Neurosciences Commons^™

Acute Kynurenine Challenge Upregulates Activation Of Orexinergic Neurons In The Lateral Hypothalamus, Hayley Nicholson

Senior Theses

Abnormalities in the kynurenic pathway (KP) of tryptophan catabolism are implicated in various neurocognitive disorders, including schizophrenia, bipolar disorder, and Alzheimer’s disease. Elevated levels of the astrocyte-derived metabolite kynurenic acid (KYNA) are found in the postmortem brain of individuals with these illnesses. KYNA is a neuroactive metabolite and acts as an antagonist at glutamatergic N-methyl-D-aspartate (NMDA) and cholinergic α7 nicotinic acetylcholine (α7nACh) receptors. As glutamatergic and cholinergic transmission are critically involved in sleep-dependent plasticity and cognition, KYNA is hypothesized to play a key role in cognitive and sleep disruptions present in these brain disorders. Sleep and cognitive disturbances are pathophysiologically …

New Insights Into The Genetic Etiology Of Alzheimer’S Disease And Related Dementias, Céline Bellenguez, Fahri Küçükali, Iris Jansen, Luca Kleineidam, Sonia Moreno-Grau, Najaf Amin, Adam C. Naj, Rafael Campos-Martin, David W. Fardo, Yuriko Kastumata, Erin L. Abner, Radb, Gr@Ace, Degesco, Eadi, Gerad, Demgene, Finngen, Adgc, Charge

Sanders-Brown Center on Aging Faculty Publications

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly …

Applications And Challenges Of Neural Stem Cell Therapy, John Brewster

Senior Honors Theses

In response to the many neurological disorders that plague humanity, no treatment shows more promise than stem cell therapy. By using these special cells to regrow damaged neurons and combat sources of disease in affected patients, researchers hope to treat neurological disorders of all kinds. While great strides have been made in laboratory settings, the widespread use of stem cells to treat neurological disorders in humans is still a distant goal. Recent advancements have been made in the area of neural stem cell therapy, but complications arise when using this method to treat neurological disorders.

Determining The Genomic Localization And Binding Partners Of Zinc Finger Protein 410, Mariko Locke

Senior Honors Theses

The results of a folate deficiency study affecting cognition in mice suggested the altered genes may be controlled by a transcription factor known as Zinc Finger Protein 410 (Zfp410). Due to a lack of literature on Zfp410’s interacting proteins and DNA-binding location, our study aims to further elucidate the role Zfp410 plays in affecting cognition. A custom antibody was used to determine the Zfp410 isoforms present in mouse and rat brains. Moreover, the antibody was used to determine the binding partners of Zfp410 in the brain and locate specific genomic regions/sequences with which it associates in vivo. These results may …

Epigenetic Pathogenesis Of Neurological Disorders In Utero And Considerations For Genetic Counseling, Lauren Juga

Senior Honors Theses

Epigenetic modifications are a major focus of study in the pathogenesis of many disorders regarding metabolism, aging, neurodevelopment, and neurodegeneration. Epigenetic mechanisms are present throughout life but are especially vital to guiding fetal development. The precise timing of gene activation and deactivation guides stem cell differentiation through each embryonic stage. After exposure to environmental stimuli, gene expression can be altered by transcription factors, resulting in observable phenotypes and even pathology. Here, the epigenetic mechanisms responsible for the pathogenesis of neurodevelopmental and neuropsychiatric disorders are explored in response to environmental perturbations in utero. The present goal is to identify correlations between …

Noninvasive In Vivo Optoacoustic Imaging Of Alcohol Use Disorder Using A Mouse Model Of Alcohol Use Disorder, Augustine Meombe Mbolle

USF Tampa Graduate Theses and Dissertations

This research has two parts. The first part focuses on the use of photoacoustic imaging (PAI) to study alcohol-induced effects in the cerebral vasculature of selectively bred alcohol-preferring mice. Part two extends the application of PAI by developing a novel Photoacoustic imaging guided system for repetitive low intensity focused ultrasound (PAI-LIFU) stimulation treatment for alcohol use disorder in crossed high alcohol preferring (cHAP) mice.

Photoacoustic imaging is an emerging hybrid non-invasive optical imaging modality which relies on optical absorption contrast to visualize deep tissue structures and function. It combines the high contrast associated with pure optical imaging and the high …

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 …

Disrupting The Myc-Tfeb Circuit Impairs Amino Acid Homeostasis And Provokes Metabolic Anergy, Mario R Fernandez, Franz X Schaub, Chunying Yang, Weimin Li, Seongseok Yun, Stephanie K Schaub, Frank C Dorsey, Min Liu, Meredith A Steeves, Andrea Ballabio, Alexandar Tzankov, Zhihua Chen, John M Koomen, Anders E Berglund, John L Cleveland

Duncan NRI Faculty and Staff Publications

MYC family oncoproteins are regulators of metabolic reprogramming that sustains cancer cell anabolism. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Here we report that the autophagy pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eμ-Myc transgenic mice, and in human MYC-driven Burkitt lymphoma. Myc suppresses autophagy by antagonizing the expression and function of transcription factor EB (TFEB), a master regulator of autophagy. Mechanisms that sustained AA pools in MYC-expressing B cells include coordinated induction of the proteasome and increases in AA …

Neuroscience Directed Study/Special Topics Neu 391, Joanna Burkhardt

Library Impact Statements

No abstract provided.

Small Heat Shock Protein 22 Preserves Neuronal Function In A Murine Model Of Tauopathy, Santiago Rodriguez Ospina

USF Tampa Graduate Theses and Dissertations

Proteinopathies is a family of diseases associated with the pathological aggregation of protein. There are a multitude of proteinopathies, like tauopathy and synucleinopathy that contribute to neurodegenerative diseases like Alzheimer’s disease (AD), Creutzfeldt-Jakob, Pick’s disease, Frontotemporal dementia, and Parkinson’s disease (PD). Currently, one focus of research in the field is mitigating aggregation-prone proteins contributing to disease state. One method of targeting aggregation is the use of chaperones. Chaperones are molecular machinery that help maintain homeostasis in the cells, through various roles and mechanisms, one of those methods is to regulate protein aggregation. Chaperones can achieve this by affecting protein-protein interactions, …

Dissociation Of Tau Pathology And Neuronal Hypometabolism Within The Atn Framework Of Alzheimer’S Disease, Michael Tran Duong, Sandhitsu R. Das, Xueying Lyu, Long Xie, Hayley Richardson, Sharon X. Xie, Paul A. Yushkevich, Alzheimer’S Disease Neuroimaging Initiative, David A. Wolk, Ilya M. Nasrallah, Charles D. Smith, Gregory A. Jicha, Peter A. Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Michael W. Weiner, Paul Aisen, Ronald C. Petersen, Clifford R. Jack Jr.

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) is defined by amyloid (A) and tau (T) pathologies, with T better correlated to neurodegeneration (N). However, T and N have complex regional relationships in part related to non-AD factors that influence N. With machine learning, we assessed heterogeneity in ¹⁸F-flortaucipir vs. ¹⁸F-fluorodeoxyglucose positron emission tomography as markers of T and neuronal hypometabolism (N_M) in 289 symptomatic patients from the Alzheimer’s Disease Neuroimaging Initiative. We identified six T/N_M clusters with differing limbic and cortical patterns. The canonical group was defined as the T/N_M pattern with lowest regression residuals. Groups resilient to …

Mutant Lrrk2 In Lymphocytes Regulates Neurodegeneration Via Il-6 In An Inflammatory Model Of Parkinson's Disease, Elena Kozina, Matthew D. Byrne, Richard Jay Smeyne

Department of Neuroscience Faculty Papers

Mutations in a number of genes contribute to development of Parkinson's disease (PD), including several within the LRRK2 gene. However, little is known about the signals that underlie LRRK2-mediated neuronal loss. One clue resides in the finding that the neurodegenerative cascades emanate from signals arising from the peripheral immune system. Here, using two chimeric mouse models, we demonstrate that: 1) the replacement of mutant LRRK2 with wt form of the protein in T- and B-lymphocytes diminishes LPS-mediated inflammation and rescues the SNpc DA neuron loss in the mutant LRRK2 brain; 2) the presence of G2019S or R1441G LRRK2 mutation in …

Cleavage Stimulating Factor 64 Depletion Mitigates Cardiac Fibrosis Through Alternative Polyadenylation, Rahul Neupane, Keith Youker, Hari Krishna Yalamanchili, Katarzyna A Cieslik, Harry Karmouty-Quintana, Ashrith Guha, Rajarajan A Thandavarayan

Duncan NRI Faculty and Staff Publications

Alternative polyadenylation (APA) regulates gene expression by cleavage and addition of poly(A) sequence at different polyadenylation sites (PAS) in 3'UTR, thus, generating transcript isoforms with different lengths. Cleavage stimulating factor 64 (CstF64) is an APA regulator which plays a role in PAS selection and determines the length of 3'UTR. CstF64 favors the use of proximal PAS, resulting in 3'UTR shortening, which enhances the protein expression by increasing the stability of the target genes. The aim of this study is to investigate the role of CstF64 in cardiac fibrosis, a key event leading to heart failure (HF). We determined the expression …

Drosophila Functional Screening Of De Novo Variants In Autism Uncovers Damaging Variants And Facilitates Discovery Of Rare Neurodevelopmental Diseases, Paul C Marcogliese, Samantha L Deal, Jonathan Andrews, J Michael Harnish, V Hemanjani Bhavana, Hillary K Graves, Sharayu Jangam, Xi Luo, Ning Liu, Danqing Bei, Yu-Hsin Chao, Brooke Hull, Pei-Tseng Lee, Hongling Pan, Pradnya Bhadane, Mei-Chu Huang, Colleen M Longley, Hsiao-Tuan Chao, Hyung-Lok Chung, Nele A Haelterman, Oguz Kanca, Sathiya N Manivannan, Linda Z Rossetti, Ryan J German, Amanda Gerard, Eva Maria Christina Schwaibold, Sarah Fehr, Renzo Guerrini, Annalisa Vetro, Eleina England, Chaya N Murali, Tahsin Stefan Barakat, Marieke F Van Dooren, Martina Wilke, Marjon Van Slegtenhorst, Gaetan Lesca, Isabelle Sabatier, Nicolas Chatron, Catherine A Brownstein, Jill A Madden, Pankaj B Agrawal, Boris Keren, Thomas Courtin, Laurence Perrin, Melanie Brugger, Timo Roser, Steffen Leiz, Frederic Tran Mau-Them, Julian Delanne, Elena Sukarova-Angelovska, Slavica Trajkova, Erik Rosenhahn, Vincent Strehlow, Konrad Platzer, Roberto Keller, Lisa Pavinato, Alfredo Brusco, Jill A Rosenfeld, Ronit Marom, Michael F Wangler, Shinya Yamamoto

Duncan NRI Faculty and Staff Publications

Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novo mutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD pathogenesis, which DNMs cause functional consequences in vivo remains unclear. We functionally test the effects of ASD missense DNMs using Drosophila through "humanization" rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed …

Impact Of Arginine Metabolism And Sensing In Mouse Models Of Alzheimer’S Disease, Chao Ma

USF Tampa Graduate Theses and Dissertations

Alzheimer’s disease (AD) remains the most common neurodegenerative disease in the central nervous system (CNS), with amyloidosis and tauopathy as their two main hallmarks. Typical AD pathologies include cerebral plaques deposited by amyloid-β, neurofibrillary tangles aggregated by tau, and neuroinflammation caused by activated brain myeloid cells. A critical theme is centered on impaired brain metabolism. Emerging evidence showed that impaired arginine metabolism was a novel biomarker pathway for AD. The manipulation of arginine metabolism by a critical enzyme arginase 1 (ARG1) in neurons indicated therapeutic benefits in alleviating tau pathology. Balanced cellular proteostasis was governed by the mechanistic target of …

Investigations Into The Improvement Of Angelman Syndrome Therapeutics, Austin W. Nenninger

USF Tampa Graduate Theses and Dissertations

Angelman syndrome (AS) is a rare genetic neurodevelopmental disease caused by interruption of the function of the ubiquitin ligase UBE3A gene. Patients experience an early life onset of symptoms which include pronounced intellectual disability, drastic speech impairmentor inability to speak, severe movement disorders, seizures, aggression, disruptive sleep impairment, and unusual personality traits. Estimates of prevalence show that approximately 1:15000 births are affected.

The disease is severe, and the burden can be devastating to the patients and the caregivers that they require for the duration of their relatively normal lifespan. Current treatments for the disease are lacking. Many are expensive and …

Astrocyte-Secreted Chordin-Like 1 Regulates Spine Density After Ischemic Injury, Elena Blanco-Suarez, Nicola J Allen

Department of Neuroscience Faculty Papers

Ischemic injury occurs when the brain is deprived of blood flow, preventing cells from receiving essential nutrients. The injury core is the brain region directly deprived and is surrounded by the peri-infarct area, the region with recovery potential. In the peri-infarct area neurons undergo acute loss of dendritic spines, which modifies synaptic plasticity and determines neuronal survival. Astrocytes can be protective or detrimental to the ischemic injury response depending on the specific stage, yet we lack clear understanding of the underlying mechanisms. Chordin-like 1 (Chrdl1) is an astrocyte-secreted protein that promotes synaptic maturation and limits experience-dependent plasticity in the mouse …

Neural Activity During Story Listening Is Synchronized Across Individuals Despite Acoustic Masking., Vanessa C Irsik, Ingrid Johnsrude, Björn Herrmann

Brain and Mind Institute Researchers' Publications

Older people with hearing problems often experience difficulties understanding speech in the presence of background sound. As a result, they may disengage in social situations, which has been associated with negative psychosocial health outcomes. Measuring listening (dis)engagement during challenging listening situations has received little attention thus far. We recruit young, normal-hearing human adults (both sexes) and investigate how speech intelligibility and engagement during naturalistic story listening is affected by the level of acoustic masking (12-talker babble) at different signal-to-noise ratios (SNRs). In Experiment 1, we observed that word-report scores were above 80% for all but the lowest SNR (-3 dB …

Rotenone Induces Regionally Distinct Α-Synuclein Protein Aggregation And Activation Of Glia Prior To Loss Of Dopaminergic Neurons In C57bl/6 Mice, Savannah M Rocha, Collin M Bantle, Tawfik Aboellail, Debotri Chatterjee, Richard Jay Smeyne, Ronald B Tjalkens

Department of Neuroscience Faculty Papers

Rotenone is a naturally occurring insecticide that inhibits mitochondrial complex I and leads to neurochemical and neuropathological deficits closely resembling those in Parkinson's disease (PD). Deficits include loss of dopaminergic neurons (DAn) in the substantia nigra pars compacta (SNpc), decreased dopamine levels and aggregation of misfolded alpha-synuclein (p129). In rat models of rotenone-induced parkinsonism, the progression of neuronal injury has been associated with activation of microglia and astrocytes. However, these neuroinflammatory changes have been challenging to study in mice, in part because the systemic rotenone exposure model utilized in rats is more toxic to mice. To establish a reproducible murine …