Medicine and Health Sciences Commons^™

A Neurophysiological Investigation Of Listening Effort In Normal Hearing Adults Using Fnirs And Pupillometry, Jessica Defenderfer

Theses and Dissertations (ETD)

Real-world conversations are often accompanied by some sort of interference that challenges the clarity of the speaker’s message, causing listeners to exert more effort to understand speech. Previous research has demonstrated that when listening to speech becomes difficult, various regions of the brain are recruited beyond those which engage during optimal listening conditions. However, the neural correlates that underly listening effort are not fully understood. Importantly, the pupillary response can be used to index listening effort, such that pupil size increases with increasing cognitive demand. I proposed that pupillometry can be used to characterize the cortical response, such that changes …

A Rodent Animal Model For Forelimb To Lower Jaw Reorganization In Primary Somatosensory Cortex (Si) Barrel Field, Violeta Pellicer Morata

Theses and Dissertations (ETD)

The goal of this study is to examine mechanisms underlying cortical reorganization in rat primary somatosensory (SI) cortex that follows forelimb deafferentation. The majority of human patients suffering from limb loss or brachial plexus avulsion injury, as well as patients that receive brachial plexus anesthesia, report phantom limb sensations/pain which are often associated with cortical reorganization. Patients with upper-limb deafferentation report sensations of the missing hand during tactile stimulation of the face, and this phenomenon has been termed hand-to-face remapping. We sought to develop a rodent model of deafferentation; our model system is the rat SI cortex barrel field present …

Immunomodulatory Roles Of The Lysosomal Sialidase Neuraminidase 1, Leigh Ellen Fremuth

Theses and Dissertations (ETD)

Background Sialic acids are key sugar moieties located at the non-reducing terminals of glycan chains on glycoproteins and glycolipids. By virtue of their location, they influence the functions and biochemical properties of the macromolecules they are bound to. Removal of sialic acids in mammalian cells is carried out by four sialidases, which are differentially expressed and localized in distinct subcellular compartments. Neuraminidase 1 (NEU1), the most abundant and ubiquitous of the four sialidases, functions primarily in the acidic environment of the lysosomes, but can hydrolyze substrates at the plasma membrane, at least in certain cell types. The enzyme initiates the …

Effects Of Genetics And Sex On Hippocampal Gene Expression And Adolescent Behaviors Following Neonatal Ethanol Exposure In Bxd Recombinant Inbred Mice, Jessica A. Baker

Theses and Dissertations (ETD)

Fetal alcohol spectrum disorders (FASD) are the leading preventable neurodevelopmental disorders in the western world. A hallmark symptom of FASD is cognitive and learning deficits that present in early childhood and continue throughout adulthood. Teratogenic effects of alcohol include increased cell death in the hippocampus, a brain region critically important in learning and memory. Genetics have been shown to have a role in the severity of alcohol’s teratogenic effect on the developing brain. Previous work in our lab identified differential vulnerability to ethanol-induced call death in the hippocampus using fourteen BXD strains and the two parental strains. The goal of …

Taste Learning In Insular Cortex: Plasticity Is Influenced By Experience Type, Stephanie Marie Staszko

Theses and Dissertations (ETD)

The gustatory cortex (GC) has long been studied as the main cortical area encoding taste stimuli and likely integrates sensory, visceral, and emotional information to guide taste-related behaviors. However, our understanding of cortical taste coding on a single-cell level has only become clear in recent years. The anatomical location of GC on the lateral and ventral surface of the brain makes it difficult to target with traditional imaging methods. Thus, much of what we know about cortical taste coding and cortical taste plasticity has been derived either from multiunit electrode recordings or anesthetized imaging experiments, techniques which lack the ability …

Systems Genetics And Systems Biology Analysis Of Paraquat Effects In Bxd Recombinant Inbred Mice, Carolina Del Valle Torres Rojas

Theses and Dissertations (ETD)

Paraquat (PQ) is a chemical herbicide that is used in many countries including the United States. It is also highly acutely toxic to humans and has been used as a means of suicide. As PQ is applied mainly in agricultural settings, it moves to soil and well water. Chronic low dose exposure via drinking water may have adverse effects on humans, including increased risk for sporadic Parkinson’s disease (sPD). The etiology of sPD is unclear and the most accepted hypothesis states it is the result of the interaction between environmental factors and genetic susceptibility. Increasing evidence led us to infer …

Role Of Cerebral Vasculature And Effect Of Circulating Exosomes In Propagation Of Systemic Inflammatory Responses Into The Central Nervous System, Mahesh Chandra Kodali

Theses and Dissertations (ETD)

Sepsis-associated encephalopathy (SAE) is an acutely progressing brain dysfunction induced by systemic inflammation. The mechanism of initiation of neuroinflammation during SAE, which ultimately leads to delirium and cognitive dysfunction, remains elusive. The goal of this project was to study the molecular events of SAE to capture its onset and progression into the central nervous system (CNS), and further identify the cellular players involved in mediating acute inflammatory signaling. Gene expression profiling on the cerebral vessels isolated from the brains of the mice treated with peripheral lipopolysaccharide (LPS) revealed that the cerebral vasculature responds within minutes to acute systemic inflammation by …

Conditional Loss Of Engrailed 1/2 In Rhombic Lip-Derived Neurons Increases Intrinsic Rhythmicity And Decreases Overall Variability Of Eupneic Respiration, Angela P. Taylor

Theses and Dissertations (ETD)

Evidence for a cerebellar role during cardiopulmonary challenges has long been established, but investigation into cerebellar involvement in eupneic breathing has been inconclusive. Given the view of the cerebellum (CRB) as a temporally coordinating structure, any investigation into the CRB during respiration must evaluate rhythm and variability of the respiratory sequence. In this study, we chose an elegant model of cerebellar neuropathology, Atoh1-En1/2 CKO, where mutant animals have conditional loss of the developmental patterning gene Engrailed 1/2 in rhombic lip-lineage neurons and exhibit a proportional scaling-down of neuron number in hypoplastic lobules of the CRB. We utilized whole-body unrestrained plethysmography …

Genomic Instability And The Oncohistone H3k27m Drive Gliomagenesis In A Murine Model, Lee J. Pribyl

Theses and Dissertations (ETD)

Maintaining genome stability is crucial for human health and it is of particular importance in neural cells during early brain development. Genome maintenance occurs at two broad stages; surveillance during DNA replication and DNA damage repair in differentiating and mature cells. Neural cells are particularly sensitive to DNA strand breaks and defective DNA damage responses can result in detrimental effects on the nervous system, including cancer. Multiple DNA repair pathways play critical roles in preventing DNA damage accumulation in stem and neural progenitor cells. The mechanisms that protect progenitor genomes also suppress DNA mutations that can result in cancer. A …

Fear Learning And The Olfactory Bulb: Neural Correlates Of Behavioral Fear Generalization, Jordan Marie Ross

Theses and Dissertations (ETD)

The exploration of how learning alters neural coding to guide behaviors remains fundamental to neuroscience. At the most basic level, the ability for organisms to flexibly adapt to changing environments and situations is paramount to biological success and often manifests in behavioral responses controlled by neural activity. For example, organisms must modify their behavior to defensive responses in the face of biological threat. Neural circuitry is involved in coordinating an initial defensive behavioral response but must undergo reorganization in order to reliably employ defensive responses in subsequent encounters based on a cue that signals imminent danger. One such form of …

Investigation Of Cell-Type-Specific Effects And Synergistic Interactions Between Genes In Duplication 15q Syndrome, Kevin A. Hope

Theses and Dissertations (ETD)

Duplication 15q syndrome (Dup15q) is a genetic disorder caused by duplications of the 15q11.2-q13.1 region and is characterized by developmental delay, autism spectrum disorder, and treatment resistant epilepsy. Extra copies of the E3 ubiquitin ligase UBE3A and elevated levels of UBE3A expression in neurons are thought to be the primary cause of Dup15q phenotypes. However, animal models overexpressing UBE3A in neurons have not successfully recapitulated all aspects of Dup15q syndrome, especially epilepsy. Here, we used Drosophila melanogaster (fruit flies) to investigate Dup15q syndrome. In Chapter 2 we explored whether Dube3a, the Drosophila homolog of UBE3A, is imprinted in the fly …

Using Genetic Diversity To Understand Susceptibility To Cognitive Decline In Aging And Alzheimer’S Disease, Sarah M. Neuner

Theses and Dissertations (ETD)

An individual's genetic makeup plays an important role in determining susceptibility to cognitive aging and transition to dementia such as Alzheimer's disease (AD). Identifying the specific genetic variants that contribute to cognitive aging and AD may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we turned to genetically diverse mice from the BXD genetic reference panel (GRP) to overcome some of the …

Pathogenicity And Protection Mediated By A Single Tcrβ In Experimental Autoimmune Encephalomyelitis, Tianhua Wu

Theses and Dissertations (ETD)

How the TCR repertoire, together with risk-associated major histocompatibility complex (MHC), imposes susceptibility for autoimmune disease is not fully understood. A small fraction of TCR α or β chains are “public”, and are shared by most individuals.High-throughput sequencing of the mouse TCRβ repertoire during myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmuneencephalomyelitis (EAE) identified a public TCRβ chain, TCRβ1, which was highly shared among individual mice and preferentially deployed during EAE. Retrogenic expression of TCRβ1 resulted in spontaneous early-onset EAE in mice with high penetrance and severity, despite being paired with a diverse endogenous TCRα repertoire. To further study autoimmunity conferred by …

An Interface Of The Taste And Reward Systems In The Brainstem And Its Role In Feeding, Louis Saites

Theses and Dissertations (ETD)

We eat what tastes good. We also eat because it is necessary for our health. In fact, some of the most nutritious foods (e.g., vegetables) are often less appetizing, and the tastiest (e.g., fast food, ice cream) may be the least healthy. Despite the former, we may also have a lower limit of what we accept at which point nutrition becomes irrelevant (e.g., “spinach is just too yucky”). Further, we may eat unhealthily because of overwhelming urges. We investigated the complex interactions of taste and feeding at the neurobiological level using the experiments described.

In one sense, this neurobiology begins …

Pip2 Modulation Of Afterhyperpolarizations In Magnocellular Supraoptic Neurons, Matthew Karl Kirchner

Theses and Dissertations (ETD)

Magnocellular neurosecretory cells (MNCs) are large oxytocin (OT)- and vasopressin (VP)-releasing neurons that secrete these hormones into the circulatory system in response to physiological stimuli. These cells exhibit unique phasic and burst firing patterns to release these peptides into the circulatory system where they primarily control milk ejection and parturition (OT) as well as salt-water balance and vasoconstriction (VP). This firing is underlain by intrinsic ionic mechanisms that shape the duration and frequency of these bursts. One of these mechanisms is the Ca2+-dependent afterhyperpolarization (AHP), which activates during bursts and causes spike frequency adaptation. This afterhyperpolarization has three distinct conductances: …

Habituation And Dishabituation In The Olfactory Bulb: From Neural Responses To Behavior, Mary Cameron Ogg

Theses and Dissertations (ETD)

Habituation and dishabituation modulate the neural resources and behavioral significance allocated to incoming stimuli across the sensory systems. The purpose of the research presented in this dissertation was to characterize these processes in the mouse olfactory bulb (OB) and to determine if OB acetylcholine (ACh) has a role in physiological and behavioral olfactory dishabituation. Calcium imaging was used to determine the timecourse and magnitude of habituation in different parts of the OB during and after a prolonged odor presentation. Widefield imaging of the dendritic, or glomerular, response of OB output cells demonstrated that prolonged odor input habituates glomerular responses during …

The Role Of Hsf1 Protein Regulation On Neurodegeneration, Eunhee Kim

Theses and Dissertations (ETD)

Cellular protein homeostasis is achieved by a delicate network of molecular chaperones and various proteolytic processes such as ubiquitin–proteasome system (UPS) to avoid a build-up of misfolded protein aggregates. The latter is a common denominator of neurodegeneration. Neurons are found to be particularly vulnerable to toxic stress from aggregation-prone proteins such as α-synuclein. Induction of heat-shock proteins (HSPs), such as through activated heat shock transcription factor 1 (HSF1) via Hsp90 inhibition, is being investigated as a therapeutic option for proteinopathic diseases. HSF1 is a master stress-protective transcription factor which activates genes encoding protein chaperones (e.g. iHsp70) and anti-apoptotic proteins. However, …

Dissecting The Physiological Roles Of Ulk1/2 In The Mouse Brain, Bo Wang

Theses and Dissertations (ETD)

Mammalian UNC-51–like kinases 1 and 2 (ULK1 and ULK2), Caenorhabditis elegans UNC-51 and Drosophila melanogaster Atg1 are redundant serine/threonine kinases that regulate flux through the autophagy pathway in response to various types of cellular stress. C. elegans UNC-51 and D. melanogaster Atg1 also promote axonal growth and defasciculation, and disruption of these genes results in defects in axon guidance in invertebrates. Germline Ulk1/2-deficient mice die perinatally. Therefore, we used a conditional-knockout approach to investigate the roles of ULK1/2 in the brain. Mice lacking Ulk1 and Ulk2 in their central nervous systems (CNS) showed defects in axonal pathfinding and defasciculation affecting …

Multipronged Approach To Study Glaucoma-Associated Phenotypes, Sumana Rameshbabu Chintalapudi

Theses and Dissertations (ETD)

Glaucoma refers to a group of conditions characterized by death of RGCs, increase in intraocular pressure is usually a precursor to glaucoma and irreversible optic neuropathy leads to visual impairment and blindness. Recent advances have seen a surge of new ideas and technologies to aid in the early detection, efficacious treatments and neuroprotection. Despite advances we face several challenges in understanding the pathophysiology of glaucoma. One of the many challenges scientists and ophthalmologists are facing is, to better understand IOP, its role in glaucomatous damage and design safer, more predictable IOP-lowering therapies. Another challenge is to find a practical method …

Neuroanatomical Maps And Taste Reactivity To Sweet, Umami, And Bitter Taste In The Pbn Of C57bl/6j Mice, Jennifer Marie Saputra

Theses and Dissertations (ETD)

Humans can distinguish at least five different taste qualities, sour, salty, bitter, sweet, and umami (the savory taste of certain amino acids). In neuroscience research, behavioral testing is used to measure the ability of rodents (including inbred mice) to discriminate between the different taste qualities. Taste reactivity and two-bottle preference are behavioral tests that are utilized to investigate different aspects of taste. These tests involve either voluntary or forced consumption of taste stimuli, respectively. Either test can be used to infer the preference and palatability of the stimulus consumed by an animal.

In order to understand the basis of taste …

Evaluating The Therapeutic Effect Of An Hsp90 Inhibitor In Mouse Models Of Alzheimer’S Disease, Bin Wang

Theses and Dissertations (ETD)

The excessive accumulation of amyloid peptides (Aβ) represents one major pathological hallmark of Alzheimer’s disease (AD), which is most notably characterized by synaptic dysfunction. Strategies targeting heat shock protein 90 (Hsp90) inhibition have been widely investigated in the treatment of cancer for over two decades. Its application in the treatment of neurodegenerative diseases however, has emerged more recently in the last decade. The role of the Hsp90 chaperone in clearing misfolded protein aggregates has been well established (in vitro only), but its function in synaptic activity remains elusive.

In our study, we utilized a widely used Hsp90 inhibitor, 17-AAG …

Repeated Zolpidem Treatment Effects On Sedative Tolerance, Withdrawal, Mrna Levels, And Protein Expression, Brittany T. Wright

Theses and Dissertations (ETD)

Zolpidem and benzodiazepines (BZs) potentiate the inhibitory action of gamma-Aminobutyric acid (GABA) by allosterically binding to GABAA receptors (GABAAR). Prolonged use of GABAAR positive allosteric modulators (PAM) can lead to behavioral tolerance, the diminished response to the same drug dose with repeated use, and withdrawal, a group of symptoms that occur due to abrupt end of drug treatment. Zolpidem is a short-acting, non-BZ GABAAR PAM whose potential for tolerance and withdrawal is unclear. Zolpidem demonstrates sedative efficacy similar to BZs and has become a main treatment of insomnia in lieu of BZs. Zolpidem replaced BZs due to lower incidences of …

Examining The Roles Of Gabaa Receptor Subtypes In Anxiety And Anxiolysis: Focusing On The Basolateral Amygdala, Yudong Gao

Theses and Dissertations (ETD)

The investigation of the differential roles GABA_A receptor (GABA_AR) subtypes play in mediating various behaviors such as fear and anxiety was an intriguing research topic over the past decade. At present, most evidence suggests that benzodiazepine (BZ)-induced anxiolysis is primarily mediated by GABA_ARs containing the α2-subunit (α2-subtype). However, there is conflicting evidence as to whether α1- and α3-subtypes might also be involved in BZ-induced anxiolysis. In an attempt to further discern the role played by different α-subtype GABA_ARs in BZ-induced anxiolysis both systemically and within the basolateral amygdala (BLA), a brain region crucial …

Mild Traumatic Brain Injury With Associated Visual System Dysfunction: Investigating Histopathology, Functional Correlates, And A Novel Therapeutic Immune Modulator, Natalie M. Guley

Theses and Dissertations (ETD)

Background. Traumatic brain injury (TBI) is a significant source of morbidity and mortality worldwide. Injuries associated with moderate to severe TBI can be profound, and have historically overshadowed the significant impact mild TBI (mTBI) can have on the lives of affected individuals. Mild TBI can manifest in a number of different ways, but one of the most significant and often debilitating is its impact on the visual system. In order to further investigate the underlying pathology of mTBI and test potential therapeutics, we developed a mouse model of mTBI induced by blast overpressure. In this model, a 50-60 psi …

Antibodies To Heterogenous Nuclear Ribonucleoprotein A1 Penetrate Neurons Leading To Multiple Downstream Effects Resulting In Neurodegeneration, Joshua Nathan Douglas

Theses and Dissertations (ETD)

Multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system. MS is believed to occur in genetically susceptible individuals due to an unknown environmental stimulus. MS patients produce autoantibodies to heterogenous nuclear ribonuclearprotein A1 (hnRNP A1), an RNA binding protein (RBP) highly expressed in neurons. hnRNP A1 functions in pre-mRNA splicing, mRNA trafficking, and translation. Furthermore, the anti-hnRNP A1 antibodies are specific to a N-terminal region termed ‘M9’ which serves as a nuclear export sequence/nuclear localization sequence (NES/NLS) responsible for nuclear/cytoplasmic transport of the protein. In this manuscript we will provide data revealing that anti-hnRNP A1 …

Effects Of Cocaine Sensitization On Drug Self-Administration, Mesocorticolimbic Sapap Levels, And Prefrontal Ionotropic Glutamate Receptors, Kyle Christopher Summers

Theses and Dissertations (ETD)

Towards the goal of improving the knowledge base of how drugs of abuse function to create addicts and using currently uninvestigated areas of this knowledge base, we focused our research studies the male albino rat, and strived to explain how cocaine sensitization alters particular molecular mechanisms in the mesocorticolimbic system related to glutamate receptors, SAPAPs, and affects drug self-administration. Taking all the previously discussed research studies into consideration, we hypothesized that low-dose cocaine self-administration would yield a significant elevation in drug seeking behavior for psychostimulant sensitized animals. For specific changes at the PSD, we hypothesized that acute cocaine exposure and/or …

Integration Of Atm, Atr, And Dna-Pkcs Signaling Maintains Genome Integrity During Neurogenesis, Vanessa D. Enriquez-Rios

Theses and Dissertations (ETD)

The DNA damage response (DDR) orchestrates a network of cellular processes such as cell cycle progression, DNA repair, and apoptosis when complex DNA lesions arise to maintain genomic integrity. ATM, ATR, and DNA-PKcs (encoded by PRKDC) are related phosphatidylinositol-3-kinase like serine/threonine kinases (PIKK) that collectively regulate the DDR network. Studies have demonstrated these kinases can phosphorylate many of the same substrates, suggesting a significant potential for functional redundancy. However, deficiencies in these kinases have been linked to distinct neural degenerative and developmental disorders, underscoring their unique functions for maintain genomic integrity during nervous system development.

Here we utilized mouse genetic …

Genetic And Chemical Dissection Of Bloodbrain Barrier Development In Zebrafish, Robyn Anne Umans

Theses and Dissertations (ETD)

The blood-brain barrier (BBB) maintains a homeostatic environment as well as prohibits the entrance of xenobiotics into the brain. Because of these qualities, drug delivery is a fundamental challenge for the treatment of many diseases of the central nervous system (CNS). Along with limiting the access of therapeutics into the brain, the BBB is also impaired in CNS pathologies. Understanding the molecular cues that are essential for healthy BBB development and integrity may reveal targets for drug delivery leading to decreased progression or possible treatment of many detrimental CNS diseases. While the central features of the BBB have been accepted, …

Preliminary Study On How Tumor Suppressor Nf2 Inhibits Transcriptional Coactivators Yap/Taz In The Developing Mouse Brain, Yu He

Theses and Dissertations (ETD)

Normal brain development requires precise coordination of neural progenitor proliferation and differentiation, the mechanism of which is not well known. Recently the tumor suppressor neurofibromatosis 2 (Nf2) was shown to regulate the balance of neural progenitor proliferation and differentiation in the developing mouse brain through the Hippo pathway effectors, transcriptional coactivators Yap/Taz. The molecular mechanism of how Nf2 regulates Yap/Taz is not understood. Here I showed that Nf2 regulated the Yap/Taz activity by decreasing the stability of Yap/Taz. The regulation was independent of Yap-S366 phosphorylation, which is required for Yap degradation. I also showed that Nf2 did not regulate Lats1/2 …

Developmental Characterization Of The Choroid Plexus In Sialidosis (Neu1 Deficient) Mice, Danielle Lee Helton

Theses and Dissertations (ETD)

The lysosomal sialidase Neuraminidase-1 (Neu1) initiates the hydrolysis of sialoglycoconjugates by cleaving their terminal sialic acid residues. Neu1 creates a complex with the carboxypeptidase protective protein/cathepsin A (PPCA), which is necessary for its catalytic activation and its transport to the lysosomal compartment. In humans, a primary deficiency of this enzyme leads to a pediatric, catastrophic, neurodegenerative lysosomal storage disorder called sialidosis. Mice deficient in Neu1 exemplify the early-onset severe form of sialidosis. Our laboratory has recently discovered that loss of Neu1 exacerbates the process of lysosomal exocytosis (LyEXO) in various cell types by influencing the sialic acid content of lysosomal …