neurodevelopment, repair, and physiological brain function. During a viral infection, NSC activity can disturbed by direct infection of NSCs by the virus or by anti-viral immune response. Here, we aimed to assess whether the anti-viral immune response can impact NSC activity during an immunocompetent response in the adult brain. We utilized a transgenic mouse model of Measles virus infection where only the CNS …

The Effects Of Physical Function And Genetics On Cognition And Blood Biomarkers In Individuals At-Risk For Alzheimer’S Disease And Related Dementias, Joshua Louis Gills

Graduate Theses and Dissertations

Alzheimer’s disease and related dementia (ADRD) rates are expected to triple by the year 2050. Early detection and specific mitigation efforts are warranted to blunt the alarming rate. Physical function (PF) declines with age, but higher physical function is associated with better cognitive functioning in middle-to- older age individuals. Moreover, greater physical activity (PA) is associated with better global cognition; however, Apoliporotein e4 carriers may not gain the same benefits with exercise. Additionally, plasma phosphorylated tau 217 (p-tau217) has been identified as a novel diagnostic ADRD biomarker which needs further research to examine associations with risk factors. Therefore, the aims …

Neurogenesis And Functional Recovery In The Adult Mouse Retina Using An Alpha7 Nachr Agonist After Blast Exposure, Jake Bennett Spitsbergen

Masters Theses

Previous studies have provided evidence that eyedrop application of the selective α7 nicotinic acetylcholine receptor agonist, PNU-282987, induces neurogenesis and regeneration of retinal neurons from Müller glia in adult rodents. The objectives of this research include: 1) examination of the cellular and functional damage associated with ocular blast exposure, and 2) evaluation of structural and functional recovery post PNU-282987 treatment. Significant ocular blast damage was induced in adult mice after exposure to a single blast of 35 psi to the left eye. Blast-exposed transgenic mice expressing tdTomato Müller glia were treated daily with eyedrops containing PNU-282987 for 4 weeks following …

Analysis Of The Distributed Representation Of Operant Memory In Aplysia, Renan Murillo Costa

Dissertations and Theses (Open Access)

Operant conditioning, a ubiquitous form of learning in which animals learn from the consequences of behavior, engages a high-dimensional neuronal population space spanning multiple brain regions. A complete characterization of an operant memory remains elusive. Some sites of plasticity participating in the engram underlying an example of operant memory in Aplysia have been previously uncovered. Three studies are described here that sought to draw closer to a thorough characterization of this memory. The first study used a computational model to examine the ways in which sites of plasticity (individually and in combination) contribute to memory expression. Each site of plasticity …

Chloride Channels That Mediate A Transient Nitric Oxide-Dependent Synaptic Polarity Switch In Retinal Amacrine Cells., Tyler Christopher Rodriguez

LSU Doctoral Dissertations

Cytosolic chloride (Cl^-) concentration determines whether GABAergic and glycinergic synapses are inhibitory or excitatory. Ionotropic GABA and glycine receptors passively conduct Cl­^- leading to membrane depolarization or hyperpolarization depending on the Cl^- equilibrium potential. Accordingly, the distribution of Cl^- across the plasma membrane has the potential to determine the properties of networks of retinal amacrine cells (ACs) and their postsynaptic partners. Ion channels are responsible for establishing Cl^- reversal potential. Nitric oxide (NO) is a signaling molecule that can be generated in the inner retina where ACs form synapses. We have shown that NO …

Genetic Heterogeneity In Schizophrenia And Contribution Of Context To Vowel Recognition, Eva Childers

Dartmouth College Ph.D Dissertations

This dissertation is composed of three chapters that address two distinct topics. Chapter 2 addresses the use of consonantal context in vowel perception. Previous studies have demonstrated that context is important for vowel identification, however, this effect may be an artifact of stimuli production. To address this potential confound, we used stimuli extracted from an audiobook and asked subjects to identify vowels encased in consonants and isolated by themselves. We show that subjects had improved vowel identification when the vowel is presented with a consonantal framing, suggesting there is information contained in the surrounding context that is important for phoneme …

Mirnas Levels In A Streptozocin Model Of Alzheimer’S Disease, Nada Moustafa

Theses and Dissertations

Dementia entails a progressive decrease in cognitive functions, with 50%-75% of cases attributed to Alzheimer’s disease (AD); an aging-associated condition characterized by the build-up of tangled phosphorylated Tau (p-Tau) protein and beta-amyloid (Aβ) depositions. Sporadic AD (sAD) is multifactorial in nature, resulting from a combination of environmental and genetic predisposing factors. Type 2 diabetes mellitus (T2DM) is a leading risk factor for dementia, and deregulation of brain glucose metabolism is associated with early cognitive affection in sAD. Thus, the diabetogenic agent Streptozotocin (STZ) is used to experimentally create an AD model in animals (STZ-induced sAD), in which abnormalities in cerebral …

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, …

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 …

Evaluating The Brain-Enhancing Mitohormesis Of N-Propargylglycine, A Suicide Inhibitor Of Proline Dehydrogenase, To Offset The Proteotoxic Mechanisms Underlying Neurodegeneration In Huntington’S Disease And Evaluating The Phenotype Of A Mutant Pdia3 Knock-In Mouse Line As A Novel Genetic Model Of Neurological Disorders, Fadzai Teramayi

Natural Sciences and Mathematics | Biological Sciences Master's Theses

Huntington’s Disease (HD) is characterized by atrophy of the striatal and cerebral cortical neurons producing a variety of severe, and life-shortening neurologic symptoms including motor dysfunction, cognitive decline, psychiatric disturbances, and weight loss. As with other life-threatening neurodegenerative disorders, HD has no effective treatment capable of preventing or mitigating its underlying hallmark, subcellular and pathogenetic mechanism, that is, proteotoxicity. While it has been suggested that inducing brain mitohormesis might offer a promising therapeutic strategy, to date, no brain-penetrating mitohormesis-inducing agent has yet been identified or tested in any neurodegenerative disease mouse model. Recently, N-propargylglycine (N-PPG) was shown …

Sex-Specific Effects Of Chaperone And Glial Defenses On Experimental Lewy Body Disease, Tarun Bhatia

Electronic Theses and Dissertations

Lewy body disorders are a group of neurodegenerative conditions characterized by the pathological misfolding and aggregation of the abundant protein, α-synuclein. The most common Lewy body disorders are Parkinson’s disease and dementia with Lewy bodies. Apart from ageing, male sex is a major risk factor for Lewy body disorders, as men are at ~1.5-fold higher risk for these diseases than women. Yet, preclinical studies on Lewy body disorders rarely examine sex as a biological variable, and the mechanisms underlying sex-skewedness in disease risk remain undetermined.

Here, we developed a sex-stratified model of Lewy body disorders by exposing primary neurons harvested …

Estimating Glutamate Transporter Surface Density In Mouse Hippocampal Astrocytes, Anca R. Radulescu, Annalisa Scimemi

Biology and Medicine Through Mathematics Conference

No abstract provided.

Effects Of Neuronal Activation And Psychiatric Drug Treatment On Circhomer1 Biogenesis, Grigorios Papageorgiou

Biomedical Sciences ETDs

There are currently only very few efficacious drug treatments for SCZ and BD, none of which target and improve cognitive symptoms. Thus, there is an emerging need to develop novel therapeutics targeting molecular pathways linked to cognitive function and antipsychotic treatment. Circular RNAs (circRNAs) are stable non-coding RNAs, derived from the covalent back-splicing of precursor mRNA molecules. CircHomer1is a neuronal-enriched, activity-dependent circRNA, derived from the precursor of the long HOMER1B mRNA isoform, which is abundantly expressed in the adult frontal cortex and significantly downregulated in the prefrontal cortex of subjects with psychosis. Even though its relevance to psychiatric disorders …