Neuroscience and Neurobiology Commons^™

Characterizing Galectin And Lysosomal Rupture's Role In Spreading Parkinson Disease Pathology, Kevin Burbidge

Dissertations

The misfolding and subsequent accumulation of alpha-synuclein (α-syn) is central to the pathogenesis of Parkinson's disease (PD). Several lines of evidence suggest pathological α-syn spread cell-to-cell via a "prion-like" mechanism. Furthermore, this pathological α-syn is capable of "seeding" further misfolding of non-pathological α-syn, converting them to the pathological form. While a vast body of both genetic and experimental evidence indicates that α-syn is critical to PD development, how α-syn induces progressive neuronal dysfunction and cell death remains unclear.Autophagy, conventional for macroautophagy, is the primary degradation pathway for α-syn aggregates. Autophagy also influences the unconventional secretion of both pathological and non-pathological …

Understanding The Role Of Lipids Derived From The Gut Microbes In A Mouse Model Of Obesity-Induced Peripheral Pain, Raiza Rafael-Bonomo Hardy

Dissertations

The increase in obesity has been accompanied by a rise in the prevalence of painful peripheral neuropathy. Recently, studies have suggested a role for gut microbiome in the development of some peripheral pain, including chemotherapy- induced pain and fibromyalgia. In the present dissertation, we showed that modulation of gut microbiome in obese mice alleviated neuropathic indices, concurrent with changes in immune cell profile within the peripheral nerve system. We demonstrated that fecal transplantation from lean to obese mice decreased obesity-induced pain and restored nerve density in the skin. These improvements were accompanied by changes in peripheral nerve system gene expression, …

The Effects Of Alcohol And Traumatic Brain Injury On Neural Stem Cell Responses, Son Trung Ton

Dissertations

Traumatic brain injury (TBI) is a major source of disability in modern societies. However, there are no good pharmacological strategies for treating long-term TBI complications because we do not fully understand the injury processes that occur afterward. Moreover, a significant percent of patients entering the emergency room with TBI have a blood alcohol level above the legal limit. Alcohol use and intoxication is a widespread issue in our society. Binge drinking is the most common way in which alcohol is consumed, and alarmingly, Americans of all age groups binge drink on a frequent basis. Despite the prevalence of alcohol intoxication …

Endocytic Vesicle Rupture In The Pathogenesis And Propagation Of Neurodegenerative Proteinopathies, William P. Flavin

Dissertations

Numerous pathological amyloid proteins spread from cell-to-cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression. Understanding the mechanism by which disease-associated amyloid protein assemblies enter target cells and induce cellular dysfunction is therefore key to understanding the progressive nature of such neurodegenerative proteinopathies. In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to induce the rupture of intracellular vesicles following endocytosis, as well as to elucidate the cellular consequences of this damaging mechanism of invasion. We observed that the ability to induce vesicle rupture is a conserved feature of …

Sex Differences In Stroke Recovery: Synaptic Proteins And The Growth Inhibitory Protein Nogo A, Vincent Joseph Borkowski

Dissertations

Ischemic stroke is a major world-wide health problem, resulting in death and disability especially in the older population. A sex difference exists in functional recovery post-stroke, with post-menopausal women having worse functional outcome as compared to age-matched men. Although the mechanisms underlying this sex difference are not entirely clear, it is recommended that any potential therapy for stroke recovery be tested in pre-clinical models including both male and females in order to determine the efficacy of the proposed treatment on the entire population. We have reported a novel therapy to enhance brain plasticity and improve functional recovery after stroke in …

The Molecular Components Of Estrogen Receptor Beta (Erβ) Signaling In Neuronal Sytems, Natasha Mott

Dissertations

With increasing life expectancy, women are now living upwards of 50 years without circulating estrogens, therefore, it is essential to investigate how the brain is changed by estrogen deprivation and also how aging influences these changes. The Women's Health Initiative (WHI) study spurred rigorous debate regarding estrogen therapy for postmenopausal women due to dichotomous effects of estrogens in menopausal and post-menopausal women. Meta-analyses of the WHI study revealed that after circulating estrogens are depleted for many years re-exposure may cause aberrant, negative health effects, indicating that there is an age-related `switch' in estrogen signaling around menopause. These age-related effects of …

Molecular Expression Of Neuroprotective And Neurodestructive Signaling Systems Following Axotomy-Induced Target Disconnection: Relevance To Als, Melissa Marie Haulcomb

Dissertations

Amyotrophic Lateral Sclerosis (ALS) is the most common adult motoneuron (MN) degenerative disease. Discovery of a portion of familial cases with a mutation in the gene superoxide dismutase 1 (SOD1) gene led to the development of a transgenic mouse model. Pre-symptomatic SOD1 mice show no symptoms well into adulthood, however once symptom onset has occurred they display pathological hallmarks of ALS. The initial pathological event is loss of neuromuscular junctions in the lower limbs and therefore the die-back theory of ALS, suggests disconnection from the target musculature leads to MN degeneration. Our lab utilizes a peripheral nerve injury model to …

The Role Of Nogo-A In Memory And Neuronal Plasticity In The Aged Rodent Brain, Rebecca Lynn Gillani

Dissertations

The long-term effects of stroke often include cognitive impairments, but other than cognitive rehabilitation, which is often not fully successful, there is no intervention to treat cognitive impairments in stroke survivors. Our laboratory has previously shown that immunotherapy directed against the Nogo-A protein, which is enriched on oligodendrocytes, improves recovery of skilled forelimb sensorimotor function in adult and aged rats after an ischemic stroke lesion to the sensorimotor cortex. Furthermore, this recovery was correlated with axonal sprouting from intact pathways to denervated areas, as well as dendritic sprouting and increased dendritic spine density in the contralateral sensorimotor cortex. In the …

Effects Of Electrical Stimulation And Testosterone In Translational Models Of Facial Nerve Injury, Nijee Sharma

Dissertations

Among the various peripheral nervous system injuries seen clinically, facial nerve lesions are prevalent and have significant functional and emotional impact on patients. As injuries can occur in different segments of the facial nerve and lead to different pathophysiological outcomes, animal models that mimic the common sites of injury need to be developed so that potential therapies can be appropriately investigated. The extratemporal facial nerve axotomy model, in which the nerve is crushed at its exit from the skull, has been well established in the past and used to study the regeneration program of motoneurons. The present study uses this …

Effects Of Neuronal Nogo-A On Properties Of Excitatory Synapses Of The Sensorimotor Cortex, Alicia Marie Case

Dissertations

Recovery after central nervous system (CNS) injury has long been a challenge for clinical investigators. Blockade of the oligodendrocyte-associated inhibitor Nogo-A has shown great promise in promoting neuronal regeneration, sprouting, and plasticity, as well as functional recovery in rodent and primate models of CNS injury. The high expression of Nogo-A in neurons of the postnatal CNS led us to look for potential roles of this protein in this stage of development. We hypothesized that postnatal, neuronal NogoA influences the density and morphology of dendritic spines in the developing CNS, in part, by regulating the maturation and stability of glutamatergic synaptic …

The Role Of Sdf1/Cxcr4 Signaling In Opioid-Induced Hypernociception, Natalie Wilson

Dissertations

Opioids currently represent the best treatment option for severe and chronic pain conditions. Opioids while effective at controlling pain states also come with a number of side effects such as respiratory depression, urinary retention, dependence, tolerance, and opioid-induced hypernociception (OIH). OIH is a phenomenon in which opioids induce pain and this pain is often experienced at a site separate from the site of injury. Much research has been conducted investigating the mechanism of OIH, but the mechanism remains unsolved. One potential mechanism that has yet to be adequately explored is chemokines. Chemokines role in OIH is warranted given recent studies …

Neuroendocrine Consequences Of Binge Alcohol Exposure During Peri-Puberty On Functioning Of The Hypothalamo-Pituitary-Adrenal (Hpa) Axis, Magdalena Malgorzata Przybycien-Szymanska

Dissertations

Binge alcohol (EtOH) exposure in adolescence is a fundamental health concern. In 2005, over 20% of teenagers between ages 15 and 17 reported binge drinking behavior within a one month period preceding the survey (Dept. of Health and Human Services: Substance Abuse and Mental Health Services Administration). Binge drinking is defined as consuming enough alcohol within a 2.0 h period to bring blood alcohol concentration above 0.08%. In the adolescent population, this type of alcohol exposure tends to be repeated. In adults, alcohol abuse has been correlated with increased incidence of mood disorders and these disorders are characterized by dysregulation …

Involvement Of The Nmda Receptor In Moderate Ethanol Preconditioning-Dependent Neuroprotection From Amyloid-Beta In Vitro, Robert Matthew Mitchell

Dissertations

Alzheimer's disease (AD) is a progressive, mentally crippling, and eventually fatal form of dementia with growing prevalence in aging populations. In 2009 it was estimated that 5.3 million Americans have AD, with 5.1 million older than age 65 and 200,000 under 65. That accounts for 1 in 8 adults over 65. Furthermore, AD costs Americans 148 billion dollars in direct expenses, and is the leading cause of dementia and the 6th leading cause of death. Since improved medical care in general is increasing average life span and age is the primary risk factor for AD, there is need for basic …

Hindbrain Serotonin Neurons Activate 5-Ht1a Receptors In The Nucleus Tractus Solitarius (Nts) To Modulate Sympathetic And Ventilatory Recovery Following Hypotensive Hemorrhage, Ling-Hsuan Kung

Dissertations

Trauma is the leading cause of death of young people in the United States. Most such deaths result either from the initial blood loss or from secondary reperfusion injury following resuscitation.

Currently, the standard treatments for hypovolemic shock include volume resuscitation and using of vasoconstrictors to raise pressure. However, these treatments can exacerbate reperfusion injury, and require technical care when apply to patients. Therefore, novel therapies that can safely restore perfusion pressure are needed.

Our lab has found that 5-HT1A-receptor agonist, 8-OH-DPAT, increases perfusion pressure and improves acid-base balance in hypovolemic rats by stimulation of sympathetic-mediated increases in venous tone. …

Forced-Exercise Alleviates Neuropathic Pain In Experimental Diabetes: Effects On Voltage-Gated Calcium Channels, Sahadev A. Shankarappa

Dissertations

Exercise is now established as an integral adjunct to the management of diabetes. Diabetic polyneuropathy, a painful complication of diabetes, remains untreatable, emphasizing a critical need for improved therapeutic strategies. Recent evidence suggests that exercise may facilitate recovery of peripheral nerve function in diabetes. However, the mechanism by which exercise protects against diabetes-induced nerve dysfunction is unknown. In this dissertation we hypothesized that forced-exercise protects against experimental DPN by preventing glucose-associated alterations of voltage-gated calcium currents (VGCC) in small diameter dorsal root ganglion (DRG) neurons. Using behavioral, nerve-electrophysiology and patch-clamp methodology we examined the functional consequences of forced-exercise (treadmill, 5.4 …

Mechanisms Of Ipsapirone-Mediated Neuroprotection Of Ethanol-Treated Fetal Rhombencephalic Neurons: Role Of Endogenous Antioxidants, Jongho Lee

Dissertations

Prenatal exposure to ethanol can cause serious damage to the developing central nervous system. Both in vivo and in vitro studies demonstrate the vulnerability of the developing serotonergic system to the damaging effects of ethanol. However, treatment with a serotonin-1A (5-HT1A) agonist prevents the ethanol-associated apoptosis in developing 5-HT neurons. One mechanism by which 5-HT1A agonists exert their neuroprotective effects appears to involve activation of the phosphatidylinositol 3'kinase (PI-3K) pro-survival pathway and activation of NF-κB dependent anti-apoptotic genes. Additional NF-κB dependent genes might also be involved with the neuroprotective effects of ipsapirone.

There is also considerable evidence that ethanol augments …

Regulation Of Transglutaminase By 5-Ht2a Receptor Signaling And Calmodulin, Ying Dai

Dissertations

Transglutaminase (TGase), nature’s biological glue, catalyzes the post-translational modification of proteins by formation of intra- and intermolecular protein cross-links or by primary amine incorporation. TGase has various physiological functions, such as skin-barrier formation and blood clot stabilization, whereas increasing evidence indicates they may also involved in neurodegenerative diseases including Huntington’s disease (HD), Alzheimer disease’s, and progressive supranuclear palsy. Mutant huntingtin (htt) and small G proteins (e.g. Rac 1) are potential substrates of TGases. The purpose of this dissertation was to characterize the mechanisms by which 5-HT2A receptor signaling and calmodulin (CaM) regulate TGase-catalyzed transamidation of Rac1 and htt in cultured …

A Rat Model Examining Behavioral And Neurochemical Effects Of Passive Exposure To Aggression On Observers, Hideo Suzuki

Dissertations

Previous studies have consistently reported that passive exposure to aggression is a risk of aggressive inclinations for a human witness. However, it is unclear whether a witness' aggressiveness is semi-permanently socialized or temporarily primed. Furthermore, a neurochemical mechanism of passive exposure to aggression also remains unaddressed in clinical literature. The present research used a rat model to clarify the behavioral and neurochemical effects of passive exposure to aggression. First, rats were screened for their aggressiveness after they were acutely or chronically exposed to aggression or non-aggression. It was found that observer rats chronically exposed to aggression exhibited more aggression than …

Estrogen Influences On The Developing Rat Hippocampus Through Interactions With The Brain Derived Neurotrophic Factor And P160 Coactivator Proteins, Derek Tyler Solum

Dissertations

In addition to their primary role in the maintenance and regulation of reproductive capacity, ovarian steroid hormones acting through specific nuclear receptors influence more general neurobiological functions, such as perceptual-spatial skills and learning and memory. Estrogens act to alter certain aspects of cognitive performance and pathology such as epileptic seizure activity and Alzheimer’s disease. Furthermore, ovarian steroids act during development to alter the neuronal cytoarchitecture and synaptic connectivity. These early influences of steroids on the brain are essentially permanent and in part determine the steroid responsiveness of the adult brain. The mechanism and sites of action for the effects of …

N-Methylation Of Beta-Carbolines As A Potential Bioactivation Route In Parkinson's Disease, Debra Ann Gearhart

Dissertations

No abstract provided.

Circulating Androgens And The Response To Stress, Elena W. Bingaman

Dissertations

No abstract provided.

Integration Of Fetal Neocortical Transplants With The Damaged Host Brain, Mette Katrine Schulz

Dissertations

No abstract provided.

Neuronal Degeneration In Rat Olfactory And Cortical Brain Regions Following Subchronic Ethanol Intoxication, Thomas David Corso

Dissertations

No abstract provided.

In Vitro Investigations Of The Acth4-9 Analogue, Org2766, Ralph F. Murry

Dissertations

No abstract provided.

The Role Of The Hypothalamic Paraventricular Nucleus In Stress-Induced Renin And Corticosterone Secretion, Kathy Richardson Morton

Dissertations

No abstract provided.