Neuroscience and Neurobiology Commons^™

Targeting The Subacute Progression Of Hippocampal Cellular Senescence Following Repetitive Mild Traumatic Brain Injury, Jacob Edward Exline

Master's Theses

Repetitive mild traumatic brain injury (rmTBI) increases an individual’s risk for developing persistent deficits in recognition memory with symptoms experienced by up to 30% of rmTBI patients. Cellular senescence has been suggested as an underlying mechanism of persistent rmTBI symptoms; however, the subacute progression of cellular senescence following rmTBI has not been evaluated. Furthermore, the use of subacute testosterone administration to treat persistent recognition memory deficits and the cellular and molecular underpinnings has yet to be well characterized. Our lab utilizes a 5-hit closed-head rmTBI rat model to induce deficits in recognition memory and determine the effects of subacute testosterone …

Somatic Inhibition By Microscopic Magnetic Stimulation, Hui Ye

Biology: Faculty Publications and Other Works

Electric currents can produce quick, reversible control of neural activity. Externally applied electric currents have been used in inhibiting certain ganglion cells in clinical practices. Via electromagnetic induction, a miniature-sized magnetic coil could provide focal stimulation to the ganglion neurons. Here we report that high-frequency stimulation with the miniature coil could reversibly block ganglion cell activity in marine mollusk Aplysia californica, regardless the firing frequency of the neurons, or concentration of potassium ions around the ganglion neurons. Presence of the ganglion sheath has minimal impact on the inhibitory effects of the coil. The inhibitory effect was local to the …

The Identification Of Lxr-Dependent Pathways In The Dorsal Root Ganglia In Models Of Obesity, Nadia Elshareif

Master's Theses

Peripheral Neuropathy is characterized as injury to the peripheral nervous system. In terms of sensory neuropathy, metabolic syndrome is involved in chronic inflammation and ER stress pathways induced by lipid overload, leading to the structural and physiological damage of afferent sensory nerves. To protect the cell from lipid-induced ER stress, Liver X Receptors (LXRs) are sterol-activated nuclear transcription factors that are of particular interest due to its role in the regulation of lipid homeostasis, membrane phospholipids, and inflammation in metabolic tissues. Their role in the peripheral nervous system remains to be elucidated. LPCAT3, regulated by LXRs, has been shown to …

Characterizing A Putative Membrane Androgen Receptor In Glioma Cell Models, Emma Yuen

Master's Theses

The goal of this current research was to explore the role of a putative membraneandrogen receptor (AR) in modulating the viability of various models of glioma/astrocytoma, relative to normal (non-tumor) astrocytes. We hypothesized that binding to the membrane AR could enhance the sensitivity of glioma cells to toxic insult (i.e., the chemotherapeutic, Temozolomide, TMZ), while leaving “normal” astrocytes unscathed. Our data reveal that binding to the putative membrane AR sensitized C6 glioma cells to TMZ and the oxidative/metabolic insult, iodoacetic acid (IAA). And while there was some evidence that binding to the membrane AR could enhance the effect of TMZ …

Advancing Our Understanding Of Mechanosensitive Microtubule Acetylation In Neurons, Margaret Earl Utgaard

Master's Theses

Stiffness is a signaling cue in the brain, and neuronal response to stiffness impacts development, injury and disease. Mechanotransduction is the process of cells interpreting and converting mechanical cues to biochemical signals. Tubulin acetylation increases microtubule stability and could be mechanosensitive. The impact of stiffness on tubulin acetylation and role of septins is the focus of this project.It was hypothesized that stiffer surfaces would increase tubulin acetylation. SH-SY5Y cells were plated on varying stiffness and the ratio of acetylated to alpha tubulin was measured using immunocytochemistry. This study found SH-SY5Y cells had the highest acetylation on hard surfaces. SH-SY5Y cells …

The Effect Of Gonadal Steroids Following Repeat Mild Traumatic Brain Injury On Anxiety-Like Behaviors In Rats, Trevor Nykamp

Master's Theses

Traumatic brain injury (TBI) affects millions of people in the U.S. each year. This thesis worked to address anxiety, a common emotional symptom following TBI, by utilizing a five-hit repeat mild TBI (rmTBI) experimental model. First, changes in gonadal status following injury and the severity of anxiety symptoms experienced were investigated. Our data revealed that suppressed testosterone levels following rmTBI resulted in significantly more anxiety-like behaviors across several observational variables. Even more, some of these behaviors were reduced by providing testosterone supplementation immediately following injury.Another goal of this work was to investigate the role of mitochondrial dysfunction, measured by COX4i1 …

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, …

Characterization And Targeting Of Voltage-Gated Ion Channels In Meningioma Cell Lines, Erik White

Master's Theses

Meningiomas (MN) are primary brain tumors originating in the meningeal covering of the central nervous system. These tissues can evolve through familial inheritance (NF2, Cowden Syndrome, or Werner Syndrome) or sporadic mutations. The WHO categorizes MNs into three grades (I-III); Grade I contain benign tumors and Grade III the most aggressive. Increasing grade coincides with an increase in genetic diversity, making universal treatments difficult. MNs are typically treated with hydroxyurea (HU), but this chemotherapy agent has many adverse side effects, leading to research in less toxic options. This study uses ion channel antagonists for T- and L-type calcium channels using …

Axonal Blockage With Microscopic Magnetic Stimulation, Hui Ye

Biology: Faculty Publications and Other Works

Numerous neurological dysfunctions are characterized by undesirable nerve activity. By providing reversible nerve blockage, electric stimulation with an implanted electrode holds promise in the treatment of these conditions. However, there are several limitations to its application, including poor bio-compatibility and decreased efficacy during chronic implantation. A magnetic coil of miniature size can mitigate some of these problems, by coating it with biocompatible material for chronic implantation. However, it is unknown if miniature coils could be effective in axonal blockage and, if so, what the underlying mechanisms are. Here we demonstrate that a submillimeter magnetic coil can reversibly block action potentials …

Chronic Circadian Misalignment Leads To Reduced Longevity And Largescale Changes In Gene Expression In Drosophila Melanogaster, Alex Christ Boomgarden

Master's Theses

As a result of earth's orientation toward the sun producing day and night, organisms have evolved an endogenous circadian timing system that is responsible for the 24-hour oscillation of most physiological and behavioral processes. This timing system is constantly synchronized to the external environment to adapt to and anticipate changes in light, temperature, food, and mate availability. In modern society, social and work constraints cause people to live schedules that are out of sync with their internal circadian clocks, producing a chronic circadian misalignment (CCM). While epidemiological studies in humans point to potentially damaging metabolic and cognitive consequences of CCM, …

Inhibitory Or Excitatory? Optogenetic Interrogation Of The Functional Roles Of Gabaergic Interneurons In Epileptogenesis, Hui Ye

Biology: Faculty Publications and Other Works

Alteration in the excitatory/inhibitory neuronal balance is believed to be the underlying mechanism of epileptogenesis. Based on this theory, GABAergic interneurons are regarded as the primary inhibitory neurons, whose failure of action permits hyperactivity in the epileptic circuitry. As a consequence, optogenetic excitation of GABAergic interneurons is widely used for seizure suppression. However, recent evidence argues for the context-dependent, possibly “excitatory” roles that GABAergic cells play in epileptic circuitry. We reviewed current optogenetic approaches that target the “inhibitory” roles of GABAergic interneurons for seizure control. We also reviewed interesting evidence that supports the “excitatory” roles of GABAergic interneurons in epileptogenesis. …

Application Of Stem Cell Derived Neuronal Cells To Evaluate Neurotoxic Chemotherapy, Claudia Wing, Masaaki Komatsu, Shannon M. Delaney, Matthew Krause, Heather E. Wheeler, M. Eileen Dolan

Bioinformatics Faculty Publications

The generation of induced pluripotent stem cells (iPSCs) and differentiation to cells composing major organs has opened up the possibility for a new model system to study adverse toxicities associated with chemotherapy. Therefore, we used human iPSC-derived neurons to study peripheral neuropathy, one of the most common adverse effects of chemotherapy and cause for dose reduction. To determine the utility of these neurons in investigating the effects of neurotoxic chemotherapy, we measured morphological differences in neurite outgrowth, cell viability as determined by ATP levels and apoptosis through measures of caspase 3/7 activation following treatment with clinically relevant concentrations …

Higher-Order Power Harmonics Of Pulsed Electrical Stimulation Modulates Corticospinal Contribution Of Peripheral Nerve Stimulation, Chiun-Fan Chen, Marom Bikson, Li-Wei Chou, Chunlei Shan, Niranjan Khadka, Wen-Shiang Chen, Felipe Fregni

Engineering Science Faculty Publications

It is well established that electrical-stimulation frequency is crucial to determining the scale of induced neuromodulation, particularly when attempting to modulate corticospinal excitability. However, the modulatory effects of stimulation frequency are not only determined by its absolute value but also by other parameters such as power at harmonics. The stimulus pulse shape further influences parameters such as excitation threshold and fiber selectivity. The explicit role of the power in these harmonics in determining the outcome of stimulation has not previously been analyzed. In this study, we adopted an animal model of peripheral electrical stimulation that includes an amplitude-adapted pulse train …

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 …

Anti-Nogo-A Immunotherapy Does Not Alter Hippocampal Neurogenesis After Stroke In Adult Rats, Timothy O'Brien, Daniel Shepherd, Gwendolyn Kartje-Tillotson, Shih-Yen Tsai, Robert G. Farrer

Mathematics and Statistics: Faculty Publications and Other Works

Ischemic stroke is a leading cause of adult disability, including cognitive impairment. Our laboratory has previously shown that treatment with function-blocking antibodies against the neurite growth inhibitory protein Nogo-A promotes functional recovery after stroke in adult and aged rats, including enhancing spatial memory performance, for which the hippocampus is critically important. Since spatial memory has been linked to hippocampal neurogenesis, we investigated whether anti-Nogo-A treatment increases hippocampal neurogenesis after stroke. Adult rats were subject to permanent middle cerebral artery occlusion followed 1 week later by 2 weeks of antibody treatment. Cellular proliferation in the dentate gyrus was quantified at the …

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 …

Adams As Potential Regulators Of Stem Cell Quiescence In The Olfactory Epithelium, Elaine Elizabeth Orendorff

Master's Theses

I demonstrate that a member of the protein family A Disintegrin and Metalloprotease (ADAM), ADAM23, is expressed in the olfactory epithelium (OE) and may inhibit neural progenitor cell (NPC) proliferation. I generated a list of ten gene candidates and selected ADAM23 for further study, based on its conserved protein structure and accumulating evidence for its role in cell cycle progression of proliferative cells. I next determined ADAM23 protein localization using immunohistochemistry and measured both mRNA and protein expression post-lesion with RT-qPCR and Western blot. ADAM23 is expressed in multiple cell types of the OE, including glial Sustentacular (Sus) cells and …

The Brain Geography Mini-Course: A Neuroscience Outreach Effort, Mark Albert

Computer Science: Faculty Publications and Other Works

The way we experience the world - how we go between sensing, thinking, and acting - is in some ways no more of a mystery than understanding how a computer works. Brains are quite complicated and we may never understand the details, but what we know in general can be very interesting. In this mini-course, we will learn how we think. When we see, hear, smell, touch, taste, remember, rehearse, fear something, understand or produce language, move our bodies...specific parts of the brain are used. Students will get a rough introduction to each part and how they interact. This will …

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 …

Spartin Protein Associates With Phospholipids Via Its Plant-Related Senescence Domain And Functions As A Lipid Transfer Protein, Maureen Ashlee Shaw

Theses (1 year embargo)

Troyer syndrome is a hereditary spastic paraplegia caused by a mutation that leads to a complete loss of expression of spartin protein. The plant-related senescence domain in spartin is highly conserved and present in over 150 proteins, but its function is unknown. Our results indicate that spartin associates with phospholipids via its senescence domain.

Phospholipids are important components of intracellular membranes and play roles in many cellular processes. Knock-down of spartin results in impaired cell division. The phospholipid phosphatidylinositol 3-phosphate (PI3P) is present at midbodies, where it recruits proteins for cytokinesis. Our findings demonstrate that spartin colocalizes with PI3P at …

Forced-Exercise Dependent Changes In Cellular Immunity: Effects On Experimental Autoimmune Neuritis, Michael W. Calik

Dissertations (6 month embargo)

Guillain-Barré Syndrome (GBS) is a debilitating inflammatory autoimmune disease of the peripheral nervous system that is characterized by rapid-onset paraparesis with areflexia progressing to neuromuscular paralysis. The most common form of GBS observed in North America and Europe is acute inflammatory demyelinating polyneuropathy (AIDP). Enhanced infiltration of pro-inflammatory type 1 helper T (Th1) cells into peripheral nerves of AIDP patients leads to demyelination.

Increasing evidence supports exercise as an effective rehabilitative intervention. Exercise attenuates the onset and progression of autoimmune diseases. Whether exercise alters the progression of GBS remains unclear.

In this study, we determined the effects of forced-exercise on …

Serotonin 1a Receptor Signaling In The Hypothalamic Paraventricular Nucleus Of The Peripubertal Rat, Maureen Lynn Petrunich Rutherford

Dissertations (6 month embargo)

Serotonin (5-HT) is a ubiquitous neurotransmitter in the brain that is involved in various physiologic functions including the regulation of hypothalamic hormones and has been implicated in various mood disorders such as depression. Preclinical and clinical data from studies in adults have shown that antidepressant drugs produce time-dependent changes in serotonergic and other systems and can also normalize dysfunction associated with the hypothalamic-pituitary-adrenal (HPA) axis. To date, our understanding of the mechanisms of 5-HT receptor signaling and the actions of drugs on serotonergic function have been derived from extensive preclinical research carried out using cell lines in vitro or in …

Mglur5 Involvement In Methamphetamine Reward And The Co-Morbidity Of Schizophrenia And Stimulant Use Disorders, Amy Anne Herrold

Dissertations (2 year embargo)

Methamphetamine (Meth) is a potent, widely-used stimulant. Stimulant abuse occurs more frequently in the schizophrenia patient population than the general population. The co-morbidity of stimulant use disorders and schizophrenia presents an understudied phenomenon and suggests overlapping brain states of these two pathologies.

There are currently no FDA-approved pharmacotherapies for Meth addiction and relapse to Meth use remains a substantial challenge for abstinent Meth addicts. One factor that contributes to craving and relapse is exposure to environmental or contextual cues associated with Meth use. This effect is the consequence of associative learning that occurs between the rewarding properties of drugs and …

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 …