Molecular and Cellular Neuroscience Commons^™

Molecular Basis Of Membrane Pore Formation By Amyloid Beta Peptide, Nabin Kandel

Electronic Theses and Dissertations

Alzheimer's Disease (AD) is a neurodegenerative disorder that affects around 50 million people worldwide and causes cognitive decline, brain atrophy and death. Despite extensive basic and clinical studies and drug development efforts, currently no effective treatments are available for AD. The amyloid β (Aβ) peptide is neurotoxic and is tightly associated with AD pathology, but the molecular mechanism of its action remains unclear. There are various forms of Aβ in the brain, ranging from the full length Aβ1-42 to shorter peptides, such as a strongly toxic Aβ25-35 fragment. The Amyloid Cascade Hypothesis (ACH) postulated that extracellular Aβ deposits cause the …

Rapid No• Measures In Rat Nucleus Accumbens And Frontal Cortex Following Nasal Administration Of Nitroglycerin, Victoria A. Scott

Theses and Dissertations--Medical Sciences

Nitric Oxide (NO) is a powerful endogenous free radical that has numerous biological functions including vasodilation and serves as a post synaptic second messenger in the central nervous system (CNS). Numerous studies implicate NO• involvement in CNS disorders such as schizophrenia and drug abuse. These studies address the direct in vivo determination of an FDA-approved NO• donor (nitroglycerin) on extracellular levels of NO• in the frontal cortex and core of the nucleus accumbens in a lightly anesthetized rat. State-of-the-art in vivo amperometric recording techniques coupled with a novel 4-channel low noise pre-amplifier system and new generation microelectrode arrays (MEAs) will …

Neuroprotective Strategies Following Experimental Traumatic Brain Injury: Lipid Peroxidation-Derived Aldehyde Scavenging And Inhibition Of Mitochondrial Permeability Transition, Jacqueline Renee Kulbe

Theses and Dissertations--Neuroscience

Traumatic brain injury (TBI) represents a significant health crisis. To date there are no FDA-approved pharmacotherapies available to prevent the neurologic deficits caused by TBI. Following TBI, dysfunctional mitochondria generate reactive oxygen and nitrogen species, initiating lipid peroxidation (LP) and the formation of LP-derived neurotoxic aldehydes, which bind mitochondrial proteins, exacerbating dysfunction and opening of the mitochondrial permeability pore (mPTP), resulting in extrusion of mitochondrial sequestered calcium into the cytosol, and initiating a downstream cascade of calpain activation, spectrin degradation, neurodegeneration and neurologic impairment.

As central mediators of the TBI secondary injury cascade, mitochondria and LP-derived neurotoxic aldehydes make promising …

Autologous Peripheral Nerve Grafts To The Brain For The Treatment Of Parkinson's Disease, Andrew Welleford

Theses and Dissertations--Neuroscience

Parkinson’s disease (PD) is a disorder of the nervous system that causes problems with movement (motor symptoms) as well as other problems such as mood disorders, cognitive changes, sleep disorders, constipation, pain, and other non-motor symptoms. The severity of PD symptoms worsens over time as the disease progresses, and while there are treatments for the motor and some non-motor symptoms there is no known cure for PD. Thus there is a high demand for therapies to slow the progressive neurodegeneration observed in PD. Two clinical trials at the University of Kentucky College of Medicine (NCT02369003, NCT01833364) are currently underway that …

The Role Of Endoplasmic Reticulum Stress In Ethanol-Induced Neurodegeneration, Yongchao Wang

Theses and Dissertations--Pharmacology and Nutritional Sciences

Heavy ethanol use causes neurodegeneration manifested by neuronal loss and dysfunction. It is becoming imperative to delineate the underlying mechanism to promote the treatment of ethanol-induced neurodegeneration. Endoplasmic reticulum (ER) stress is a hallmark and an underlying mechanism of many neurodegenerative diseases. This study aims to investigate the role of ER stress in ethanol-induced neurodegeneration. In experimental design, adult mice were exposed to binge ethanol drinking by daily gavage for 1, 5, or 10 days and the response of ER stress was examined. We found the induction of ER stress appeared at 5 days and remained at 10 days. Moreover, …

Exploring The Role Of Insulin Receptor Signaling In Hippocampal Learning And Memory, Neuronal Calcium Dysregulation, And Glucose Metabolism, Hilaree N. Frazier

Theses and Dissertations--Pharmacology and Nutritional Sciences

In the late 90’s, emerging evidence revealed that the brain is insulin-sensitive, highlighted by broad expression of brain-specific insulin receptors and reports of circulating brain insulin. Contemporary literature robustly supports the role of insulin signaling in normal brain function and suggests that insulin-related processes diminish with aging, evidenced by decreased signaling markers, reduced insulin receptor density, and lower levels of insulin transport across the blood-brain barrier. In the context of pathological cognitive decline, clinical trials using intranasal insulin delivery have reported positive outcomes on memory and learning in patients with mild cognitive decline or early-stage Alzheimer’s disease. However, while the …

Identifying Dopamine Receptor Genes And Transcription Marbled Crayfish, Wolfgang Stein, Saisupritha Talasu

Faculty Publications – Biological Sciences

Modulatory transmitters are major contributors to nervous system plasticity and behavioral flexibility, they determine motivational states and are involved in psychiatric and neurological disorders. Neuromodulators act through a variety of distinct receptors and due to the diversity in receptor subtypes and distribution, a single neuromodulator can exert many different actions. A prerequisite to understand the ways modulators work is thus to identify which receptors are expressed in an animal.

I studied which Dopamine receptors are present in the Procambarus virginalis, a highly invasive species of all female genetic clones with high quality genome and transcriptomes. Their broad behavioral repertoire makes …

Investigating Neurogenesis As A Veritable Epigenetic Endophenotype For Alzheimer's Disease, Layne Wells

Scripps Senior Theses

Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by progressive amyloid plaque aggregation, neurofibrillary tangles, and cortical tissue death. As the prevalence of AD is projected to climb in coming years, there is a vested interest in identifying endophenotypes by which to improve diagnostics and direct clinical interventions. The risk for complex disorders, such as AD, is influenced by multiple genetic, environmental, and lifestyle factors. Significant strides have been made in identifying genetic variants linked to AD through the genome-wide association study (GWAS). It has been estimated in more recent years, however, that GWAS-identified variants account for limited …

Mutations Of Fus Cause Aggregation Of Rna Binding Proteins, Disruptions In Protein Synthesis, And Dysregulation Of Nonsense Mediated Decay, Marisa Elizabeth Kamelgarn

Theses and Dissertations--Toxicology and Cancer Biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron death and subsequent muscle atrophy. Approximately 15% of ALS cases are inheritable, and mutations in the Fused in Sarcoma (FUS) gene contribute to approximately 5% of these cases, as well as about 2% of sporadic cases. FUS performs a diverse set of cellular functions, including being a major regulator of RNA metabolism. FUS undergoes liquid- liquid phase transition in vitro, allowing for its participation in stress granules and RNA transport granules. Phase transition also contributes to the formation of cytoplasmic inclusions found in the …

Induction Of Cerebral Hyperexcitability By Peripheral Viral Challenge: Role Of Cxcl10 Chemokine, Tiffany J. Petrisko

Graduate Theses, Dissertations, and Problem Reports (ETD)

Peripheral viral infections are po­tent comorbid factors that exacerbate neuro­degene­ration. Although the under­lying mecha­nisms have not been defined, neuronal hyperexcitability has been established as an underlying feature. Our lab has developed a preclinical model in which a viral mimetic, poly­inosinic-poly­cytidylic acid (PIC) is injected in­tra­peritoneally to induce an anti-viral acute phase response (APR). APR in turn elicits robust neuronal hyperexcitability. The present study was undertaken to characterize molecular mechanisms that mediate the development of hyperexcitability in response to PIC challenge. The analysis of brain tissue after PIC challenge revealed a robust elevation of CXCL10 chemokine, indicating its putative role in …

Evidence-Based Probiotic Intervention For Behavioral And Social Deficits In Autism Spectrum Disorder, Allisen To

Scripps Senior Theses

Autism Spectrum Disorder (ASD) refers to a heterogeneous neurological condition characterized by repetitive and restrictive behaviors and social communication deficits. ASD diagnoses are at a record high, at approximately 1 in 59 children according to the US Center for Disease Control. Currently, there are no available interventions that effectively treat the core symptoms of ASD. All pharmaceutical options address comorbid side effects of ASD but not core deficits and are particularly associated with negative side effects. Additionally, there are economic and geographic barriers that can prevent families of individuals with ASD from seeking or receiving effective interventions. Many of the …

M1 Melanopsin Ganglion Cells In The ​Mus Musculus​ Retina Are Similar In Shape And Size, Geoffrey K. Sarpong

Williams Honors College, Honors Research Projects

An M1 melanopsin retinal ganglion cell (mRGC) is a subtype of the five melanopsin ganglion cells. The M1-type mRGC is distributed on the dorsal retina of a mouse and has an extensively overlapping dendritic network in both the sublamina a (OFF) and sublamina b (ON) layers of the inner plexiform layer. In the dorsal retina, the M1-type mRGCs are distinct and asymmetric.

The aim of this study was to examine the morphological similarity (shape and size) of M1-type mRGCs. The study traced 20 neurons in the first four months of a glaucoma retina of a DBA mouse, made measurements of …

The Role Of Syndecan-1 And Extracellular Vesicles In Breast Cancer Brain Metastasis, Megan R. Sayyad

Theses and Dissertations

Breast cancer metastasizes to the brain in 15-30% of all breast cancer cases, and metastasis is the predominant cause of breast cancer-related deaths. Patients with HER2-enriched and triple-negative breast cancers (TNBCs) are more likely to develop brain metastases. While targeted therapies exist for HER2-enriched breast cancers, there are no effective treatments for TNBCs. Thus, a greater understanding of how these cancers spread to the brain is critical. In order to spread to the brain, disseminated breast cancer cells must overcome 2 major steps—crossing the blood-brain barrier (BBB) and survival and successful colonization of the distinctive and mostly cellular brain environment. …

Sonic Hedgehog Is Expressed By Hilar Mossy Cells And Regulates Cellular Survival And Neurogenesis In The Adult Hippocampus, Luis E. Gonzalez-Reyes, Chia-Chu Chiang, Mingming Zhang, Joshua Johnson, Manuel Arrillaga-Tamez, Nicholas H. Couturier, Neha Reddy, Lev Starikov, Jeffrey R. Capadona, Andreas H. Kottmann, Dominique M. Durand

Publications and Research

Sonic hedgehog (Shh) is a multifunctional signaling protein governing pattern formation, proliferation and cell survival during embryogenesis. In the adult brain, Shh has neurotrophic function and is implicated in hippocampal neurogenesis but the cellular source of Shh in the hippocampus remains ill defined. Here, we utilize a gene expression tracer allele of Shh (Shh-nlacZ) which allowed the identification of a subpopulation of hilar neurons known as mossy cells (MCs) as a prominent and dynamic source of Shh within the dentate gyrus. AAV-Cre mediated ablation of Shh in the adult dentate gyrus led to a marked degeneration …

Biochemical Approaches For The Diagnosis And Treatment Of Lafora Disease, Mary Kathryn Brewer

Theses and Dissertations--Molecular and Cellular Biochemistry

Glycogen is the sole carbohydrate storage molecule found in mammalian cells and plays an important role in cellular metabolism in nearly all tissues, including the brain. Defects in glycogen metabolism underlie the glycogen storage diseases (GSDs), genetic disorders with variable clinical phenotypes depending on the mutation type and affected gene(s). Lafora disease (LD) is a fatal form of progressive myoclonus epilepsy and a non-classical GSD. LD typically manifests in adolescence with tonic-clonic seizures, myoclonus, and a rapid, insidious progression. Patients experience increasingly severe and frequent epileptic episodes, loss of speech and muscular control, disinhibited dementia, and severe cognitive decline; death …

The Effects Of A Ketone Body On Synaptic Transmission, Alexandra Elizabeth Stanback

Theses and Dissertations--Biology

The ketogenic diet is commonly used to control epilepsy, especially in cases when medications cannot. The diet typically consists of high fat, low carb, and adequate protein and produces a metabolite called acetoacetate. Seizure activity is characterized by glutamate excitotoxicity and therefore glutamate regulation is a point of research for control of these disorders. Acetoacetate is heavily implicated as the primary molecule responsible for decreasing glutamate in the synapse; it is believed that acetoacetate interferes with the transport of glutamate into the synaptic vesicles. The effects on synaptic transmission at glutamatergic synapses was studied in relation to the ketogenic diet …

Mechanisms Of Microglia Mediated Apolipoprotien E Neurotoxicity, Pardeep Singh

Dissertations and Theses

No abstract provided.

Sodium Channel Distribution In The Apical Dendrites Of Pyramidal Cells Vary In The Hindbrain Of Apteronotus Leptorhynchus., Sree Indrani Motipally

Graduate Theses, Dissertations, and Problem Reports (ETD)

Apteronotid weakly electric fish heavily rely on their electrosensory system for behaviors like spatial navigation, communication and prey capture. Since the behaviorally important information about their environment is contained in the spatial and temporal modulations of the electrosensory signal, efficient mechanisms to process this information with great fidelity are of the utmost importance. Efficient sensory processing often involves having multiple parallel processing streams so that each stream can specialize to treat signals with different properties. This strategy requires the response properties and neural dynamic to be adjusted in each pathway to implement different neural coding strategies. One of the neural …

Role Of Extracellular Vesicles In Neuroinflammatory Progression And Mitochondrial Functional Alterations, Ashley E. Russell

Graduate Theses, Dissertations, and Problem Reports (ETD)

Inflammation within the central nervous system (CNS), termed neuroinflammation, is a defining characteristic of many neuropathological conditions, including Alzheimer’s disease (AD) and stroke. Certain inflammatory mediators activate the transcription factor NF-κB, which induces transcription of many pro-inflammatory genes, including miR-34a and miR-146a. Several target candidate genes of these miRNAs encode for proteins of the mitochondrial electron transport chain. In our studies, we demonstrate that in response to inflammatory stimuli, such as TNF-α, the expression of miR-34a and -146a is significantly increased in several CNS cell types, and in their secreted extracellular vesicles (EVs). Exposure to TNF-α-derived EVs significantly increases cellular …

Regulator Of G Protein Signaling-12 (Rgs12) In Dopaminergic And Kappa Opioid Receptor-Dependent Signaling And Behavior, Joshua David Gross

Graduate Theses, Dissertations, and Problem Reports (ETD)

Dopaminergic neurotransmission is critically involved in the etiology and treatment of many psychiatric and neurological disorders. One modulator of dopaminergic neurotransmission is the kappa opioid receptor (KOR) -- a G protein-coupled receptor (GPCR) that is densely expressed within dopaminergic neurons and circuits. GPCRs are tightly regulated by a variety of intracellular signaling molecules, including Regulator of G Protein Signaling (RGS) proteins. Canonically, RGS proteins act as GTPase accelerating proteins (GAPs) on GTP-bound Ga subunits following GPCR activation, thereby hastening the rate at which GPCR-mediated G protein signaling is terminated. However, some RGS proteins exhibit more complex mechanisms of action on …

Spag17 Deficiency Impairs Neuronal Cell Differentiation In Developing Brain, Olivia J. Choi

Theses and Dissertations

The development of the nervous system is a multi-level, time-sensitive process that relies heavily on cell differentiation. However, the molecular mechanisms that control brain development remain poorly understood. We generated a knockout (KO) mouse for the cilia associated gene Spag17. These animals develop hydrocephalus and enlarged ventricles consistent with the role of Spag17 in the motility of ependymal cilia. However, other phenotypes that cannot be explained by this role were also present. Recently, a mutation in Spag17 has been associated with brain malformations and severe intellectual disability in humans. Therefore, we hypothesized that Spag17 plays a crucial role in …

Structure-Activity Relationship Studies Of Synthetic Cathinones And Related Agents, Rachel A. Davies

Theses and Dissertations

Synthetic cathinones and related agents represent an international drug abuse problem, and at the same time an important class of clinically useful compounds. Structure-activity relationship studies are needed to elucidate molecular features underlying the pharmacology of these agents. Illicit methcathinone (i.e., MCAT), the prototype of the synthetic cathinone class, exists as a racemic mixture. Though the differences in potency and target selectivity between the positional and optical isomers of synthetic cathinones and related agents have been demonstrated to have important implications for abuse and therapeutic potential, the two MCAT isomers have never been directly compared at their molecular targets: the …

Molecular Targets Of Psychedelics And Their Role In Behavioral Models Of Hallucinogenic Action, Hiba Z. Vohra

Theses and Dissertations

Psychedelics are a subset of hallucinogenic drugs that exert their characteristic effects through agonist activity at the serotonin receptor 2A (5-HT_2A). In this study, I aimed to characterize the modulatory role of the metabotropic glutamate subtype 2 receptor (mGluR2) in the 5-HT_2A-specific rodent model of hallucinogenic action, head-twitch response (HTR). Secondly, I aimed to explore if 5-HT_2A agonist-induced deficits in prepulse inhibition (PPI) of the startle response, an additional model of hallucinogenic action, could be produced in mice. Though 5-HT_2A agonist-induced PPI deficits, which represent interruptions in normal sensorimotor gating, have been described in …

An Investigation On The Role Of Β-Arrestin 2, Protein Kinase C And Sex On The Mechanism Of Morphine Tolerance In The Mouse Ileum, Karan Hitesh Muchhala

Theses and Dissertations

Opioids such as morphine are frequently used in the clinic to treat pain. However, the perennial bane of chronic opioid use is the rapid development of tolerance to the analgesic effects but delayed development of tolerance to the respiratory depressant and constipating effects. As constipation is one of the most common opioid-related adverse effects in humans, it is important to delineate mechanisms that drive opioid tolerance in the ileum and lack of it in the colon. The overarching goal of this thesis was to investigate mechanisms of morphine tolerance in the ileum by comparing the mechanism of morphine tolerance in …

Improving Dopamine Monitoring With Ncam And The Effects Of Intranasal Oxytocin On Dopamine Signaling In The Rat Brain, Darren Earl Ginder

EWU Masters Thesis Collection

Dopamine (DA) is a neurohormone highly involved in learning and memory. Oxytocin (OXT), another neurohormone, has also been implicated in learning and memory. Fast-scan cyclic voltammetry (FSCV) is a method used for the real-time examination of DA neurotransmission in the brain. Implanting FSCV electrodes is an invasive technique that likely results in an inflammatory response (i.e. gliosis) that can restrict FSCV recording of DA signals. Neural cell adhesion molecule (NCAM) may reduce gliosis and potentially improve the ability of FSCV electrodes to monitor DA signaling. Chapter 1 Methods: FSCV electrodes were coated with NCAM and implanted in the rat brain. …

The Progression Of Aβ Proteins In The Retrosplenial Cortex Using An App/Ps1 Alzheimer’S Disease Transgenic Rodent Model, Maha H. Rashid

Senior Independent Study Theses

Alzheimer’s disease is the most common form of dementia in the world with a new case of dementia diagnosed every 3.2 seconds. For over 25 years the amyloid cascade hypothesis has existed as a mechanism of understanding and diagnosing Alzheimer’s Disease. The amyloid cascade hypothesis suggests that Alzheimer’s Disease is sequential in protein progression and proliferative from the medial temporal lobe to the rest of the brain. Hypometabolism of brain regions has also been correlated to plaque deposition and hypometabolism is observed in brain regions that make up the default mode network, specifically the retrosplenial cortex, which is not accounted …