Structural And Functional Consequences Of Pde6 Prenylation In Rod And Cone Photoreceptors, Faezeh Moakedi

Graduate Theses, Dissertations, and Problem Reports

Phosphodiesterase-6 (PDE6) serves as a pivotal component in the phototransduction pathways of both cone and rod photoreceptors. In cones, PDE6 consists of tetrameric subunits: inhibitory (γ') and catalytic (α'). The catalytic subunit, PDE6α', contains a C-terminal prenylation motif. Deletion of this motif is associated with achromatopsia (ACHM), a form of color blindness. The mechanisms underlying the disease and the roles of PDE6 lipidation in vision remain elusive. Meanwhile, rod PDE6 is composed of α and β catalytic subunits and γ inhibitory subunits, with alterations in the C-terminal "prenylation motif" of PDE6β linked to retinitis pigmentosa (RP) pathology. In this comprehensive …

Traumatic Brain Injury Induces Cerebrovascular Dysfunction: Consequences For Ischemia And Cerebral Hypoperfusion, Bailey J. Whitehead

Graduate Theses, Dissertations, and Problem Reports

Traumatic brain injury (TBI) is a significant health concern across the United States as well as the broader globe, affecting millions of individuals on an annual basis. While most recover from their TBI and resume their lives normally, some subsets of TBI survivors continue to experience impairments and increased risk for future diseases like cardiovascular disease, stroke, and aging related disease like Alzheimer’s Disease or VCID.

TBI remains a fundamentally difficult neurological injury to pin down mechanistically, due to the variability in severity, timing, and age of patient, among other factors. One significant factor in the pathology has consistently been …

Puberty-Associated Changes In Kiss1r, Mc3r, And Mc4r In The Ewe, Ashleigh Caitlyn Thomson

Graduate Theses, Dissertations, and Problem Reports

The neural mechanisms that control the onset of puberty are not completely understood. In livestock, the onset of puberty relies on an increase in gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH). Kisspeptin, neurokinin B, and dynorphin neurons (KNDy) and their receptors, Kiss1r, NK3R, and KOR, respectively, are important regulators of puberty. Previous data from our laboratory has shown that KNDy neurons may be responding to other inputs, including the melanocortin system, that will affect the timing of puberty. Given this, we examined kisspeptin receptor (Kiss1r) mRNA expression in GnRH neurons as well as examining melanocortin 3 and 4 receptor …

Estradiol’S Role In Timely Puberty Onset In The Ewe, Eliana Gerardine Aerts

Graduate Theses, Dissertations, and Problem Reports

In female sheep, the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus triggers luteinizing hormone (LH) to be released from the pituitary. Luteinizing hormone, in turn, acts on the ovaries to elicit estradiol (E₂) release. E₂ acts in a negative feedback manner to control the amount of LH released. The increase in LH release that drives puberty onset results from a decrease in sensitivity to E₂ as the animal ages. However, the neural mechanisms mediating this change in sensitivity are not known, as is where in the hypothalamus E₂-negative feedback occurs. In the arcuate …

Sex Differences In Endothelial Function, Metabolism, And Sleep: Responses To Disrupted Circadian Rhythms, Olga Hecmarie Meléndez-Fernández

Graduate Theses, Dissertations, and Problem Reports

Circadian rhythms are endogenous cycles that recur approximately every 24 h, and manifest in virtually every physiological and behavioral process among the vast majority of organisms. These rhythms, sustained by the central circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus, allow for optimal timing of biological processes that ensure organisms’ homeostasis, and are entrained to precisely 24 h by daily exposure to light. Disruption of the molecular mechanisms that drive these rhythms have negative consequences on physiology and behavior that may impair survival. The molecular mechanisms that underlie these effects are widely studied and linked to multiple diseases and …

Multimodal Neuron Classification Based On Morphology And Electrophysiology, Aqib Ahmad

Graduate Theses, Dissertations, and Problem Reports

Categorizing neurons into different types to understand neural circuits and ultimately brain function is a major challenge in neuroscience. While electrical properties are critical in defining a neuron, its morphology is equally important. Advancements in single-cell analysis methods have allowed neuroscientists to simultaneously capture multiple data modalities from a neuron. We propose a method to classify neurons using both morphological structure and electrophysiology. Current approaches are based on a limited analysis of morphological features. We propose to use a new graph neural network to learn representations that more comprehensively account for the complexity of the shape of neuronal structures. In …

Effects Of Development On Hpa Function Following Pubertal Stress, Brittany D. Elliott

Graduate Theses, Dissertations, and Problem Reports

For women, two of the greatest risk factors for affective disorders are adversity experienced during puberty and later becoming pregnant. We have created a translationally relevant mouse model where we address these complex risk factors. Previously, we discovered that pregnant mice (dams) that experienced chronic variable stress (CVS) during puberty display a blunted hypothalamic-pituitary-adrenal (HPA) response when exposed to an acute stressor. Interestingly, this alteration only first becomes apparent during pregnancy, which is a sensitive period for these effects due to normative neuroendocrine changes. Further investigation of the mechanisms underlying this dysfunction revealed altered gene expression in the paraventricular nucleus …

Artificial Light At Night Disrupts Pain Behavior And Cerebrovascular Structure In Mice, Jacob Raymond Bumgarner

Graduate Theses, Dissertations, and Problem Reports

Artificial Light at Night Disrupts Pain Behavior and Cerebrovascular Structure in Mice

Jacob R. Bumgarner

Circadian rhythms are intrinsic biological processes that fluctuate in function with a period of approximately 24 hours. These rhythms are precisely synchronized to the 24- hour day of the Earth by external rhythmic signaling cues. Solar light-dark cycles are the most potent environmental signaling cue for terrestrial organisms to align internal rhythms with the external day. Proper alignment and synchrony of internal circadian rhythms with external environmental rhythms are essential for health and optimal biological function.

The modern human environment on Earth is no longer …

Cue Reactivity In Electronic Cigarette Users With Sign-Tracking Or Goal-Tracking Behaviors, Polina Krom

Graduate Theses, Dissertations, and Problem Reports

Polina Krom

Cue reactivity is an important predictor of addiction course and relapse. However, cue reactivity is only observed after an addiction develops. As such, it is unclear to what degree cue reactivity represents a state stemming from the addiction process versus a trait-like propensity towards developing cue-reward associations. Work in animal models has pointed to important individual differences in trait-like inclination to attribute incentive salience to reward-predictive cues that is associated with addiction-relevant behavioral and neurobiological features. These individual differences manifest as sign-tracking (ST) and goal-tracking (GT) behaviors during Pavlovian conditioning. Little research has attempted to translate ST and …

Spiking Neural Network That Maps From Generalized Coordinates To Cartesian Coordinates, Chloe K. Guie

Graduate Theses, Dissertations, and Problem Reports

In this thesis, I look to understand how insects compute task-level quantities by integrating range-fractionated sensory signals to create a sparse-spatial coding of Cartesian positions. I created biologically plausible 2-D and 3-D models of one species of the stick insect (Carausius morosus) leg and encoded the foot position through a spiking neural network. This model used spiking afferents from three angles of an insect leg which are integrated by one non-spiking interneuron. This model contains many dendritic compartments and one somatic compartment that encode the foot’s position relative to the body. The Functional Subnetwork Approach (FSA) was used …

Computational Mechanisms Of Face Perception, Jinge Wang

Graduate Theses, Dissertations, and Problem Reports

The intertwined history of artificial intelligence and neuroscience has significantly impacted their development, with AI arising from and evolving alongside neuroscience. The remarkable performance of deep learning has inspired neuroscientists to investigate and utilize artificial neural networks as computational models to address biological issues. Studying the brain and its operational mechanisms can greatly enhance our understanding of neural networks, which has crucial implications for developing efficient AI algorithms. Many of the advanced perceptual and cognitive skills of biological systems are now possible to achieve through artificial intelligence systems, which is transforming our knowledge of brain function. Thus, the need for …

Sense And Sensitivity: Spatial Structure Of Conspecific Signals During Social Interaction, Keshav Ramachandra

Graduate Theses, Dissertations, and Problem Reports

Organisms rely on sensory systems to gather information about their environment. Localizing the source of a signal is key in guiding the behavior of the animal successfully. Localization mechanisms must cope with the challenges of representing the spatial information of weak, noisy signals. In this dissertation, I investigate the spatial dynamics of natural stimuli and explore how the electrosensory system of weakly electric fish encodes these realistic spatial signals. To do so In Chapter 2, I develop a model that examines the strength of the signal as it reaches the sensory array and simulates the responses of the receptors. The …

Spatial Processing Of Conspecific Signals In Weakly Electric Fish: From Sensory Image To Neural Population Coding, Oak Everette Milam

Graduate Theses, Dissertations, and Problem Reports

In this dissertation, I examine how an animal’s nervous system encodes spatially realistic conspecific signals in their environment and how the encoding mechanisms support behavioral sensitivity. I begin by modeling changes in the electrosensory signals exchanged by weakly electric fish in a social context. During this behavior, I estimate how the spatial structure of conspecific stimuli influences sensory responses at the electroreceptive periphery. I then quantify how space is represented in the hindbrain, specifically in the primary sensory area called the electrosensory lateral line lobe. I show that behavioral sensitivity is influenced by the heterogeneous properties of the pyramidal cell …

Exploiting Modulation Of The Blood-Brain And Blood-Tumor Barrier Permeability By Translational Focused Ultrasound For Therapeutic Delivery To Cns Metastases, Tasneem A. Arsiwala

Graduate Theses, Dissertations, and Problem Reports

Transcranial low-intensity focused ultrasound is a unique technology to modulate the integrity of tight endothelial junctions and transiently increase BBB/BTB permeability to enhance therapeutic delivery. Despite promising early studies, present literature lacks agreement on key experimental conditions, which restricts our knowledge and the technique's widespread translation. This dissertation first provides a critical review of the current gaps in knowledge regarding the universal use of LiFUS in preclinical and clinical use. We then identify key parameters for translational and predictable opening of the BBB using a 3T MRI coupled with a clinical device. Our investigation highlights that passive permeability of the …

Examining Development And Function Of Pretectal Visual Neural Circuits In Gs Homeobox 1 Mutant Zebrafish, Alexandra Rose Schmidt

Graduate Theses, Dissertations, and Problem Reports

Brain development requires a coordinated genetic code to regulate initial cell identity determination, migration, and connectivity, to establish function of neural circuits. Independent neural circuits underlie our ability to produce both complex and innate behavioral responses to sensory stimuli that are often conserved across vertebrate organisms. Sensory processing disruptions are associated with several neurodevelopmental disorders (NDDs). Therefore, gene mutations altering neurodevelopment can lead to changes influencing structure and function of individual neural circuits, causing behavioral deviations in sensory responsiveness. Crucial gene networks that define functional properties of sensory domains are often explored using non-mammalian vertebrate models, such as the zebrafish. …

A Combinatorial 5-Htr Expression Pattern Within The Ventral Projection Neurons Of The D. Melanogaster Olfactory Circuit., Mohd Freezely Ezzani Bin Mazri

Graduate Theses, Dissertations, and Problem Reports

Neuromodulation allows neurons within a circuit to respond to stimuli from the environment according to the correct ecological value, context, and internal state of the animal. Serotonin (5-HT) is a neuromodulator that can generate different outcomes based on its target’s serotonin receptor (5-HTR) expression by affecting secondary messenger cascades. Within the Drosophila olfactory system, ventral projections neurons (vPN) express all five insect 5-HTR that project into two olfactory processing regions, the antennal lobe (AL) and the lateral horn (LH). The significance of this 5-HTR expression is unknown. In this study, I theorized the patterns of 5-HTR expression of vPNs. I …

Mechanistic Insight Into Chronic Stress-Induced Cerebrovascular Dysfunction, Emily Nicole Burrage

Graduate Theses, Dissertations, and Problem Reports

Despite decades of research psychological stress remains a prevalent problem in society, often diminishing quality of life and increasing the risk of developing dementia. The brain plays a central role in the response to stress and as it is unable to store energy substrates, the brain relies heavily on dynamically regulated blood flow. Therefore, it is important that there is a tight coupling between neural activity and cerebral blood flow to meet metabolic demands and maintain critical brain function. It has been established that chronic psychological stress has detrimental effects on cerebrovascular function, potentially through increased superoxide anion production through …

An Investigation Into The Mechanism Of Proteasome Dysfunction In Neurodegenerative Disease And The Biological Impact Of Proteasome Hyperactivation In C. Elegans, Raymond T. Anderson

Graduate Theses, Dissertations, and Problem Reports

Aging is an inevitable process that occurs as humans grow older. It is characterized by the chronological accumulation of cellular damage over time leading to functional decline as an organism grows older. Several processes are thought to contribute to the aging phenomenon, but one of the most prolific of these is the disruption of protein homeostasis (proteostasis). The collapse of proteostasis can lead to accelerated aging and the development of age-related diseases including devastating neurodegenerative diseases (NDs) like Alzheimer and Parkinson disease. Virtually all NDs are characterized by the buildup of proteins in and around neurons resulting in neuronal death …

Using Zebrafish To Elucidate The Expression And Gene Regulatory Network Of The Genomic Screen Homeobox Transcription Factors And Bring Innovative Science Learning Experiences To West Virginia, Rebecca Ann Coltogirone

Graduate Theses, Dissertations, and Problem Reports

Central nervous system (CNS) development requires a code of regionally expressed transcription factors that impart initial neuronal cell identity, connectivity, and function. The absence of a transcription factor code would eliminate the neurodevelopmental logic producing diverse cell types in the CNS. Furthermore, early disruptions in transcription factor expression can affect later connectivity and function of neuronal circuits mediating sensory processing, defects in which are often observed as comorbid with various neurodevelopmental disorders (NDDs). Characterizing transcription factor expression and function is therefore an essential step in discerning the molecular mechanisms underlying human NDDs. genomic screen homeobox 1 and 2 (gsx1 …

Investigating The Role Of Attention And Memory In Visual Exploration, Jacob E. Suffridge

Graduate Theses, Dissertations, and Problem Reports

This research investigates the role that attention and memory plays in visual exploration through a comprehensive analysis of eye movement and behavioral data, alongside incorporation of a computational saliency model. The purpose of this project is to quantify differences in visual attention over repeated viewings of natural scene images by employing a free viewing task that contains a memory component. In Chapter 2, we explore the task’s behavioral data showing that participants generally memorize our images well before we investigate the effect of numerous object and individual feature inclusion. In Chapter 3, we develop four primary methods to quantify visual …

The Receptor Basis Of Serotonergic Modulation In An Olfactory Network, Tyler Ryan Sizemore

Graduate Theses, Dissertations, and Problem Reports

Neuromodulation is a nearly ubiquitous process that endows the nervous system with the capacity to alter neural function at every level (synaptic, circuit, network, etc.) without necessarily adding new neurons. Through the actions of neuromodulators, the existing neural circuitry can be adaptively tuned to achieve flexible network output and similarly dynamic behavioral output. However, despite their near ubiquity in all sensory modalities, the mechanisms underlying neuromodulation of sensory processing remain poorly understood. In this dissertation, I address three main questions regarding the mechanisms of one modulator (serotonin) within one sensory modality (olfaction). I begin by establishing a "functional atlas" of …

Meta-Analyses Support A Taxonomic Model For Representations Of Different Categories Of Audio-Visual Interaction Events In The Human Brain, Matt Csonka, Nadia Mardmomen, Paula J. Webster, Julie A. Brefczynski-Lewis, Chris Frum, James W. Lewis

Faculty & Staff Scholarship

Our ability to perceive meaningful action events involving objects, people and other animate agents is characterized in part by an interplay of visual and auditory sensory processing and their cross-modal interactions. However, this multisensory ability can be altered or dysfunctional in some hearing and sighted individuals, and in some clinical populations. The present meta-analysis sought to test current hypotheses regarding neurobiological architectures that may mediate audio-visual multisensory processing. Reported coordinates from 82 neuroimaging studies (137 experiments) that revealed some form of audio-visual interaction in discrete brain regions were compiled, converted to a common coordinate space, and then organized along specific …

Describing A Putative Corollary Discharge Circuit In Drosophila, Kaitlyn Nicole Boone

Graduate Theses, Dissertations, and Problem Reports

Corollary discharge (CD) circuits provide critical information about movement and behavior to provide context to sensory processing. However, to date, there has not been a comprehensive study of CD circuits at a single-cell level. In this thesis, I aimed to resolve the connectivity of ascending histaminergic neurons, consisting of two pairs, the mesothoracic pair (MsAHNs) and metathoracic pair (MtAHNs) at a single-cell level and characterize contexts of activation. Using transgenic techniques, connectomics and transcriptomics, we identify neural populations receiving input from the AHNs and neural populations with significant output to the AHNs. We explored where the AHNs predominantly receive synaptic …

Bypassing The Blood-Brain Barrier: A Physical And Pharmacological Approach For The Treatment Of Metastatic Brain Tumors, Samuel A. Sprowls

Graduate Theses, Dissertations, and Problem Reports

This dissertation (a) provided an in depth literature review of methods to disrupt the BBB/BTB and improve therapeutic distribution to brain tumors, (b) evaluated the use of azacitidine as a single agent therapy for the treatment of brain metastasis of breast cancer and a potential molecular mechanism by which brain tropic cells are sensitized to hypomethylating agents, (c) determined the impact cannabidiol has on P-glycoprotein mediated efflux at the blood-brain barrier and its potential for use as a single agent treatment for metastatic brain tumors, (d) developed a preclinical radiation therapy protocol for use in small animals and in vitro …

Biomechanically Inspired Assistive Technology To Restore Movement Of The Upper Limbs After Stroke, Ariel Thomas

Graduate Theses, Dissertations, and Problem Reports

A stroke often damages the neural structures responsible for movement. Stroke is a heterogeneous disease, affecting each survivor differently. There are common motor features of a stroke, but even these features vary across time as an individual proceeds through different stages of recovery. The different ways in which stroke motor impairment can present itself are often overlooked, but these differences are fundamental to the understanding of the disease and its recovery. When motor assessments are capable of acquiring information necessary to parse out a detailed profile of each stroke case, this will lead to an improved neuromechanical understanding of the …

Manipulating The Perineuronal Net In The Deep Cerebellar Nucleus, Deidre E. O'Dell

Graduate Theses, Dissertations, and Problem Reports

Perineuronal nets (PNN) are a type of specialized extracellular matrix in the central nervous system. The PNN forms during postnatal development but the ontogeny of the PNN has yet to be elucidated. Studying the PNN in the rat brain may allow us to further understand the PNN’s role in development, learning, and memory. The PNN is fully developed in the deep cerebellar nuclei (DCN) of rats by post-natal day 18. By using enzymatic digestion of the PNN with chondroitinase ABC (ChABC), we studied how digestion of the PNN affects cerebellar-dependent eyeblink conditioning (EBC) and performed electrophysiological recordings from DCN neurons. …

Targeting The Cerebrovasculature In Sepsis: A Focus On The Brain Microvascular Endothelium, Divine C. Nwafor

Graduate Theses, Dissertations, and Problem Reports

The blood-brain barrier (BBB) is a critical interface between the systemic circulation and the brain. It is a specialized multicellular unit composed of brain microvascular endothelial cells (BMECs), pericytes, a basement membrane, and astrocytic end foot processes. BMECs are a principal component of the BBB that provide the structural framework needed for the stringent transport of molecules into the brain. BMEC dysfunction permits the trafficking of neurotoxins from systemic circulation into the brain, which ultimately exacerbates BBB dysfunction and neuroinflammation. Studies have shown that BBB dysfunction is a key determinant of cognitive decline in sepsis. However, there are critical knowledge …

Mitochondrial Aspects Of Neuronal Pathology In Triple-Transgenic Alzheimer’S Disease Mice, John Zachary Cavendish

Graduate Theses, Dissertations, and Problem Reports

Alzheimer’s disease (AD) is a fatal, progressive neurodegenerative disease afflicting millions of people in the United States alone and is the only one of the top leading causes of morbidity and mortality with no effective disease-modifying therapies. It is the most common form of dementia, affecting one in three people over the age of 85. While the hallmarks of the disease include accumulation of beta-amyloid-based extracellular plaques and hyperphosphorylated tau-based intracellular neurofibrillary tangles, treatment strategies centered on removing or mitigating these components of AD have all failed in humans. Mitochondrial dysfunction has been increasingly recognized as an early and consistent …

Cerebrovascular Dysfunction And Degeneration In Alzheimer’S Disease Pathophysiology, Dominic Dimitri Quintana

Graduate Theses, Dissertations, and Problem Reports

Alzheimer’s disease (AD) is a terminal illness and the most common form of dementia, which disproportionately affects the aged population. The pathophysiology of AD is characterized by neurodegeneration that slowly progresses, affecting regions of the brain that are involved in learning, memory, language, and executive function. In patients with the disease, early symptoms include non-disruptive forgetfulness that evolves into the inability to form new memories and ultimately the loss of autonomy at late stages. Histopathological hallmarks in the brain from patients with AD is the presence of amyloid-β (Aβ)-plaques and neurofibrillary tangles (NFT) deposited in the parenchyma. Since the discovery …

Factors Influencing Huntingtin Aggregation At Surfaces: Implications For Huntington’S Disease, Sharon E. Groover

Graduate Theses, Dissertations, and Problem Reports

Huntington’s Disease (HD) is a genetic, neurodegenerative disease characterized by an abnormal polyglutamine (polyQ) expansion in the first exon of the huntingtin protein (htt). The polyQ domain facilitates aggregation and initiates the formation of a diverse collection of aggregate species, including fibrils, oligomers and annular aggregates. The first 17 amino acids of htt (Nt17) directly flank the polyQ domain and is a key factor in htt’s association to membranous structures. In addition to Nt17 being an amphipathic αhelix, it also promotes aggregation through self-association and contains numerous posttranslational modifications (PTMs) that can modulate toxicity and subcellular localization. For in depth …