Medicine and Health Sciences Commons^™

Investigation Of Whether Sedentary And Physically Active Conditions Lead To Altered Gabaergic Signaling In The Rvlm, Maryetta Donna Dombrowski

Wayne State University Dissertations

Investigation of whether sedentary and physically active conditions lead to altered GABAergic signaling in the RVLM

MD Dombrowski, and PJ Mueller

Department of Physiology, Wayne State University, School of Medicine, Detroit, MI

A sedentary lifestyle is a major risk for cardiovascular disease. Cardiovascular disease has been associated with elevated basal sympathetic nerve activity. The rostral ventrolateral medulla is a bilateral brainstem region that is an important for the control of resting and reflex control of sympathetic nerve activity and blood pressure. The activity of these neurons in this region is tonically inhibited by the neurotransmitter γ-butyric amino acid (GABA). Interestingly, …

Using A Novel Optogenetic Approach To Directly Assess 5-Ht1a Somatodendritic Autoreceptor Function In Response To Chronic Selective Serotonin Reuptake Inhibitor Treatment, Kelly Marie Mcgregor

Wayne State University Dissertations

Antidepressant drugs are widely used but their mechanism of action remains only partially understood. One leading hypothesis holds that a key effect of chronic treatment with a Selective Serotonin Reuptake Inhibitor (SSRI) is loss of somatodendritic 5-HT1A receptor-mediated autoinhibition in serotonergic neurons of the dorsal raphe nucleus (DRN). However, technical limitations have prevented direct testing of this hypothesis. In the current study we took advantage of optogenetic strategies to assess the effects of the classic SSRI fluoxetine on 5-HT1A receptor-mediated autoinhibition. We conducted these experiments in mice expressing the light-sensitive ion channel Channelrhodopsin (ChR) in 5-HT neurons to facilitate their …

An Investigation Of The Relationship Between Axonal Injury, Biomarker Expression And Mechanical Response In A Rodent Head Impact Acceleration Model, Yan Li

Wayne State University Dissertations

In the United States 1.4 million people sustain traumatic brain injury (TBI) each year, resulting in 235,000 hospitalizations and 50,000 fatalities annually. Traumatic axonal injury (TAI) is a serious outcome of TBI that accounts for 40-50% of hospitalizations due to head injury and one third of the mortality due to TBI, and it is difficult to diagnose and evaluate. The purpose of this dissertation is to determine mechanical injury predictors for TAI and identify potential biomarkers to evaluate TAI.

In this dissertation, a modified Marmarou impact acceleration injury model was developed to allow the monitoring of velocity of the impactor …

Evaluation Of Presynaptic Dopamine Dynamics After: Toluene Inhalation Or Trkb Receptor Activation, Aaron Kwaku Apawu

Wayne State University Dissertations

Dopamine (DA) neurons in the striatum mediate several functions of the brain and have been linked to a host of neurological disorders including Parkinson's disease and addiction, both of which occur as a result of dysfunction in the DA system. In the present study, our first objective was to understand how the striatal DA system adapts to acute and repeated administration of inhalant toluene. The use of toluene as inhalant, like other drugs of abuse, is known to perturb DA neurotransmission in the brain reward pathway. However, the exact mechanism underling toluene's influence on striatal DA neurotransmission is unknown. The …

Alterations In The Mouse Striatum Following Acute And Repeated Ethanol Exposure, Brooke D. Newman

Wayne State University Dissertations

Brain-derived neurotrophic factor (BDNF) is an important neuromodulator that has implicated in regard to several neurological disorders, including alcohol addiction. BDNF is also an important modulator of dopamine (DA), a neurotransmitter that is heavily implicated in addiction with one of the DA rich brain regions being referred to as the reward center of the brain. One of the focuses in alcohol dependence research includes determining risk factors that make an individual more susceptible to becoming dependent. BDNF has been of interest as a risk factor due to its involvement in ethanol consumption and addiction evidenced in a vast number of …

Longitudinal Change In Regional Cortices And Fluid Intelligence, Peng Yuan

Wayne State University Dissertations

Fluid intelligence (Gf) and crystalized intelligence (Gc) are two factors of the general intelligence. They have distinct age-related trajectories of change. Jung and Haier proposed Parieto-Frontal Integration Theory (P-FIT, 2007) to account for the inter-person variance in reasoning intelligence. Some brain regions such as prefrontal, parietal, temporal and anterior cingulate cortices were included in the P-FIT model and were hypothesized to be involved in fluid reasoning task. Therefore, in the current study, we examined latent growth curves (LGC) of longitudinal change in Gf, Gc, prefrontal cortex, parietal cortex, anterior cingulate, temporal cortex and primary visual cortex. Forty-six healthy middle-aged and …

Blast-Induced Tinnitus: A Combined Behavioral, Memri, And Electrophysiology Study, Jessica Pengyun Ouyang

Wayne State University Dissertations

ABSTRACT

BLAST-INDUCED TINNITUS: A COMBINED BEHAVIORAL, MEMRE, AND ELECTROPHYSIOLOGY STUDY

by

JESSICA OUYANG

May 2014 Advisor: Drs. Steve Cala & Jinsheng Zhang

Major: Physiology

Degree: Doctor of Philosophy

Tinnitus and hearing loss are the frequent auditory-related co-morbidities of blast trauma. The etiology of blast-induced tinnitus is also muddled by brain mechanisms associated with emotional and cognitive problems such as anxiety, memory loss, and depression. We set out to develop a realistic and ecologically valid model to address changes of cognitive status and psychological state that are associated with blast- induced tinnitus. In this study, 19 adult rats were randomly divided …

Accumulation Of Subcortical Iron As A Modifier Of Volumetric And Cognitive Decline In Healthy Aging: Two Longitudinal Studies, Ana Marie Daugherty

Wayne State University Dissertations

Accumulation of non-heme iron in the brain has been theorized as a cellular mechanism underlying global neural and cognitive decline in normal aging and neurodegenerative disease. Relatively few studies of brain iron in normal aging exist and extant studies are almost exclusively cross-sectional. Here, I estimated iron content via T2* and measured volumes in several brain regions in two independent samples of healthy adults. The first sample (N = 89) was measured twice with a two-year delay; and the second sample (N = 32) was assessed four times over a span of 7 years. Latent models estimated change in iron …

Linking Molecular, Electrical And Anatomical Properties Of Human Epileptic Brain, Shruti Bagla

Wayne State University Dissertations

Epilepsy is a common neurological disorder of recurrent unprovoked seizures. It affects almost 1% of the world population. Although there is a wide range of anti-epileptic drugs (AEDs) available, they only treat the seizure symptoms and do not cure the disease itself. The poor role of AEDs can be attributed to the lack of knowledge of exact mechanisms and networks that produce epileptic activities in the neocortex. At present, the best cure for epilepsy is surgical removal of electrically localized epileptic brain tissue. Surgically removed brain tissue presents an excellent opportunity to discover the molecular and cellular basis of human …

Roles Of Neuregulin1 In Neuromuscular Junction Development, Jiajing Wang

Wayne State University Dissertations

Neuromuscular junction (NMJ) development is a multistep process mediated by coordinated interactions between nerve terminals, target muscles, and peri-synaptic glial cells, and thus requires reciprocal signals derived from every cell type. Neuregulin1s (NRG1s) are a family of predominantly neuronal growth and differentiation factors that are important for many aspects of nervous system development. In this thesis, both the effects of NRG1 on NMJ development and reciprocal effects of neurotrophic factors on NRG1 expression were studied as a means to define the complex regulatory communication at the NMJ. Using the chicken embryo as a model, methods were developed to study the …

Multi-Modality Assessment Of Language Function, Erik Carmen Brown

Wayne State University Dissertations

The work presented as part of this dissertation represents a multi-modality study of language structure and function. The primary functional modality employed is task-related electrocorticography (ECoG). This is complemented by discussion and evaluation of previously published functional magnetic resonance imaging (fMRI) data. Language-related structure is explored using diffusion-weighted magnetic resonance imaging in conjunction with ECoG data. The scientific questions pursued are broad and include reevaluation of previously proposed theories.

We start by taking the first steps in validating our naming-related ECoG approach by comparing our results from a small cohort of patients to the clinical gold-standard technique of electrical brain …

Striatal Dopamine Dynamics Upon Manganese Accumulation, Madiha Khalid

Wayne State University Dissertations

STRIATAL DOPAMINE DYNAMICS UPON MANGANESE ACCUMULATION

by MADIHA KHALID

August 2013

Advisor: Dr. Tiffany Mathews

Major: Chemistry (Analytical)

Degree: Doctor of Philosophy

Although manganese (Mn) is fundamental for many biological processes, exposure to excess amounts leads to a neurological disorder termed manganism. Due to its symptomatic similarity to Parkinson's disease, as well its preferential accumulation in dopamine rich brain regions, alterations in the dopamine system are implicated in the onset of manganism. In my research, Mn overexposure is mimicked via subcutaneous administration of manganese chloride to C57BL/6 mice over the course of seven days using a protocol that has been …

White Matter Integrity And Age Related Differences In Reaction Time Components, Yiqin Yang

Wayne State University Dissertations

Reduced speed in information processing is a well-documented phenomenon associated with advanced aging. Age-related deterioration in white matter integrity might play a role in age-related increase in reaction time (RT). However, the association between microstructural differences in particular white matter regions or tracts with RT is unclear. Decomposing RT into parts might be a better way to understand the relationship due to multiple processes involved in RT. In a lifespan sample of 90 healthy normotensive participants, this study examined the association between RT components derived from the Ratcliff diffusion model with age related difference in DTI indices of a wide …

Progress Towards Understanding Of Mechanisms Of Action Of Potent Multifunctional Disease Modifying Therapeutics For Parkinson's Disease & Investigating The Methamphetamine-Induced Striatal Microglia Activation., Mrudang M. Shah

Wayne State University Dissertations

PROGRESS TOWARDS UNDERSTANDING OF MECHANISMS OF ACTION OF POTENT MULTIFUNCTIONAL DISEASE MODIFYING

THERAPEUTICS FOR PARKINSON'S DISEASE.

by

MRUDANG MANOJKUMAR SHAH

December 2013

Advisor: Dr. Aloke Dutta

Major: Pharmaceutical Sciences

Degree: Doctor of Philosophy

Our long term goal is to design and develop potent multifunctional disease modifying therapeutics for Parkinson's disease. The objective of my dissertation was to understand the mechanisms of action of some potent small molecules (synthesized in our lab) as a disease modifying Parkinson's disease therapeutic. The objective was achieved by pursuing the following two specific aims:

1. Investigating anti-oxidant and neuroprotective effects of a lead molecule (D-512) …

The Influence Of Gender And Aging On The Neural Circuitry Supporing Facial Emotion Processing In Adults With Major Depressive Disorder, Emily Briceno

Wayne State University Dissertations

Major Depressive Disorder (MDD) is associated with decrements in facial emotion processing (FEP). Previous studies investigating the neural substrates of these decrements have often reported hyperactivity of emotion processing circuitry. Neural circuitry supporting FEP has been shown to be different between healthy men and women, and between young and elder adults. However, no prior studies have investigated how gender and aging affect emotion processing circuitry in individuals with MDD. The present study aimed to investigate the influence of gender and aging on emotion processing circuitry in MDD. One hundred-ten adults, grouped into subgroups according to MDD status, gender, and age …

Neuropsychological Outcome In Relation To Duration Of Early Orphanage Experience, Jacquelyn Marie Perry Avery

Wayne State University Dissertations

In this sample of 144 children with a history of prior orphanage experience, increasing duration of institutionalization is related to decreasing performance for a number of cognitive domains, most consistently verbal measures and executive Functioning measures. The relationships with duration for measures requiring visual-spatial skills were more mixed and a visual reasoning task was found to significantly relate to duration but not a measure of visual memory or a measure of nonverbal achievement. There was little evidence to support a relationship between the duration of institutionalization and fine-motor dexterity. The strongest relationships with duration were observed for language measures followed …

Understanding The Gender-Based Mechanism Of Mso In Als Mice: A Metabolic Characterization Of The Sod1-G93a Mouse Model, Monica Ann Bame

Wayne State University Dissertations

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by motor neuron death and a corresponding loss of neuromuscular connections resulting in muscle atrophy. Patients become paralyzed shortly after symptom onset and typically die within one to five years of pulmonary complications. ALS is a relatively rare disease, with an overall incidence of approximately 2 in 100,000 people per year and a prevalence of about 5 in 100,000 people. It is typically associated with increasing age and has a slight male prevalence, with a male to female ratio of approximately 3:2. ALS is classified as either familial (the less …

Predicting Vision Loss In Healthy Aging With Manganese-Enhanced Mri Of The Rat Eye, David Bissig

Wayne State University Dissertations

In healthy aging, visual function declines throughout adulthood. Age-related changes in neuronal ion homeostasis -- specifically, increased Ca2+ influx through L-type voltage gated calcium channels (L-VGCCs) -- are believed to contribute to certain functional declines, but this possibility has not yet been tested in the neural retina. In young, mid- and old adult Long-Evans rats, we compared visual function (optokinetic tracking), as well as retinal physiology and eye morphology (Mn2+-enhanced MRI (MEMRI), which uses neuronal Mn2+ uptake as a marker of Ca2+ influx). We documented significant age-related decreases in visual performance and increases in retinal ion influx. We confirmed that …

Axogial Communication Mediated By Soluble Neuregulin-1 And Bdnf, Zhenzhong Ma

Wayne State University Dissertations

During peripheral nervous system development, successful communication between axons and glial cells including Schwann cells in peripheral nervous system and oligodendrocytes in central nervous system, is required for the proper functions of both neurons and glia. Three types of alternatively-spliced proteins belonging to the neuregulin1 (NRG1) gene family of growth and differentiation factors are essential for Schwann cell survival and peripheral nerve development. While membrane-bound NRG1 forms (type III) has been strongly implicated in the regulation of myelination process at late stage of Schwann cell development, little is known about the role of soluble, heparin-binding forms of NRG1 (type I/II) …

Mechanisms Of Persistent Translation Arrest Following Global Brain Ischemia And Reperfusion, Jill Theresa Jamison

Wayne State University Dissertations

ABSTRACT

MECHANISMS OF PERSISTENT TRANSLATION ARREST FOLLOWING GLOBAL BRAIN ISCHEMIA and REPERFUSION

by

JILL T. JAMISON

December 2011

Advisor: Donald J. DeGracia, Ph.D.

Major: Physiology

Degree: Doctor of Philosophy

The information presented here studies the mechanisms that underlie persistent translation arrest (TA) following global brain ischemia and reperfusion (I/R). To summarize the main findings I have discovered a new mechanism for prolonged post-ischemic TA that correlated exactly with in vivo translation rates and correlated precisely with cell outcome. Through the extensive colocalization studies, my results indicate that the mRNA granules are ribonomic structures involved with mRNA regulation. This finding is …

Expression Of Microbial Rhodopsins In Retinal Neurons With Subcellular Targeting Motifs: For The Study Of The Structure/Function Of Aii Amacrine Cells And For Vision Restoration, Chaowen Wu

Wayne State University Dissertations

Protein-targeting motifs serve as addresses for subcellular protein localization. This feature of targeting-motifs was used to study the retina. The first part of the dissertation reports in the axonless spiking AII amacrine cell of the mammalian retina a dendritic process sharing organizational and functional similarities with the axon initial segment, the typical site of action potential initiation. This process was revealed through viral-mediated expression of channelrhodopsin-2-GFP (ChR2-GFP) with the AIS-targeting motif of sodium channels (NavII-III) and was shown to be the site of spike initiation. The second part of the dissertation aimed to improve microbial rhodopsin-mediated gene therapy for vision …

Mechanisms Of Translation Arrest Following Focal Brain Ischemia, Monique K. Lewis

Wayne State University Dissertations

MECHANISMS OF TRANSLATION ARREST FOLLOWING FOCAL BRAIN

ISCHEMIA

by

MONIQUE K. LEWIS

August 2011

Advisor: Dr. Donald DeGracia

Major: Physiology

Degree: Doctor of Philosophy

The loss of blood flow to the brain is termed ischemia and the subsequent resumption of blood flow is termed reperfusion. Brain ischemia and reperfusion (I/R) occurs primarily following resuscitation from cardiac arrest and stroke and presents one of the most significant clinical challenges. At present, there are no clinically effective pharmacologic interventions to halt brain damage following I/R. The major Aim of this dissertation will be to investigate possible mechanisms involved in neuron death following …

Processing Random Signals In Neuroscience, Electrical Engineering And Operations Research, Kalyan Raman

Wayne State University Dissertations

The topic of this dissertation is the study of noise in electrical engineering, neuroscience, biomedical engineering, and operations research through mathematical models that describe, explain, predict and control dynamic phenomena. Noise is modeled through Brownian Motion and the research problems are mathematically addressed by different versions of a generalized Langevin equation. Our mathematical models utilize stochastic differential equations (SDEs) and stochastic optimal control, both of which were born in the soil of electrical engineering. Central to this dissertation is a brain-physics based model of cerebrospinal fluid (CSF) dynamics, whose structure is fundamentally determined by an electrical circuit analogy. Our general …

Effects Of Managed Care On The Health And Health-Care Of The Non-Elderly With Diabetes, Meihua Lu

Wayne State University Dissertations

This dissertation attempts to examine the quality effect of managed care plans (as compared with traditional fee-for-service plans, or FFS) on the health outcome and health care use of patients with diabetes. As the number of diabetics is growing rapidly with many of them are relying on managed care plans, knowing better the effects of different plans on health status and health care utilization is of great interest and significance to consumers, employers, and policymakers, especially at a time that universal health care is under being implemented.

Using up-to-date data from MEPS, a nationally representative survey, I compared 484 HMO …

Frazzled And Abelson Interact To Regulate The Actin Cytoskeleton In Drosophila, Bridget Elsa Varughese

Wayne State University Dissertations

Guidance receptors such as Frazzled affect cell shape and motility by directly or indirectly modulating the cytoskeleton. Fra is particularly needed for the formation of the posterior commissures in a developing Drosophila embryo. The cytoplasmic tyrosine kinase, Abelson Kinase (Abl) enhances the loss of commissures observed in fra mutant. Abl physically interacts with Frazzled to help guide commissural axons across the midline. Furthermore, the loss of commissural axons is only seen when the actin dynamics are perturbed. Abl is also known to regulate actin-dependent processes underlying formation of filopodia, microspikes and membrane ruffles. So, we established a Drosophila S2 cell …

Activation Of Tumor Cell Death Program By Targeting The Ubiquitin-Proteasome Pathway: Significance In Cancer Treatment And Prevention, Michael Joseph Frezza

Wayne State University Dissertations

ACTIVATION OF TUMOR CELL DEATH PROGRAM BY TARGETING THE UBIQUITIN-PROTEASOME PATHWAY: SIGNIFICANCE IN CANCER TREATMENT AND PREVENTION

by

MICHAEL FREZZA

August 2010

Advisor: Dr. Q. Ping Dou

Major: Cancer Biology

Degree: Doctor of Philosophy

The ubiquitin-proteasome pathway serves as a quality control mechanism to regulate the degradation of intracellular proteins involved in a wide array of cellular processes including tumorigeneis. Thus targeting key features of protein turnover responsible for the growth and proliferation of cancer have emerged as a favorable approach in cancer therapy. Both in vitro and in vivo experimental and clinical results have demonstrated the potential use of …

Molecular And Therapeutic Implications Of Notch1 Signaling In Pediatric T-Cell Acute Lymphoblastic Leukemia, Amanda Larson Gedman

Wayne State University Dissertations

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of pediatric ALL cases and is associated with early relapse and inferior outcome. The poorer prognosis of T-ALL compared to B-precursor ALL may in part reflect the lack of unique features on which to base therapy. NOTCH1 mutations are of particular interest since these were reported in 37-71% of T-ALLs. The prognostic value of NOTCH1 mutations remains controversial as both favorable and unfavorable associations were reported, whereas in other studies, there were no associations between NOTCH1 mutations and treatment outcome. We explored the impact of mutations in NOTCH1, FBW7 and PTEN on …

Immunomodulatory Effect Of Host And Fungal Eicosanoids During Host-Pathogen Interactions With Candida Albicans, Gitanjali Kundu

Wayne State University Dissertations

Candida albicans, an opportunistic fungal pathogen, poses a significant clinical threat to immunocompromised patients. Diseases associated with this fungus ranges from superficial mucosal infection to life-threatening systemic candidiasis. The mechanisms by which Candida persists at mucosal surfaces in the face of an adaptive response are unclear. Candida produces immunomodulatory oxylipins that cross-react functionally with host eicosanoids, which are considered to play important role in regulating innate and adaptive immune responses. Our objective was to characterize the role of prostaglandins produced by the host and this fungus during host pathogen interactions, both in vitro with dendritic cells (DCs) and macrophages, and …

Raman Spectroscopic Modeling Of T- Lymphocyte Activation And Detection Of Acute Renal Allograft Rejection, Kristian L. Brown

Wayne State University Dissertations

ABSTRACT

RAMAN SPECTROSCOPIC MODELING OF T-LYMPHOCYTE ACTIVATION AND DETECTION OF ACUTE RENAL ALLOGRAFT REJECTION

By

KRISTIAN L. BROWN

2010

Advisor: Gregory Auner, PhD

Major: Biomedical Engineering

Degree: Doctor of Philosophy

Despite the advances made in the area of kidney transplantation, the disparity between the demand and available donated organs remains a dominant and unresolved issue. Given the paucity of available renal allografts the preservation of existing grafts is vital. One factor that has negatively impacted renal allograft survival is acute rejection (AR). Traditionally, kidney transplant centers have used elevations in serum creatinine as a screening tool for detecting AR. However, …

Beyond The Dvh - Spatial And Biological Radiotherapy Treatment Planning, Bo Zhao

Wayne State University Dissertations

Purpose: Both spatial and biological information are necessary in order to perform true optimization of a treatment plan and for predicting clinical outcome. The goal of this work is to develop an enhanced treatment plan evaluation tool which incorporates biological parameters and retains spatial dose information.

Methods: A software system named SABER (Spatial And Biological Evaluation for Radiotherapy) is developed which provides biological plan evaluation with a novel combination of features. It incorporates hyperradiosensitivity using the induced-repair model and applies the new concept of Dose Convolution Filter (DCF) to simulate dose wash-out …