Neurosciences Commons^™

Environmental Pollution And Early-Life Metabolic Programming, Lisa Koshko

Wayne State University Dissertations

Substantial evidence demonstrates that parental pollutant exposures can induce harmful health effects in the offspring, including the predisposition to Type II Diabetes. As rates of Type II Diabetes continue to rise in younger populations, a crucial gap lies in understanding the role of parental influence in the etiology of later-life metabolic disease. Therefore, the central goal of this work was to determine how early life exposure to smoking level benzene, an endocrine-disrupting air pollutant, affects the metabolic health of offspring, and to identify potential developmental mechanisms involved in disease susceptibility. This goal was achieved using two models of early life …

Plasma Neurofilament Light As A Biomarker Of Neurodegeneration And Memory Function In Older Adults, Youjin Jung

Wayne State University Dissertations

Plasma neurofilament light (NfL) is a promising biomarker for monitoring and predicting cognitive function and neurodegeneration in Alzheimer’s disease (AD). However, the field still needs a better understanding of what plasma NfL reflects about neurodegenerative and cognitive changes occurring in AD, especially in the early stages of Alzheimer’s disease, for the optimized use of plasma NfL as a biomarker for AD for clinical and research purposes. Therefore, here I investigated how NfL is associated with memory function, the functional connectivity of the default mode network, and the microstructural properties of white matter and gray matter regions vulnerable to Alzheimer’s pathologies …

Hippocampal Subfield Volumes And Memory Development From Middle Childhood To Late Adulthood: 2-Year Longitudinal Change And Modifiers Of Age Effects, Roya Homayouni

Wayne State University Dissertations

Introduction: The hippocampus (Hc) is crucial for memory function across all ages and is comprised of distinct subfields: dentate gyrus (DG), cornu ammonis sectors (CA1-3), and subiculum. Hc subfields support different aspects of memory function across the lifespan and are differentially vulnerable to late-life pathology. Increased knowledge of normative lifespan developmental trajectories of Hc subfield volumes will illuminate their cognitive and health correlates across different ages. Yet, the evidence on change and variability of Hc subfield volumes across the lifespan is sparse. Methods: Here, I conducted a meta-analysis of cross-sectional findings of subfield volumes across ages (n = 48,278 participants, …

The Importance Of Protein Context In Spinocerebellar Ataxia Type 3, Sean Luis Johnson

Wayne State University Dissertations

Spinocerebellar Ataxia Type 3 (SCA3) is a member of the family of polyglutamine (polyQ) neurodegenerative disorders that includes Huntington's Disease and several other SCAs. SCA3, the most common dominant ataxia in the world, is caused by polyQ tract expansion in the protein, ataxin-3. How SCA3 occurs and how to treat it remain unresolved issues. The primary culprit of toxicity in all polyQ diseases is the glutamine repeat: its abnormal expansion leads to neuronal dysfunction and death. With that said, there is indisputable evidence that the way polyQ-dependent toxicity presents—areas impacted, cellular processes perturbed—is predicated in large part on regions outside …

Backward Walking: A Novel Marker Of Fall Risk, Cognitive Dysfunction, And Myelin Damage In Persons With Multiple Sclerosis, Erin Edwards

Wayne State University Dissertations

Multiple sclerosis (MS) is a progressive, neurologic disease of the central nervous system that causes debilitating motor, sensory and cognitive impairments. As a result, persons with MS are at an increased risk for falls and falls represent a serious public health concern for the MS population. The current clinical measures used to assess fall risk in MS patients lack sensitivity and predictive validity for falls and are limited in their ability to capture to multiple functional domains (i.e., motor, sensory, cognitive and pathological domains) that are impaired by MS. Backward walking sensitively detects falls in the elderly and other neurologic …

Dancing The Storm: Neurobiological Correlates Of Trauma-Related Psychopathology In Youth Resettled As Refugees, And The Efficacy Of Creative Arts And Movement Therapies To Address Trauma-Related Psychopathology, Lana Ruvolo Grasser

Wayne State University Dissertations

Exposure to stress and trauma activates key adaptive pathways, including the sympathetic adrenomedullary system and the immune system, which can result in long-term health impacts of trauma especially when experienced during sensitive developmental periods. Alterations in these systems are measurable through non-invasive methods including skin conductance response (SCR), fear potentiated startle (FPS), and inflammation. Research regarding the impact of trauma, and more specifically posttraumatic stress disorder, has primarily focused on adults, and there is a paucity of neurobiological research in displaced populations—like refugees—who may experience higher rates of trauma exposure and related psychopathology. The present study measured SCR to a …

Modulation Of Pharyngeal Health In Bacterial Diet-Dependent Survival, Deniz Sifoglu

Wayne State University Dissertations

ABSTRACT

MODULATION OF PHARYNGEAL HEALTH IN BACTERIAL DIET-DEPENDENT SURVIVAL

by

DENIZ SIFOGLU

August 2021

Advisor: Dr. Joy Alcedo Major: Biological Sciences Degree: Doctor of Philosophy Both diet and bacterial microbiome modulate insulin signaling, which regulates key physiological processes that are important for survival. However, the mechanisms through which diet and the microbiome modulate insulin signaling remain unclear. To understand these mechanisms, I turned to the nematode worm C. elegans, whose diet consists of different types of bacteria. Like humans and other animals, C. elegans has to modulate its responses to its diet and to bacteria to optimize its survival. Because …

Hypochlorite-Mediated Oxidation Of Dopamine: Implications In Parkinson’S Disease And Manganism, Praneet Kaur Marwah

Wayne State University Dissertations

Both Parkinson’s disease and manganism (a condition caused by chronic exposure to excessive levels of manganese) affect the extrapyramidal system of the brain, disrupt dopaminergic signaling and cause similar motor symptoms. While there is no physiological explanation for the susceptibility of dopamine-rich regions of the brain in both disorders, dopamine itself is a likely candidate. Dopamine can undergo both enzymatic and spontaneous oxidation, and the principal product of dopamine oxidation in vivo is cysteinyl dopamine. We demonstrate here that hypochlorous acid, which is produced in the brain by the enzyme myeloperoxidase, converts cysteinyl dopamine into a neurotoxic dihydrobenzothiazine, DHBT-1, that …

Investigating Gray And White Matter Microstructure In Parkinson Disease Patients Using Diffusion Weighted Imaging, Wafaa Sweidan

Wayne State University Dissertations

Parkinson disease (PD) is a neurodegenerative disorder characterized histologically by the loss of dopaminergic neurons in the substantia nigra (SN), and clinically by motor symptoms. PD pathology extends beyond the SN, and involves the presence of intraneuronal inclusions in neuronal bodies (Lewy bodies) and dendrites (Lewy dendrites). A staging system for Lewy pathology has been proposed, where it is hypothesized that the disease initiates in the peripheral nerves system and spreads along a caudal-rostral pathway to the brain stem and the cerebral cortex. Histological and imaging studies highlight a role for cortical Lewy pathology and atrophy, respectively, in mediating the …

Age Differences In Hippocampal Glutamate Modulation During Associative Learning And Memory: A Proton Functional Magnetic Resonance Spectroscopy (1h Fmrs) Study, Chaitali Anand

Wayne State University Dissertations

Episodic and associative memory decline is one of the earliest cognitive impairments in normal aging and among the defining cognitive features of Alzheimer’s disease (AD). Since, age-related cognitive decline gradually devolves into AD, with neuropathology preceding cognitive changes by many years, the identification of biomarkers of early disease progression is crucial. Reduction in glutamate, the main excitatory neurotransmitter involved in associative memory, in key brain regions such as the hippocampus, has been theorized as one of the cellular mechanisms underlying cognitive decline in aging and AD. A few neuroimaging studies that demonstrated a link between older adults’ weaker cognitive performance …

Characterizing The Development Of Episodic Memory And Assessing The Reliability Of Fmri Measures, Lingfei Tang

Wayne State University Dissertations

The ability to remember past events is critical for everyday life and showed robust improvement over development from childhood to adulthood. With advances in noninvasive neuroimaging methods such as functional MRI in recent years, research efforts have been focused on identifying neural correlates underpinning developmental gains in memory performance. In my dissertation work, using a widely-validated subsequent memory paradigm, I aim to characterize functional MRI correlates of memory development. Specifically, I focused my investigation on identifying age differences in the functional patterns of two brain regions critical for memory, the prefrontal cortex and the hippocampus. Focusing on the prefrontal cortex …

Development Of More Light Sensitive And Red-Shifted Channelrhodopsin Variants For Optogenetic Vision Restoration, Tushar Harishkumar Ganjawala

Wayne State University Dissertations

Discovery of channelrhodopsin (ChR), a light sensitive protein from green algae, has revolutionized the field of neuroscience research by empowering scientist to control neuron through the light, the technology popularly known as optogenetics. The ChR based optogenetics is one of the promising approaches for treating blindness caused by photoreceptor degenerative diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Fundamentally, the approach is about imparting light sensitivity to surviving inner retinal cells by ectopic expression of genetically encoded light sensitive proteins, such as ChR2. Although the concept of optogenetic approach has been proved by using ChR2, a major …

Stress-Dependent Regulation Of A Major Node Of The Insulin-Like Peptide Network That Modulates Survival, Rashmi Chandra

Wayne State University Dissertations

Chronic stress disrupts insulin signaling, predisposing human populations to diabetes, cardiovascular disease, Alzheimer’s Disease, and other metabolic and neurological disorders, including post-traumatic disorders (PTSD). Thus, efficient recovery from stress optimizes survival. However, stress recovery in humans is difficult to study, but is much easier to dissect in model organisms. The worm genetic model Caenorhabditis elegans can switch between stressed and non-stressed states, and this switch is largely regulated by insulin signaling. Previously, the Alcedo lab proposed that insulin-like peptides (ILPs), which exist as multiple members of a protein family in both C. elegans and humans, implements a combinatorial coding strategy …

The Impact Of Neonatal Pain And Reduced Maternal Care On Brain And Behavioral Development, Sean Michael Mooney-Leber

Wayne State University Dissertations

In the neonatal intensive care unit (NICU) preterm infants are exposed to a multitude of stressors, which include both neonatal pain and reduced maternal care. Clinical and preclinical research has demonstrated that exposure to neonatal pain and reduced maternal care has a profound negative impact on brain and behavioral development. Currently, the biological mechanism by which both of these stressors impacts brain and behavioral outcomes remains widely unknown. To uncover a potential biological mechanism, the current dissertation project utilized a preclinical model of repetitive needle pokes and developed a novel model of reduced maternal care through tea-ball encapsulation. Briefly, rat …

The Influence Of Protein Context On Polyglutamine Toxicity In Spinocerebellar Ataxia Type 3, Joanna Rae Sutton

Wayne State University Dissertations

The polyglutamine (polyQ) disease family is composed of nine neurodegenerative diseases caused by CAG trinucleotide repeat expansions in the associated genes. Although these diseases are caused by similar mutations, the polyQ proteins are otherwise structurally and functionally unique. Thus, the protein domains surrounding the polyQ tracts, as well as their interacting partners, are thought to be critical to the pathogenesis of these clinically distinct diseases. Spinocerebellar ataxia type 3 is caused by polyQ expansion of ataxin-3, a deubiquitinating enzyme implicated in protein quality control, transcriptional regulation, and DNA repair. Rad23 and VCP are two of ataxin-3’s protein quality control partners …

Non-Invasive Mitochondrial Modulation With Near-Infrared Light Reduces Brain Injury After Stroke, Christos Dionisos Strubakos

Wayne State University Dissertations

Acute ischemic stroke is a debilitating disease that causes significant brain injury.

While rapid restoration of blood flow is critical to salvage the ischemic brain, reperfusion

of tissue can further drive brain damage by inducing generation of mitochondrial reactive

oxygen species (Chouchani et al., 2014a). Recent studies by our group found that noninvasive

mitochondrial modulation (NIMM) with near-infrared (NIR) light can limit the

production of reactive oxygen species following global brain ischemia (T. H. Sanderson

et al., 2018). NIR interacts with the rate limiting step of the mitochondrial electron

transport chain (ETC), cytochrome c oxidase (COX), and modulates mitochondrial

respiration. …

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 …

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 …

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 …

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. …