Neurosciences Commons^™

The Role Of Neurokinin Receptors And Satellite Glial Cells In Herpes Simplex Virus 1 Latency, Andrew Jerome

Wayne State University Dissertations

The ability of herpes simplex virus 1 (HSV-1) to establish a lifelong infection in neurons of the trigeminal ganglion (TG) make it a constant public health threat. Viral reactivation from its latent state is currently the leading cause of viral induced blindness in the United State, as well as the leading cause of herpes simplex encephalitis. Unfortunately, how the virus is able to both establish and maintain its latent state in the TG is not well understood. The purpose of this work was to better understand how neuropeptide signaling through neurokinin receptors, as well as how satellite glial cells (SGCs) …

Change In Processing Speed And Its Associations With Cerebral White Matter Microstructure, Muzamil Arshad

Wayne State University Dissertations

The decline of cognition with age is one of the most feared aspects of aging, while the slowing of responses, or reduced processing speed, is one of the most reliable aspects of aging. Slowing of processing has been hypothesized to affect other domains of cognition as well. Despite the well-known slowing-age relationship and central position processing speed plays in theories of cognitive aging the neurobiological mechanisms which underpin slowing is unclear. If we could identify the biology associated with processing speed we could then attempt to develop interventions to mitigate the effects of age on those variables. In turn we …

Neuropharmacological Investigation Of Stress And Nicotine Self-Administration Among Current Cigarette Smokers, Eric Woodcock

Wayne State University Dissertations

ABSTRACT

NEUROPHARMACOLOGICAL INVESTIGATION OF STRESS AND NICOTINE SELF-ADMINISTRATION AMONG CURRENT CIGARETTE SMOKERS

by

ERIC ANDREW WOODCOCK

August 2017

Advisor: Dr. Mark K. Greenwald

Major: Neuroscience (Translational)

Degree: Doctor of Philosophy

Nicotine use, especially cigarette smoking, is a significant public health problem. Existing pharmacotherapies attenuate nicotine craving and withdrawal symptoms. However, the majority of patients relapse within the first year of treatment. Treatment studies indicate a commonly cited precipitant to smoking relapse is stress. Pharmacotherapies do not attenuate, and may exacerbate, the effects of acute stress. Experimental studies (preclinical and clinical) indicate that acute stress potentiates drug-seeking behavior across drugs of …

Brain Connectivity After Concussion, Armin Iraji

Wayne State University Dissertations

Mild traumatic brain injury (mTBI) accounts for over one million emergency visits in the United States each year. While most mTBI patients have normal findings in clinical neuroimaging, alterations in brain structure and functional connectivity have frequently been reported. In this study, we investigated the large-scale brain structural and functional connectivity using diffusion MRI and resting-state fMRI data. Data from 40 mTBI patients was acquired at the acute stage (within 24 hrs after injury). 35 patients returned for data acquisition at a follow-up (4-6 weeks after injury). Data was also collected from a cohort of 58 healthy subjects, 36 of …

Synaptotagmin C2b Ca2+-Binding Loops Impose Distinct Exocytosis Phenotypes, Michael W. Schmidtke

Wayne State University Theses

Regulated exocytosis from chromaffin cells in the adrenal medulla plays a critical role in maintaining organismal homeostasis. In the absence of stress, these cells release physiologically relevant substances into the blood stream only in limited quantities, whereas stressful conditions result in a rapid deluge of signaling molecules used, for example, to increase heart rate and pain tolerance. Although the cellular mechanisms governing the switch from low-level to stress-induced secretion are not well understood, recent evidence has implicated the exocytotic Ca2+-sensing protein Synaptotagmin (Syt) in this role.

Two isoforms of Syt are expressed in chromaffin cells (Syt-1 and Syt-7), and each …

Understanding The Mechanism Of Oxidative Stress Generation By Oxidized Dopamine Metabolites: Implications In Parkinson's Disease, Nihar Mehta

Wayne State University Dissertations

Oxidation of dopamine to toxic metabolites is considered to be one of the prime factors involved in the death of dopaminergic neurons in Parkinson’s disease. Some dopamine oxidation products have the capability to redox cycle in the presence of molecular oxygen, further contributing to oxidative stress. Therefore, our aim here was to study the redox cycling of dopamine oxidized metabolites and elucidate the underlying mechanism by which they cause oxidative stress.

Redox reactions involve transfer of one or more electrons between two compounds

resulting in either oxidation or reduction. In redox cycling, a compound undergoes

alternate oxidation and reduction, transferring …

Analysis Of The Secondary Neurodegenerative Consequences Of Primary Oligodendrocyte Stress Through The Use Of The Novel Obiden Mouse Model, Daniel Zdzislaw Radecki

Wayne State University Dissertations

The work of this project was to develop, test and characterize a potential novel mouse model of the neurodegenerative disease Multiple Sclerosis (MS). Historically, MS has been identified as a primary autoimmune disease of the central nervous system (CNS). However, treatments based on this view have met with limited success, and in most cases, fail to prevent progression of MS from mild to moderate and severe forms. Original observations regarding axonal and neuronal pathology in the white and gray matter of the CNS were rediscovered in the 1990s. These observations indicated that even in the absence of the immune system, …

Estimating The Variables Of The Nonlinear Dynamical Theory Of Acute Cell Injury, Fika Tri Anggraini

Wayne State University Dissertations

This Dissertation is the first to estimate the variables D and S of the nonlinear theory of acute cell injury in hippocampal regions CA1 and CA3 using a rat model of global brain ischemia and reperfusion (I/R). D was estimated by quantifying protein aggregates using ubiquitin Western blotting. S was estimated by quantifying changes in polysomal mRNAs as measured by microarray chips. D and S time courses were sampled at 0.5, 8, 16, 24, 48, and 72 hrs of reperfusion after 10 min brain ischemia. CA1 dies and CA3 survives. The theory predicts D will be larger in CA1 and …

Carotid Ultrasound Is Not Helpful In Simple Syncope, Nicholus Yee M.D., Shilin Patel M.D., Raymond Gong

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Scott JW, Schwartz AL, Gates JD, Gerhard-Herman M, Havens JM. Choosing wisely for syncope: low-value carotid ultrasound use. J Am Heart Assoc. 2014 Aug 13;3(4). pii: e001063. doi: 10.1161/JAHA.114.001063

The Semantic Memory Imaging In Late Life Pilot Study, Michael Adam Sugarman

Wayne State University Dissertations

Introduction: Several functional magnetic resonance imaging (fMRI) studies have analyzed the famous name discrimination task (FNDT), an uncontrolled semantic memory probe requiring discrimination between famous and unfamiliar individuals. Completion of this simple task recruits a semantic memory network that has shown utility in determining risk for Alzheimer's disease (AD). Specific semantic memory probes using biographical information associated with famous individuals may build on previous findings and yield superior information regarding risk for AD.

Method: Sixteen cognitively intact elders completed the FNDT and two novel tasks during fMRI: Categories (matching famous individuals to occupational categories) and Attributes (matching famous individuals to …

Cognitive, Psychiatric, And Neuropathological Manifestations Of Repetitive Mild Traumatic Brain Injury, Denise Briggs

Wayne State University Dissertations

Millions of athletes participate in contact sports that involve repeated head impacts (e.g., football, ice hockey, boxing), often from a very young age, and it is feared that subsequent impacts can synergize with previous ones so that their effects on the brain become magnified. Repetitive mild traumatic brain injury (rmTBI) has been linked to the development of chronic traumatic encephalopathy (CTE). The neurodegeneration accompanying CTE occurs over many years following repeated head impacts and is characterized by progressive brain atrophy, accumulation of hyper-phosphorylated tau and aggregates of TDP-43, myelinated axonopathy, neuroinflammation and degeneration of white matter tracts. The relationship between …

An Analysis Of Virtual Place Learning/Navigation In Children And Young Adults Prenatally Exposed To Alcohol, Neil Christopher Dodge

Wayne State University Dissertations

Fetal alcohol spectrum disorder refers to the spectrum of disorders resulting from prenatal alcohol exposure and is the leading cause of preventable mental retardation. Rodent studies have found that prenatal alcohol exposure impairs performance on the Morris water maze. This task requires the rodent to use distal room cues to locate a hidden platform in a pool of opaque water. Successful performance on this task is dependent upon hippocampal function. Rodents prenatally exposed to alcohol are impaired on the Morris water maze and show damage to hippocampal neurons. A human analogue of the Morris water maze, the virtual water maze …

Childhood Trauma And Emotion Processing Neurocircuitry, Hilary A. Marusak

Wayne State University Dissertations

Childhood trauma is one of the strongest risk factors for a range of common and debilitating neuropsychiatric disorders, including anxiety, depression, and posttraumatic stress disorder (PTSD). These emotion-related disorders have their roots in childhood and adolescence, underscoring a critical need to understand their biological bases in early life. In this dissertation, we evaluate how childhood trauma impacts emotion processing neurocircuitry in a sample of high-risk urban youth, ages 7-15. In four inter-related studies, we test neural function and functional connectivity of core emotion processing regions, including the amygdala, insula, and pregenual/subgenual anterior cingulate cortex (pgACC/sgACC). To examine the relevance of …

Identification Of Metabolite Biomarkers In Epilepsy Using 1h Mrs, Helen Wu

Wayne State University Dissertations

Epilepsy is a serious neurological disorder that affects 1% percent of the global population. Despite its status as one of the oldest neurological disorders known to man, its mechanisms remain poorly understood. Available medications are not curative but provide symptomatic management and do not work for well for more than 30 percent of patients. Because it is nearly impossible to predict on an individual level who will eventually develop epilepsy, it is also a disorder that can only be diagnosed after the patient has experienced established seizure activity, eliminating any possibility of stopping the disorder in its prodromal phase, before …

Analgesia Followed By Long-Term Hyperalgesia Generated By Disinhibition Of The Basolateral Amygdala, Derek Atchley

Wayne State University Theses

Stress produces bimodal effects on pain peception. During exposure to a stressor pain responses are inibited (i.e. stress-induced analgesia). However, following long-term exposure to a stressor increases in responsiveness to painful stimuli may develop (i.e. stress-induced hyperalgesia). Here I evaluated how a key component of the subcortical defense circuit and target of stress hormones contributes to the development of both stress-induced analgesia and hyperalgesia. Bicuculline methiodide, a GABAA antagonist, injected into the basolateral amygdala was used to mimic the neural effects of a stressor or threat exposure. Immediately following injection pain responsiveness was decreased as measured by vocalizations after discharge …

Neural Circuitry Deficits Associated With Dysfunctional Myelin, Kathleen June Maheras

Wayne State University Dissertations

In the current study, we have generated mutant mice that lack Claudin 11 (Cldn11) tight junctions in CNS myelin sheaths. In myelin sheaths, Cldn11 forms tight junctions located along the outer and inner edges of the membrane spiral, preventing ions and small molecules from entering the intramyelinic space. The function of Cldn11 tight junctions is to improve the passive properties of the myelin membrane, by increasing membrane resistance and reducing capacitance, thereby improving the speed of saltatory conduction. In the absence of Cldn11, conduction velocity is slowed, most dramatically in small diameter myelinated fibers, somewhat analogous to reducing myelin thickness. …

Role Of Secretory Granule Heterogeneity In Calcium-Triggered Exocytosis, Tejeshwar Rao

Wayne State University Dissertations

The sympathetic nervous system is activated by a variety of threats to organismal homeostasis. The adrenomedullary chromaffin cell is the core effector of sympathetic activity in the peripheral nervous system. By design, the chromaffin cell secretory response is mutable so that release can be rapidly tuned to drive context-dependent changes in physiological function. However, the mechanisms by which this tuning is achieved with such high temporal fidelity and context specificity remain unclear. This represents a major gap in our understanding of the sympatho-adrenal system since it is known to modify the function of nearly every organ system in the body. …

An Analysis Of Plasticity In The Rat Respiratory System Following Cervical Spinal Cord Injury And The Application Of Nanotechnology To Induce Or Enhance Recovery Of Diaphragm Function, Janelle Lorien Walker

Wayne State University Dissertations

Second cervical segment spinal cord hemisection (C2Hx) results in ipsilateral hemidiaphragm paralysis. However, the intact latent crossed phrenic pathway can restore function spontaneously over time or immediately following drug administration.

WGA bound fluorochromes were administered to identify nuclei associated with diaphragm function in both the acute and chronic C2Hx models. WGA is unique in that it undergoes receptor mediated endocytosis and is transsynaptically transported across select physiologically active synapses. Comparison of labeling in the acutely injured to the chronically injured rat provided an anatomical map of spinal and supraspinal injury induced synaptic plasticity. The plasticity occurs over time in the …

Evidence Of Distinctive Structural Alterations That Differentiate Adhd Boys With And Without A Comorbid Reading Disability, Dhruman Dilip Goradia

Wayne State University Dissertations

Attention deficit hyperactivity disorder (ADHD) and reading disability (RD) are neurodevelopmental disorders that often co-occur. Children with ADHD and co-occurring RD (ADHD/+RD) tend to show greater cognitive deficits than children with ADHD alone (ADHD/-RD). However, the extents to which comorbid RD impact structural alteration in children with ADHD have never been investigated. The overall goal of this study was to assess structural alterations in the subcortical, cortical and white matter that may differentiate ADHD/-RD from ADHD/+RD. The general hypothesis was that ADHD/+RD would show extensive alterations in regions implicated in ADHD than ADHD/-RD as well as show additional abnormalities in …

Neural Alterations Influencing Skilled Reading In Adhd: A Task-Based Fmri Study, Brianne Mohl

Wayne State University Dissertations

Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous, neurodevelopmental disorder which co-occurs often with Reading Disability (RD). ADHD with and without RD consistently have higher inattentive ratings compared with typically developing controls, with co-occurring ADHD and RD (ADHD/+RD) also demonstrating impaired phonological processing. Accordingly, inattention has been associated with greater phonological impairment, though neither the neural correlates of the co-occurring disorders nor the association are well understood from a functional neuroimaging perspective. The goal was to assess to what extent ADHD/+RD differ from ADHD without RD (ADHD/-RD) and typically developing controls (TDC) in functional activation of attention- and reading-related areas during various …

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 …

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 …

Neural Correlates Of Episodic Memory Formation In Children And Adults, Lingfei Tang

Wayne State University Theses

The medial temporal lobe (MTL) and prefrontal cortex (PFC) are two key brain regions that support episodic memory formation in both children and adults, but the functional developmental of these regions remains unclear. In this study, we investigated the development of neural correlates of episodic memory formation using functional MRI with a subsequent memory paradigm, administered to a cross-sectional sample of 83 children and adults. We found that MTL subregions showed an age-related increase in activation supporting memory formation of complex scenes. In addition, a functionally defined scene-sensitive region in the posterior MTL also showed similar increase and predicted better …

Unstable Ventilatory Control During Sleep After High Spinal Cord Injury: The Contribution Of Chemosensitivity And Hypoventilation, Amy Therese Bascom

Wayne State University Dissertations

ABSTRACT

UNSTABLE VENTILATORY CONTROL DURING SLEEP AFTER HIGH SPINAL CORD INJURY: THE CONTRIBUTION OF CHEMOSENSITIVITY AND HYPOVENTILATION

by

Amy T. Bascom

May 2015

Advisor: Dr. Harry G. Goshgarian

Major: Anatomy and Cell Biology

Degree: Doctor of Philosophy

A high prevalence of sleep-disordered breathing (SDB) after spinal cord injury (SCI) has been reported in the literature; however, the underlying mechanisms are not well understood. My studies had 2 aims: 1) to determine the effect of the withdrawal of the wakefulness drive to breathe on the degree of hypoventilation in SCI patients and able-bodied controls and 2) to determine the response of …

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, …

Reduction In Post-Botulinum Toxin Flu-Like Symptoms After Injection With Incobotulinum Toxin, Edwin George, Natalya Shneyder

Neurology Faculty Publications

OBJECTIVE: To determine if patients reporting flu-like symptoms (FLS) after botulinum toxin (BoNT) injections are less susceptible to this reaction after incobotulinum toxin.

BACKGROUND: Approximately 10% of patients injected with BoNT in our clinic complain of FLS, primarily malaise, myalgias and rhinorrhea, beginning a few days to one week after injection and lasting one week or less. A review by Baizabal-Carvallo et al. (Toxicon, 2011, 58:1-7) found rates of FLS between 1.7 and 20% in patients after various preparations of botulinum toxin A, and a subsequent study showed increased cytokines in patients with FLS (Neurotoxicity Research, …

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 …

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 …