Medicine and Health Sciences Commons^™

Investigating The Viral Nature Of Neuronal Capsid Genes, Michael Manuel Long

Master's Theses

Memory formation is an essential part of everyday life. Neuronal communication is thought to be a key driver behind memory formation. There are two heavily studied methods of neuronal communication: chemical (neurotransmitter-mediated) and electrical (physically attached). When issues arise environmentally or genetically, people can experience one of many devastating memory disorders i.e. Alzheimer’s disease and other Dementias. Due to their prevalence, the treatments for disorders that hinder memory formation are a high priority for pharmaceutical companies. Currently, many of the treatments available focus on neurotransmitters or neuronal activity, and scientists are far from a cure. However, there may be an …

Delayed Testosterone Treatment In A Rodent Model Of Repeat Mild Traumatic Brain Injury Attenuates Mechanisms Of Cellular Death In The Vestibular Nucleus, Michael Volyanyuk

Master's Theses

A common complaint after repetitive mild traumatic brain injury (rmTBI) is vestibular dysfunction, which can become persistent and decrease quality of life. Delayed testosterone treatment has been shown to reduce vestibular impairment and improve neuronal survival in the vestibular nucleus following rmTBI; however, the long-term molecular pathways associated with rmTBI and testosterone treatment remain widely unexplored. We utilized a 5-hit closed-head rodent rmTBI model and administered testosterone 35 days after injury (DPI). The vestibular nuclei were removed and prepared for RT-qPCR and western blotting. Gene expression and protein levels were elevated for markers of oxidative stress (NADPH oxidase 4) and …

Mechanisms And Consequences Of Epigenetic Inheritance Following Parental Preconception Alcohol Exposure, Annadorothea Asimes

Dissertations

Recent advances in genomics research have revealed that preconception behaviors and experiences of mothers and fathers, including diet, environmental toxicants, and drug abuse, can impact future offspring through epigenetic mechanisms. This means that the risky behaviors of young people, such as the extremely popular practice of binge drinking, have potentially far-reaching consequences for generations to come. While there has been considerable research into fetal alcohol exposure and parental alcoholism, there has yet to be sufficient investigation into the mechanism of epigenetic inheritance or the functional consequences of parental preconception binge pattern alcohol abuse. The hypothesis tested herein is that parental …

Elevated Hydrostatic Pressure Selectively Enhances Matricellular Gene Expression In Human Trabecular Meshwork Cells, Jonathan Lautz

Dissertations

Primary open-angle glaucoma (POAG) is a progressive optic neuropathy

characterized by loss of peripheral vision secondarily associated with elevated intraocular pressure (IOP). Transforming growth factor (TGF)-β2 is markedly elevated in the aqueous humor (AH) of patients with POAG. It has been previously shown that TGF-β2 increases IOP, in part, by inducing expression and release of endothelin-1 (ET-1) and connective tissue growth factor (CTGF) within the trabecular meshwork (TM). ET-1 and CTGF may ultimately lead to increases in IOP by enhancing TM cell contractility and extracellular matrix (ECM) deposition. Here we confirm that TGF-β2 enhances mRNA content of ET-1, CTGF, and …

Examining The Effects Of Adolescent Binge Alcohol Exposure On The Negative Feedback Of The Hpa Axis And Adult Responses To Psychological Stress, Audrey Rose Torcaso

Dissertations

Binge drinking during adolescence is a common occurrence which is associated with increased risk of developing alcohol dependence and other mental health disorders. Hypothalamo-pituitary-adrenal (HPA) axis dysfunction is one characteristic commonly observed in many affective disorders, including anxiety and depression. Our laboratory has previously demonstrated that adolescent binge-pattern alcohol exposure results in long-term dysfunction of the HPA axis in a Wistar rat model, characterized by deficient glucocorticoid feedback inhibition. The current study aimed to characterize the behavioral phenotype of these rats in response to psychological stress during adulthood, and furthermore sought to understand the molecular mechanisms by which adolescent binge …

The Unconventional Secretion Of Alpha-Synuclein By Autophagic Mechanisms And The Novel Characterization Of Pathological Alpha-Synuclein Associated Extracellular Vesicles, Kevin Burbidge

Master's Theses

Synucleinopathies are a group of neurodegenerative diseases associated with the intracellular accumulation of aggregated α-synuclein, a neurotoxic process resulting in cell death. Research indicates that pathology results from α-synuclein misfolding and self-propagation, as well as, cell-to-cell transmission. Furthermore, pathological α-synuclein transmission may occur through unconventional secretion.

In this thesis, we investigated how autophagy influences unconventional secretion of our novel α-synuclein dual-split protein model that we first verified by reproducing documented results from treatment of known autophagic regulators. Afterwards, we investigated how knocking out autophagic proteins ATG7 and Beclin-1 influenced α-synuclein secretion.

Additionally, we developed a methodology for analyzing extracellular vesicles …

Examining The Effects Of Anti-Nogo A Immunotherapy On Post-Stroke Neurogenesis In The Adult Rat, Daniel Shepherd

Dissertations

Stroke is a leading cause of adult disability with no pharmacological treatments to restore lost function. Our laboratory has shown that treatment with neutralizing antibodies against the neurite growth-inhibitory protein Nogo-A improves sensorimotor and cognitive recovery after stroke in adult and aged rats. This recovery is paralleled by increased dendritic and axonal plasticity in anti-Nogo-A-treated rats. Neurogenesis, an alternate form of plasticity involving the de novo production of new neurons, may contribute to post-stroke neural repair. While previous studies have found roles for Nogo-A in adult neurogenesis, neurogenesis has not been investigated after stroke and anti-Nogo-A treatment. The goal of …

Cellular Consequences Of Lysosomal Rupture Induced By Alpha Synuclein, Zachary Carpenter Green

Master's Theses

Misfolded, toxic forms of amyloid alpha synuclein (α-syn) have been implicated in Parkinson’s disease (PD) pathology and have been shown to spread throughout the brain in a prion-like manner, explaining the progressive loss of neurons in PD. The mechanisms of spread and cell death are unknown, however, evidence from previous studies suggests that neurons may undergo apoptosis due to the uptake of exogenous α-syn aggregate through the endocytic pathway and subsequent lysosomal rupture.

This study aimed to corroborate previous evidence of α-syn induced lysosomal rupture and investigate the cellular repercussions of rupture with respect to cell death and α-syn transfer. …

Estrogen Regulation Of Mir-181a Stability In Neurons, Chun Kim

Master's Theses

Estrogens are an important class of steroid hormones involved in many cellular signaling processes. Levels of estrogens fluctuate across the lifespan suggesting that they target intracellular mediators, such as microRNAs, to fine-tune homeostatic cellular processes. Previous work in our lab demonstrated that 17β-estradiol (E2), the predominant circulating estrogen, stabilized miR-181a in a neuronal cell line derived from rat hypothalamus. These results lead to the hypothesis that E2 regulated miR-181a stability by altering the pool of endogenous RNA and by recruiting PNRC2 away from the miRNA degradation machinery. By utilizing miRNA degradation assays and immunostaining techniques, it was determined that the …

Consequences Of Estrogen Receptor Beta Phosphorylation In The Aged Female Brain And Heart, Elena Pinceti

Dissertations

Female life expectancy in the United States has steadily increased and now averages 81 years. Meanwhile, the age at which women reach menopause remains constant at 51 years. Both neurological and cardiovascular disorders increase following menopause, affecting women’s quality of life and leading to large health care costs. Estrogens are neuroprotective and cardioprotective for women, however when administered long after menopause, they fail to improve their health.

The effects of estrogen are mediated by Estrogen Receptor α (ERα) and Estrogen Receptor β (ERβ). Evidence supports that ERβ plays an important role in neuroprotection and cardioprotection, but aspects of ERβ molecular …

Effects Of Aggregated Alpha-Synuclein On Cultured Neuronal Cells, David Freeman

Dissertations

α-synuclein dysregulation is a critical aspect of Parkinson's disease pathology. Recent studies have observed that α-synuclein aggregates are cytotoxic to cells in culture and that this toxicity can be spread between cells. However, the molecular mechanisms governing this cytotoxicity and spread are poorly characterized. Recent studies of viruses and bacteria, which achieve their cytoplasmic entry by rupturing intracellular vesicles, have utilized the redistribution of galectin proteins as a tool to measure vesicle rupture by these organisms. Using this approach, we demonstrate that α-synuclein aggregates can induce the rupture of lysosomes following their endocytosis in neuronal cell lines. This rupture can …

Extended Treatment Window Exists For Improving Sensorimotor Recovery Using Anti-Nogo A Immunotherapy In Adult Rats With Chronic Stroke Deficits, Katherine Marie Podraza

Dissertations

Stroke related death ranks as the fourth most common cause of mortality in the United States. Current therapeutic options following stroke are limited. One potential therapy involves the use of anti-Nogo-A immunotherapy post-stroke. Our laboratory has shown that the administration of this novel treatment results in sensorimotor recovery in adult and aged rats. This therapy has been shown to be efficacious when applied immediately, 24 hours, and 1 week post-stroke in rats with mild to moderate sensorimotor deficits. In addition, recent results suggest that administration of anti-Nogo-A immunotherapy up to 9 weeks after stroke still induces functional recovery and neuroanatomical …

Peripubertal Binge Ethanol, Age And Sex Modulate Microrna Expression In The Ventral And Dorsal Hippocampus Of The Adolescent Rat, Sarah Arianne Prins

Dissertations

Adolescent binge ethanol (EtOH) abuse induces long-term changes in gene expression, resulting in an increased risk for the development of adult mood disorders. microRNAs (microRNAs) are small, noncoding RNAs that regulate gene expression by translational repression. microRNA altered in response to EtOH and puberty in the developing brain. The biogenesis of mature 22-24 nucleotide (nt), single-stranded microRNAs involves Drosha and Dicer enzymatic processing of microRNA precursors. A mature microRNA imperfectly base pairs with messenger RNA (mRNA) target genes,which leads to mRNA cleavage or translational repression. Our lab has found that repeated binge EtOH exposure alters gene expression in the hypothalamus …

Effects Of Electrical Stimulation And Testosterone In Translational Models Of Peripheral Nerve Injury, Gina Monaco

Dissertations

As functional recovery following peripheral nerve injury is dependent upon successful regeneration and target reconnection, combinatorial treatments that enhance different regeneration events may be required for recovery from severe injuries. The neurotherapeutic effects of electrical stimulation (ES) and gonadal steroids have been demonstrated independently and in combination in extratemporal and intratemporal facial nerve injuries. The goals of the first aim were to develop a reliable intracranial facial nerve crush model and to investigate the therapeutic potential of combining ES with testosterone propionate (TP) in this most proximal injury model. Adult male rats were divided into intracranial sham-operated, intracranial crush, and …

Binge Alcohol And Recovery After Traumatic Brain Injury, Ian Vaagenes

Dissertations

An estimated 275,000 Americans are hospitalized following a traumatic brain injury (TBI) every year, 80,000 of whom develop a long-term disability. The factor that places one at perhaps the greatest risk of suffering a TBI is alcohol intoxication. 30-50% of TBI sufferers have a blood alcohol level above .08 mg/dl at the time of injury, the legal limit in most U.S. states. In fact, the presence of alcohol at the time of TBI more than doubles the risk of a repeat head injury in the two years following the injury. Given the large population of TBI sufferers with alcohol intoxication …

Influence Of Pramipexole On Probability Discounting And Ventral Pallidal Function: Assessments In Parkinsonian-Like Rats, Sandra Lynn Rokosik-Kletzel

Dissertations

People with neuropathologies who are treated with dopamine agonists may be at risk to develop impulse control disorders. The overall goal of this dissertation project was to expand our knowledge on the neuropsychopharmacology of dopamine agonist-induced impulsivity. At the time this dissertation was being developed, pramipexole was the drug, gambling was the behavior, and Parkinson's disease (PD) was the pathology most widely reported for this phenomenon. Therefore, we first developed a behavioral paradigm (i.e., probability discounting) to measure risk-taking, one aspect of gambling. Utilizing this paradigm, we determine if risk-taking was altered after acute and/or chronic pramipexole treatment. We incorporated …

Alpha-Synuclein Aggregates Activate The Nlrp3 Inflammasome Following Vesicle Rupture, Rudy Orlando Cedillos

Master's Theses

Parkinson's disease (PD) and related synucleinopathies are progressive neurodegenerative disorders that feature the accumulation of intracellular inclusions known as Lewy bodies (LBs) in the brain. The presynaptic protein α-synuclein is the primary constituent of LBs and has been documented to play a major role in the pathogenesis of synucleinopathies. Recently, aggregated α-synuclein has been implicated in prompting microglia-mediated inflammation, a process associated with the progression of neuronal death in neurodegenerative disorders. Although the mechanisms surrounding the induction of neuroinflammation are not well understood, the recently discovered inflammasome-forming NLR proteins have emerged as regulators of inflammation. In this study, we sought …

Statin-Mediated Attenuation Of Chemokine Expression In Peripheral Nerve Vascular Endothelial Cells, Kelly Ann Langert

Dissertations

Pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), play a pivotal role in the pathogenesis of Guillain-Barré Syndrome (GBS), a debilitating autoimmune disorder that affects the peripheral nervous system. By up-regulating endothelial expression of chemokines and cell adhesion molecules (CAMs), TNF-α facilitates the recruitment and trafficking of autoreactive leukocytes across the blood-nerve barrier and into peripheral nerves, an early pathological hallmark of GBS. Literature indicates that TNF-α, monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) are locally increased in patients with GBS, correlating with disease severity. Similar findings have been demonstrated in an animal model of GBS, experimental autoimmune neuritis …

Resveratrol + Ethanol Preconditioning And Neuroprotection, Nastaran Khodaie

Master's Theses

Our lab established that moderate ethanol preconditioning (MEP) for 6 days blocked the Aâ25-35 toxicity in cerebellar mixed cell cultures and It has been shown that MEP cause the up regulation of the pre-survival enzymes such as proxiredoxin2 (PRX2), which suggests MEP can activate the cell survival pathways against upcoming toxins.

This study was performed to verify the possible combinatory effect of ethanol and resveratrol against Aâ25-35 toxicity. Both ethanol and resveratrol sub-protective concentrations were detected against Aâ25-35 in cerebellar mixed cell cultures. The combination of sub-protective levels of ethanol and resveratrol showed the significantly reduction in number of Aâ25-35 …

Determination Of The Molecular Mechanisms Of Hyperglycemia-Induced Changes In Cav3.2 Calcium Channel Properties, Ginny Marie Keeling

Master's Theses

Hyperglycemia can cause altered excitability due to increased CaV3.2 T-type calcium channel function, bestowing diabetics an increased neuropathy risk. The objective of this study was to understand the molecular mechanisms of increased CaV3.2 function during hyperglycemia in vitro, which leads to a 58% increase in current density and increased channel open probability (PO), among other changes. Two major findings are reported in this study:

1) The enzymatic elimination of extracellular N-acetylneuraminic acid (NANA) moieties reversed the increase in current density and the shift in PO, showing that hyper-glycosylation alters channel function in disease.

2) Treatment with GM1 (a ganglioside highly …

Forebrain Noradrenergic Alterations And Anxiety After Myocardial Infarction, Jaimee Glasgow

Dissertations

Thirty to 45% of patients who suffer a myocardial infarction (MI) develop anxiety disorders and/or depression, and the development of mood and anxiety disorders following MI is a major risk factor for cardiovascular morbidity and mortality. Depressed post-MI patients have an increased risk of fatal arrhythmias, which are often precipitated by emotional stressors. However, the central nervous system mechanisms that contribute to post-MI anxiety and arrhythmia susceptibility are unknown. Therefore, the studies reported in this dissertation were designed to test the hypothesis that alterations in noradrenergic transmission in the forebrain contribute to the development of anxiety disorders and arrhythmia susceptibility …

Effect Of Neurotrophic Factors On Cholinergic Neurons In The Septo-Hippocampal Pathway Of Normal And Af64a Treated Rats, Christopher Andrew Willson

Dissertations

No abstract provided.

Characterization Of The On And Off Pathways In Human Vision, Luisa Roveri

Master's Theses

No abstract provided.

The Role Of Methylation And Chromatin Structure In The Regulation Of The O6-Methylguanine-Dna Methyltransferase (Mgmt) Gene In Human Glioma Cells, Joseph F. Costello

Dissertations

No abstract provided.

An Anatomical And Physiological Investigation Of Hippocampal Connections Involved In Cardiovascular Control, Kenneth Gary Ruit

Dissertations

No abstract provided.