Neuroscience and Neurobiology Commons^™

Apolipoprotein E4, Tauopathy, And Brain Injury: Molecular Insights Into Alzheimer's Disease Pathology, Nashanthea J. Roland

Theses & Dissertations

Alzheimer’s disease (AD) is the world’s leading cause of dementia, characterized by progressive atrophy of the hippocampal and cortical brain regions, synapse damage and loss, and a buildup of senile plaques and neurofibrillary tangles composed of β-amyloid peptides and hyperphosphorylated tau, respectively. While age is the most significant risk factor for developing AD, apolipoprotein E4 (APOE4) is the strongest genetic risk factor for AD. Although it is known that APOE4 influences tau pathology, the molecular mechanisms by which APOE4 drives AD pathogenesis and progression remain unclear. In addition to intrinsic contributions to AD, there are many extrinsic factors that can …

Neurodegenerative Disease Mechanisms: Mitochondrial Impairment, Tau Aggregation, And Neuroinflammation As Central Drivers Of Disease Progression, Luis D. Estrella

Theses & Dissertations

The study of the intricate molecular mechanisms behind the pathology of neurodegenerative diseases has become a primary research area in the past decades. The major branches of these studies involve both disease progression and disease pathogenesis, in which neuroscientists have studied, and continue to study, the role that mitochondrial dysfunction, aberrant protein aggregation (like Tau), and immune cell reactions have on these. However, more recent studies have shined light to the fact that these three pathological features are not independent from one another and that their synchronous contributions may be the ultimate driver of neurodegeneration. This dissertation encompasses four different …

Long-Term Neurodevelopmental Outcomes Post-Chronic Midazolam Exposure During Early Life, Nghi M. Nguyen

Theses & Dissertations

In recent decades, the rising number of neonates born in the Neonatal Intensive Care Unit (NICU) due to prematurity has raised concerns about their overall well-being and development. Premature neonates are at higher risk of health complications and often require invasive procedures. These invasive procedures often induce stress and agitation, prompting physicians and healthcare providers to provide sedation or general anesthesia to manage discomfort. Epidemiological studies of human patients have revealed a correlation between childhood exposure to general anesthetic and sedative agents and subsequent cognitive deficits. This association is also supported in animal models, which shows that exposure to anesthetics …

Compensatory Changes In The Visual System As A Result Of Neurodegeneration, Liz Bierlein

Theses & Dissertations

The brain has the remarkable ability to compensate for damage and maintain physiological set points. In the visual system where even after significant damage has been done, the brain fills in visual gaps because of this compensation. This thesis attempts to understand several components of visual changes after damage in disorders such as glaucoma. This was accomplished by using several models of vision loss in mice including the DBA/2J (D2) and silicone oil (SO) models of glaucoma, the RD10 model of retinitis pigmentosa, and a retina-specific knockout of brain-derived neurotrophic factor (BDNF)— the Chx10-cre; BDNF^fl/fl mouse. Through these models …

Individual Differences In Age And Testosterone Are Uniquely Associated With Neural Oscillatory Activity Serving Verbal Working Memory In Children And Adolescents, Abraham D. Killanin

Theses & Dissertations

During the sensitive period of adolescence, the human brain undergoes dynamic changes in structure and function resulting in vast executive function gains. Verbal working memory (VWM) is one executive function that serves as a foundation to language acquisition, reading, and learning. Many have examined the development of VWM in youth, but few have probed age-related changes in the underlying neural oscillatory dynamics, and none have examined testosterone-related changes. We recorded magnetoencephalography during a modified Sternberg VWM task in 82 youth participants aged 6 – 14 years old and collected salivary testosterone samples. Significant oscillatory responses were identified and imaged using …

The Effect Of Repetitive Transcranial Magnetic Stimulation On Brain And Cognitive Variables In Patients With Amnestic Mild Cognitive Impairment, Connor J. Phipps

Theses & Dissertations

Healthy and pathological aging processes can impact human memory. Current interventions for clinical memory impairment offer little opportunity for restoration of memory ability. Fortunately, a novel therapy in the form of repetitive transcranial magnetic stimulation (rTMS) has exhibited promise in this regard. In healthy adults, rTMS of the angular gyrus (AG) has been reported to improve memory. The current study sought to determine the generalizability of these findings to individuals with clinical memory impairment by administering a clinical trial replicating an rTMS protocol reported to improve hippocampal-dependent memory in healthy individuals to individuals with amnestic mild cognitive impairment (aMCI). Individuals …

Cardiac Vagal Dysfunction And Ventricular Arrhythmogenesis In Type 2 Diabetes Mellitus After Myocardial Infarction, Dongze Zhang

Theses & Dissertations

Diabetes is the eighth leading cause of death in the United States. Every eight seconds a person dies from diabetes around the world. Among various types of diabetes, type 2 diabetes mellitus (T2DM) is the most common form, representing 90% to 95% of all diabetes populations. The leading cause of mortality and morbidity in T2DM patients is cardiovascular disease, among which acute myocardial infarction (MI)-induced ventricular arrhythmia is the major cause of death in T2DM. Patients with T2DM are two to four times more likely to die from MI than non-diabetic patients. Although well-known therapies including better glycemic control have …

The Role Of Pre- And Perinatal Oxycodone Exposure On Postnatal Brain Development And Behavior: Assessing The Impact On Later Life Brain Injuries In Juvenile Rats, Austin M. Gowen

Theses & Dissertations

There has been a long history of research investigating the role of the gestational environment on later life health and disease. The progressive widespread illicit and prescribed use of opioids in the 21^st century has seen opioids become one of the most significant gestational insults in the last century. The ability of opioids to pass both the placental barrier and blood-brain barrier makes them a particularly dangerous teratogen capable of altering the peripheral physiology, neurobiology, and behavior of affected children. The works herein investigate the impact of a widely prescribed opioid, oxycodone, on developmental neurobiology in the context of …

Improving Peripheral Nerve Regeneration Through Rehabilitation And Biomaterial-Based Drug Delivery Strategies, Yunfan Kong

Theses & Dissertations

Peripheral nerve injury (PNI) is a common problem worldwide, with trauma being a common cause. PNI can lead to loss of sensory and motor functions, chronic neuropathic pain, and mental health issues, significantly impacting patients' family life, work, and social situation. Recent studies revealed that beyond the topical injury site at peripheral nerves, PNIs can also induce dysfunctions in the central nervous system (CNS) by causing maladaptive plasticity, which will result in exaggeration and exacerbation of the pathological condition caused by primary injuries. The common therapy strategies for PNI treatment are using sutures, nerve autografts or conduits in cases requiring …

Synaptic Transmission At The Photoreceptor Ribbon Synapse, Chris Mesnard

Theses & Dissertations

Synaptic transmission relies on the Ca²⁺-dependent release of neurotransmitters packaged into synaptic vesicles. Ribbon synapses have the capability to release multiple vesicles at a time in a highly coordinated and synchronized manner. Glutamate release from rod and cone photoreceptor cells involves presynaptic ribbons composed largely of the protein RIBEYE. To examine roles of ribbons in rods and cones, we studied mice in which GCamP3 replaced the B-domain of RIBEYE. We discovered that ribbons were absent from rods and cones of both knock-in mice possessing GCamP3 and conditional RIBEYE knockout mice. Mice lacking ribbons showed reduced temporal resolution and …

Phenotypic And Target-Based Drug Discovery, Angelica Veronica Carmona

Theses & Dissertations

Batten Disease or Neuronal Ceroid Lipofuscinosis (NCL) is a group of rare, fatal, inherited pediatric neurodegenerative lysosomal storage disorders. NCLs are characterized by intracellular accumulation of an auto-fluorescent lipopigment called ceroid lipofuscin and neurodegeneration. Several forms of NCLs exist, some of which share some of the same features and symptoms but vary in severity and onset of symptoms with respect to age. Some common symptoms include progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Subtypes of NCLs occur when one of 13 different genes are mutated, and only two subtypes …

The Role Of Parkin In Mitochondrial Dna, Eliezer Lichter

Theses & Dissertations

Mitochondria are at the center of biological phenomena such as aging and diseases, especially neurodegenerative diseases. While the discovery of mitochondria only came approximately 200 years after the cell was discovered, a lot of progress has been made since. The mitochondrial genome encodes proteins vital for mitochondrial function. These proteins are only a subset of the proteins present in mitochondria; the rest are nuclear encoded. The nucleus also encodes cytosolic proteins vital for mitochondrial maintenance. One of these is Parkin, an E3 ubiquitin ligase that ubiquitinates mitochondrial proteins as mitochondria become depolarized. Its activity has been shown to be involved …

Metoprolol Disrupts Sterol Biosynthesis Through Inhibition Of 7-Dehydrocholesterol Reductase (Dhcr7), Luke B. Allen

Theses & Dissertations

Cholesterol is essential for life. It is particularly important in the brain as it relies on de novo synthesis of cholesterol following the formation of the blood brain barrier (BBB). As such, disrupting sterol biosynthesis during neurodevelopment can have devastating outcomes. The most common post-lanosterol sterol biosynthesis disorder, Smith-Lemli-Opitz Syndrome, arises from a faulty DHCR7 enzyme. DHCR7 has also been shown to be inhibited by several psychotropic medications. Here we assess six beta-blockers and their effects on sterol biosynthesis in vitro. Two beta-blockers, metoprolol and nebivolol strongly inhibit DHCR7 in four separate in vitro models of both mouse and …

Aberrant Age-Related Alterations In Spontaneous Cortical Activity In Participants With Cerebral Palsy, Hannah Bergwell

Theses & Dissertations

Cerebral Palsy (CP) is the most common neurodevelopmental motor disability, resulting in life-long sensory, perception and motor impairments. These impairments appear to drastically worsen with advancing age within the CP population, although the underlying neuro-physiological mechanisms remain poorly understood. Herein, we began to address this knowledge gap by utilizing magnetoencephalographic (MEG) to study how aging impacts the amplitude of spontaneous brain activity (i.e., resting state) in a cohort of 38 individuals with spastic diplegic CP (Age = 22.08 ± 10.46 years) and 67 neurotypical controls (NT) (Age = 19.56 ± 10.25 years). Participants completed an eyes-closed resting-state paradigm while undergoing …

Frailty And Neurocognition In Prostate Cancer, Lindsey Hanson

Theses & Dissertations

Prostate cancer (PCa) treatment often leads to distressing side effects ranging from muscle loss, physical inactivity, and fatigue to cancer associated cognitive decline (CACD). Evidence suggests that men treated with androgen deprivation therapy (ADT) may have a specifically high risk of CACD, partially due to increased frailty. However, the current literature on cognitive effects of ADT is equivocal. Therefore, the primary objectives of this study were to (1) compare cognitive function, physical activity (PA), and fitness in men receiving ADT, men scheduled to receive radiation, and men under active surveillance for PCa; (2) examine changes in cognitive performance and PA …

Astrocytic Contribution To Sensory Hypersensitivity In A Mouse Model Of Fragile X Syndrome, Lara E. Bergdolt

Theses & Dissertations

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and a leading cause of autism spectrum disorder (ASD). FXS is caused by mutations in the fragile X mental retardation gene (FMR1), which result in complete or substantial loss of expression of its protein product fragile X mental retardation protein (FMRP). Neuronal impairments in the absence of FMRP have been extensively characterized. However, much less is known about the impact that loss of FMRP has on the physiology and function of astrocytes and the implications for behavior. A common behavior exhibited by both FXS and ASD patients …

Linking Spinal Cord Circuits With Upper Limb Sensorimotor Control In Adults With Cerebral Palsy, Saihari Dukkipati

Theses & Dissertations

Cerebral palsy (CP) is the most common neurological disorder originating in childhood, but most of the people living with CP are currently adults. While people with CP continue to get older, the amount of research focused on adults has been rather limited. The early childhood insults leading to CP are thought to originate in the brain, but the effects on the entire neuromuscular system across the lifespan have only recently started to be explored. Of note, recent neuroimaging evidence suggests that the cervical spinal cord structure is atypical in adults with CP. However, it is largely unclear how the neurophysiological …

Innate Immunity In The Pathobiology And Treatment Of Infectious And Neurodegenerative Diseases, Mai Mostafa

Theses & Dissertations

Mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells) are the governors of innate immunity which is the body’s first line of defense against microbial pathogens. They act beneficial or detrimental. They are crucial for an effective non-specific immune response to invading pathogens by engulfing, destroying, then eliciting an adaptive specific immune response. Given their pivotal functions in the host immune defense, studying MP immune responses in disease is paramount important for understanding disease pathobiology and uncovering therapeutic strategies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the driver of acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) amongst …

Probing The Role Of Astrocytes In The Pathology Of Fragile X Syndrome With Human Stem Cells, Baiyan Ren

Theses & Dissertations

Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder related to intellectual disability and the most common monogenic cause of autism spectrum disorder. FXS is mainly caused by an expansion of CGG repeats in the 5’-untranslated region of fragile X mental retardation 1 (FMR1) gene, leading to the loss of expression of fragile X mental retardation protein (FMRP). Astrocytes are the most abundant glial cells in the central nervous system (CNS). Loss of FMRP in astrocytes has been found to contribute to structural and functional synaptic deficits in the Fmr1-KO mouse model. The contribution of human astrocytes, however, to the …

Multimodal Neuroimaging Of Hiv And Aging, Brandon Lew

Theses & Dissertations

HIV infection remains a significant contributor to disease burden, and with the success of antiretroviral therapies, the population of people with HIV is aging. A growing literature suggests a relationship between HIV-infection and a profile of age advancement, most notably in molecular studies of epigenetics. However, despite the widely-known high prevalence of HIV-related brain atrophy, functional deficits, and HIV-associated neurocognitive disorder (HAND), epigenetic age advancement has not been linked to HIV-related changes in neuroimaging metrics.

We applied three neuroimaging methods, structural MRI, resting state functional MRI, and resting state MEG, to study the brain structure and function of 121 virally-suppressed …

In Utero And Postnatal Oxycodone Exposure: Implications For Intergenerational Effects, Katherine E. Odegaard

Theses & Dissertations

Prescription opioid abuse during and after pregnancy is a rising public health concern. Adding a layer of complexity is the role of heredity in the overall development of these exposed offspring. The present work uses a preclinical rat model mimicking oxycodone (oxy) exposure in utero (IUO) and postnatally (PNO) to investigate comparative and intergenerational effects in the two different exposure groups.

To understand the direct effects of IUO and PNO exposure on the F1 generation, we employed a systems biology approach encompassing proton magnetic resonance spectroscopy (¹H-MRS), electrophysiology RNA-sequencing, and pain assessment to elucidate molecular and behavioral changes …

The Neurological Abnormalities Of The Brain And Spinal Cord In Individuals With Cerebral Palsy, Michael Trevarrow

Theses & Dissertations

Cerebral palsy (CP) results from an insult to the developing brain, and it is one of the most common neurodevelopmental disorders in the United States. The insult produces a cascade of activity-dependent plastic changes within the neurophysiology and structure of the brain and spinal cord that ultimately leads to sensorimotor and mobility impairments that may increase in severity throughout the lifespan. Despite this phenomenon, there are a lack of neuroimaging studies in adults with CP, generating a knowledge gap in determining how brain and spinal cord activity and structure may be altered throughout the transition into adulthood. Furthermore, the specific …

Neurocognitive Impairment In People Living With Human Immunodeficiency Virus (Hiv): Risk Factors And Mortality, Zaeema Naveed

Theses & Dissertations

Despite the widespread use of combination antiretroviral therapy (cART), HIV-associated neurocognitive impairment (NCI) persists in people living with HIV (PLWH) with clinical and public health implications. Studies have generated inconsistent results regarding etiological factors for NCI in PLWH and a brief user-friendly predictive tool is desirable in clinical practice to assess the probability of having NCI in PLWH. Furthermore, factors associated with clinically meaningful decline in neurocognitive status and survival disadvantage for patients with NCI are understudied in the post-cART era. The goal of this dissertation was to investigate factors associated with baseline NCI and neurocognitive decline and the association …

Dynamic Oscillatory Interactions Between Neural Attention And Sensorimotor Systems, Alex Wiesman

Theses & Dissertations

The adaptive and flexible ability of the human brain to preference the processing of salient environmental features in the visual space is essential to normative cognitive function, and various neurologically afflicted patient groups report negative impacts on visual attention. While the brain-bases of human attentional processing have begun to be unraveled, very little is known regarding the interactions between attention systems and systems supporting sensory and motor processing. This is essential, as these interactions are dynamic; evolving rapidly in time and across a wide range of functionally defined rhythmic frequencies. Using magnetoencephalography (MEG) and a range of novel cognitive paradigms …

Molecular And Behavioral Studies In Cdkl5 Deficiency Disorder, Ethan Schroeder

Theses & Dissertations

CDKL5 Deficiency Disorder (CDD) is an X-linked neurodevelopmental disorder associated with epilepsy, developmental retardation, autism, and related phenotypes. Currently, there is no cure available for the disorder. Thus, the identification of cellular and molecular aberrations in this disorder and the generation and validation of mouse models that recapitulate core aspects of the disorder are a pressing need in the field. Our studies are aimed at filling this gap.

Mutations in the CDKL5 gene, encoding CDKL5, have been identified in this disorder. CDKL5 is a protein with homology to the serine-threonine kinases and incompletely characterized function. Mutations in CDKL5 are predominately …

Flavonoid And Cannabidiol Neural Glyoxalase Pathway Enhancement Against Aging And Alzheimer’S Disease, Joel R. Frandsen

Theses & Dissertations

Alzheimer’s Disease is a neurodegenerative condition featuring neural cell death and a decline in cognitive capacity caused by elevated inflammation and production of reactive oxygen species. The glyoxalase pathway is an endogenous antioxidant system that neutralizes reactive methylglyoxal through sequential reactions. Dysfunction of the glyoxalase pathway contributes to oxidative stress and the accumulation of inflammatory metabolic byproducts. Plant-produced compounds with antioxidant activity can enhance endogenous antioxidant pathways and protect cells from elevated ROS production. We hypothesize that flavonoids and limited Cannabis Sativa-produced cannabidiol can enhance glyoxalase pathway function through regulation of antioxidant and pro-apoptotic signaling pathways to prevent methylglyoxal-mediated …

Role Of Astrocyte-Derived Extracellular Vesicles In Neuroinflammation Mediated By Drug Abuse, Ke Liao

Theses & Dissertations

Neuronal damage and neuroinflammation is a hallmark feature of HIV-associated neurological disorders (HANDs). Opioids abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Extracellular vesicles (EVs) are essential conduits in HIV and drug abuse-mediated synaptodendritic injury and neuroinflammation. Findings from our group have demonstrated that astrocyte-derived EV (ADEV)-miRNA-29b mediates HIV Tat and morphine-induced neuronal injury, thus underscoring the importance of such interactions in NeuroHIV.

Besides, HIV Tat and morphine-mediated synaptodendritic injury via ADEVs, we are also interested in whether ADEVs contributes to neuroinflammation. Microglia are critical players in …

Roles Of Autism Gene Arid1b In Murine Brain Development And Behavior, Amanda L. Smith

Theses & Dissertations

Autism spectrum disorder (ASD) and intellectual disability (ID) are highly prevalent neurodevelopmental disorders characterized by social and communication deficits, stereotyped behaviors, cognitive dysfunction, and deficits in adaptive behaviors. The pathogenesis underlying these disorders remains unknown, and thus no pharmacologic or genetic therapies are currently available. Recent progress in the field has shown that haploinsufficiency of the AT-rich interactive domain-containing 1B (ARID1B) gene is a genetic cause of ASD and ID. Our lab recently developed an Arid1b knockout mouse model to better study its role in the pathogenesis of these disorders. One theory regarding the cause of neurodevelopmental disorders …

Cholesterol Biosynthesis In The Nervous System With An Emphasis On Desmosterolosis, Luke Allen

Theses & Dissertations

Cholesterol biosynthesis is integral to proper neurodevelopment due to the reliance on de novo synthesis of cholesterol in the brain. Disruptions in this process have devastating outcomes for human life characterized by several phenotypic manifestations concomitant with developmental delay. The cholesterol biosynthesis disorder desmosterolosis is an extremely rare disorder with a severe clinical phenotype, however, the models used to study this disease are not well characterized. In addition to genetic disruptions in cholesterol biosynthesis, pharmacological perturbation is an understudied side effect of many commonly prescribed drugs. Here we present a characterization of the sterol profile of the mouse model of …

Novel Antiviral Effect Of A Small Molecule Onc201 And Its Potential Application In Hiv-1 Eradication, Runze Zhao

Theses & Dissertations

Despite the success of antiretroviral therapy (ART), eradication of HIV-1 from brain reservoirs remains elusive. HIV-1 brain reservoirs include perivascular macrophages that are behind the blood-brain barrier and difficult to access by ART. Macrophages express transcription factor FOXO3a and the TNF superfamily cytokine TRAIL, which are known to target HIV-1-infected macrophages for viral suppression. ONC201 is a novel and potent FOXO3a activator capable of inducing TRAIL. It can cross the blood-brain barrier, and has shown an antitumor effect in clinical trials. We hypothesized that activation of FOXO3a/TRAIL by ONC201 will reduce the size of HIV-1 brain reservoirs. Using primary human …