Neurosciences Commons^™

Reduction Of Mutant Atxn1 Rescues Premature Death In A Conditional Sca1 Mouse Model, James P Orengo, Larissa Nitschke, Meike E Van Der Heijden, Nicholas A Ciaburri, Harry T Orr, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disorder. As disease progresses, motor neurons are affected, and their dysfunction contributes toward the inability to maintain proper respiratory function, a major driving force for premature death in SCA1. To investigate the isolated role of motor neurons in SCA1, we created a conditional SCA1 (cSCA1) mouse model. This model suppresses expression of the pathogenic SCA1 allele with a floxed stop cassette. cSCA1 mice crossed to a ubiquitous Cre line recapitulate all the major features of the original SCA1 mouse model; however, they took twice as long to develop. We found that …

A Combined Conduit-Bioactive Hydrogel Approach For Regeneration Of Transected Sciatic Nerves, Cheuk Sun Edwin Lai, Viridiana Leyva-Aranda, Victoria H Kong, Tania L Lopez-Silva, Adam C Farsheed, Carlo D Cristobal, Joseph W R Swain, Hyun Kyoung Lee, Jeffrey D Hartgerink

Duncan NRI Faculty and Staff Publications

Transected peripheral nerve injury (PNI) affects the quality of life of patients, which leads to socioeconomic burden. Despite the existence of autografts and commercially available nerve guidance conduits (NGCs), the complexity of peripheral nerve regeneration requires further research in bioengineered NGCs to improve surgical outcomes. In this work, we introduce multidomain peptide (MDP) hydrogels, as intraluminal fillers, into electrospun poly(ε-caprolactone) (PCL) conduits to bridge 10 mm rat sciatic nerve defects. The efficacy of treatment groups was evaluated by electromyography and gait analysis to determine their electrical and motor recovery. We then studied the samples' histomorphometry with immunofluorescence staining and automatic …

Clinical Diagnosis Of Metabolic Disorders Using Untargeted Metabolomic Profiling And Disease-Specific Networks Learned From Profiling Data, Lillian R Thistlethwaite, Xiqi Li, Lindsay C Burrage, Kevin Riehle, Joseph G Hacia, Nancy Braverman, Michael F Wangler, Marcus J Miller, Sarah H Elsea, Aleksandar Milosavljevic

Duncan NRI Faculty and Staff Publications

Untargeted metabolomics is a global molecular profiling technology that can be used to screen for inborn errors of metabolism (IEMs). Metabolite perturbations are evaluated based on current knowledge of specific metabolic pathway deficiencies, a manual diagnostic process that is qualitative, has limited scalability, and is not equipped to learn from accumulating clinical data. Our purpose was to improve upon manual diagnosis of IEMs in the clinic by developing novel computational methods for analyzing untargeted metabolomics data. We employed CTD, an automated computational diagnostic method that "connects the dots" between metabolite perturbations observed in individual metabolomics profiling data and modules identified …

The Effects Of Paclitaxel On Cellular Migration And The Cytoskeleton, Ashley Salguero-Gonzalez

Thinking Matters Symposium

In a clinical setting, some patients are exposed to an anti-cancer chemotherapy agent, paclitaxel. Cancerous cells undergo rapid, continuous cell division without control. Chemotherapy treatments try to slow and stop the uncontrollable cell division cycles and eliminate cancerous cells in the process. Paclitaxel serves as a treatment for some types of cancers, including lung, melanoma, bladder, and esophageal. Because it targets the cytoskeleton, paclitaxel can also influence cell migration. This project utilizes a cellular migration assay and an immunohistochemistry assay to analyze the effects of paclitaxel on the movement of cells and on the cytoskeleton of neuroglia rat cells with …

Impact Of Interleukin-34 On The Promotion Of Bone Osteolysis And Neuroinflammation In Experimental Models Of Alzheimer’S Disease, Anny Ho

All HCAS Student Capstones, Theses, and Dissertations

Alzheimer’s disease (AD) is a growing health concern and is the most common type of dementia worldwide. Emerging evidence indicates that aggregated amyloid-beta (Aβ) peptides, one of the hallmark features of AD neuropathology, can increase RANKL-mediated osteoclast activity leading to the prevalence and severity of inflammatory osteolysis, e.g., osteoporosis and periodontal bone loss. Conversely, osteolytic lesions are associated with increased risk of dementia diagnosis indicating that there is a direct link between dementia and inflammatory osteolysis. It was demonstrated that the neuronal cells primarily produce interleukin-34 (IL-34) and microglia, macrophages, and osteoclast precursors express colony-stimulating factor 1 receptor (CSF-1R), a …

Dynamics Of Huntingtin Protein Interactions In The Striatum Identifies Candidate Modifiers Of Huntington Disease, Todd M Greco, Christopher Secker, Eduardo Silva Ramos, Joel D Federspiel, Jeh-Ping Liu, Alma M Perez, Ismael Al-Ramahi, Jeffrey P Cantle, Jeffrey B Carroll, Juan Botas, Scott O Zeitlin, Erich E Wanker, Ileana M Cristea

Duncan NRI Faculty and Staff Publications

Huntington’s disease (HD) is a monogenic neurodegenerative disorder with one causative gene, huntingtin (HTT). Yet, HD pathobiology is multifactorial, suggesting that cellular factors influence disease progression. Here, we define HTT protein-protein interactions (PPIs) perturbed by the mutant protein with expanded polyglutamine in the mouse striatum, a brain region with selective HD vulnerability. Using metabolically labeled tissues and immunoaffinity purification-mass spectrometry, we establish that polyglutamine-dependent modulation of HTT PPI abundances and relative stability starts at an early stage of pathogenesis in a Q140 HD mouse model. We identify direct and indirect PPIs that are also genetic disease modifiers using in-cell two-hybrid …

Stroke Network Of Wisconsin (Snow) Scale Predicts Large Vessel Occlusion Stroke In The Prehospital Setting, Kessarin Panichpisal, Sarah Erpenbeck, Paul Vilar, Reji P. Babygirija, Maharaj Singh, M. Riccardo Colella, Richard A. Rovin

Journal of Patient-Centered Research and Reviews

Purpose: In previous trials, the Stroke Network of Wisconsin (SNOW) scale accurately predicted large vessel occlusion (LVO) stroke in the hospital setting. This study evaluated SNOW scale performance in the prehospital setting and its ability to predict LVO or distal medium vessel occlusion (DMVO) in patients suspected of having acute ischemic stroke (AIS), a scenario in which transport time to an endovascular treatment-capable facility (ECSC) is critical.

Methods: All potential AIS patients with last-known-well time of ≤ 24 hours were assessed by Milwaukee County Emergency Medical Services for LVO using SNOW. Patients with a positive SNOW score were transferred to …

Associations Between Residential Greenspace, Socioeconomic Status, And Stroke: A Matched Case-Control Study, Heloise Cheruvalath, Jennifer Homa, Maharaj Singh, Paul Vilar, Amin Kassam, Richard A. Rovin

Journal of Patient-Centered Research and Reviews

Purpose: Studies have shown increased residential greenspace is associated with improved outcome following stroke. This study sought to determine if residential greenspace is an independent stroke risk factor.

Methods: A retrospective 1:4 matched case-control study involving 1174 stroke and 4696 control patients over a 3-year period from Milwaukee County, Wisconsin, was conducted. Greenspace was determined using normalized difference vegetation index (NDVI) for a 250-meter radius surrounding a subject’s residence. The area deprivation index (ADI) for the census block tract of a subject’s residence was obtained from the Neighborhood Atlas® (University of Wisconsin School of Medicine and Public Health). …

Actl6a Coordinates Axonal Caliber Recognition And Myelination In The Peripheral Nerve, Hye-Jin Park, Eric Tsai, Dennis Huang, Michael Weaver, Luciana Frick, Ace Alcantara, John J. Moran, Julia Patzig, Carmen V. Melendez-Vasquez, Gerald R. Crabtree, M.L. Feltri, John Svaren, Patricia Casaccia

Advanced Science Research Center

Cells elaborate transcriptional programs in response to external signals. In the peripheral nerves, Schwann cells (SC) sort axons of given caliber and start the process of wrapping their membrane around them. We identify Actin-like protein 6a (ACTL6a), part of SWI/SNF chromatin remodeling complex, as critical for the integration of axonal caliber recognition with the transcriptional program of myelination. Nuclear levels of ACTL6A in SC are increased by contact with large caliber axons or nanofibers, and result in the eviction of repressive histone marks to facilitate myelination. Without Actl6a the SC are unable to coordinate caliber recognition and myelin production. Peripheral …

Acute Oxygen-Sensing Via Mitochondria-Generated Temperature Transients In Rat Carotid Body Type I Cells, Ryan J. Rakoczy, Clay M. Schiebrel, Christopher N. Wyatt

Neuroscience, Cell Biology & Physiology Faculty Publications

The Carotid Bodies (CB) are peripheral chemoreceptors that detect changes in arterial oxygenation and, via afferent inputs to the brainstem, correct the pattern of breathing to restore blood gas homeostasis. Herein, preliminary evidence is presented supporting a novel oxygen-sensing hypothesis which suggests CB Type I cell “hypoxic signaling” may in part be mediated by mitochondria-generated thermal transients in TASK-channel-containing microdomains. Distances were measured between antibody-labeled mitochondria and TASK-potassium channels in primary rat CB Type I cells. Sub-micron distance measurements (TASK-1: 0.33 ± 0.04 µm, n = 47 vs TASK-3: 0.32 ± 0.03 µm, n = …

Association Between Concussions And Suicidality In High School Students In The United States, Grant L. Iverson, Justin E. Karr

Sanders-Brown Center on Aging Faculty Publications

Importance: Prior research has shown a statistically significant association between sustaining a concussion and suicidality in adolescents, but this prior research controlled for relatively few variables predictive of suicidality.

Objective: To examine whether sustaining a concussion remained a significant predictor of suicidality after controlling for relevant covariates (e.g., sexual abuse/assault, bullying, substance use, depression), hypothesizing that the relationship between concussion and suicidality would become non-significant after controlling for these variables.

Design: This study involved secondary data analysis of the 2019 Youth Risk Behavior Surveillance (YRBS) System, a national cross-sectional study of adolescents. Analyses were stratified by gender. …

Manifestations Of Alzheimer’S Disease Genetic Risk In The Blood Are Evident In A Multiomic Analysis In Healthy Adults Aged 18 To 90, Laura Heath, John C. Earls, Andrew T. Magis, Sergey A. Kornilov, Jennifer C. Lovejoy, Cory C. Funk, Noa Rappaport, Benjamin A. Logsdon, Lara M. Mangravite, Brian W. Kunkle, Eden R. Martin, Adam C. Naj, Nilüfer Ertekin-Taner, Todd E. Golde, Leroy Hood, Nathan D. Price, Erin Abner, David W. Fardo, Linda J. Van Eldik, Alzheimer’S Disease Genetics Consortium

Sanders-Brown Center on Aging Faculty Publications

Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical …

Loss-Of-Function Variants In Tiam1 Are Associated With Developmental Delay, Intellectual Disability, And Seizures, Shenzhao Lu, Rebecca Hernan, Paul C Marcogliese, Yan Huang, Tracy S Gertler, Meltem Akcaboy, Shiyong Liu, Hyung-Lok Chung, Xueyang Pan, Xiaoqin Sun, Melahat Melek Oguz, Ulkühan Oztoprak, Jeroen H F De Baaij, Jelena Ivanisevic, Erin Mcginnis, Maria J Guillen Sacoto, Wendy K Chung, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with bi-allelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay, and seizures. Bioinformatic analyses demonstrate that these variants are rare and likely pathogenic. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS) and is mainly expressed in a subset of neurons, but not in …

A Mouse Model With Widespread Expression Of The C9orf72-Linked Glycine-Arginine Dipeptide Displays Non-Lethal Als/Ftd-Like Phenotypes, Brandie Morris Verdone, Maria Elena Cicardi, Xinmei Wen, Sindhu Sriramoji, Katelyn Russell, Shashirekha S Markandaiah, Brigid K Jensen, Karthik Krishnamurthy, Aaron R. Haeusler, Piera Pasinelli, Davide Trotti

Department of Neuroscience Faculty Papers

Translation of the hexanucleotide G4C2 expansion associated with C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) produces five different dipeptide repeat protein (DPR) species that can confer toxicity. There is yet much to learn about the contribution of a single DPR to disease pathogenesis. We show here that a short repeat length is sufficient for the DPR poly-GR to confer neurotoxicity in vitro, a phenomenon previously unobserved. This toxicity is also reported in vivo in our novel knock-in mouse model characterized by widespread central nervous system (CNS) expression of the short-length poly-GR. We observe sex-specific chronic ALS/FTD-like phenotypes in these …

Patterns Of Amygdala Region Pathology In Late-Nc: Subtypes That Differ With Regard To Tdp-43 Histopathology, Genetic Risk Factors, And Comorbid Pathologies, Matthew D. Cykowski, Anithachristy S. Arumanayagam, Suzanne Z. Powell, Andreana L. Rivera, Erin L. Abner, Gustavo C. Roman, Joseph C. Masdeu, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology is a hallmark of limbic-predominant agerelated TDP-43 encephalopathy (LATE). The amygdala is afected early in the evolution of LATE neuropathologic change (LATE-NC), and heterogeneity of LATE-NC in amygdala has previously been observed. However, much remains to be learned about how LATE-NC originates and progresses in the brain. To address this, we assessed TDP-43 and other pathologies in the amygdala region of 184 autopsied subjects (median age=85 years), blinded to clinical diagnoses, other neuropathologic diagnoses, and risk genotype information. As previously described, LATE-NC was associated with older age at death, cognitive impairment, …

Spata7 Is Required For Maintenance Of The Retinal Connecting Cilium, Jiaxiong Lu, Kaitlyn Xiong, Xinye Qian, Jongsu Choi, Yoon-Kyung Shim, Jacob Burnett, Graeme Mardon, Rui Chen

Faculty, Staff and Students Publications

SPATA7, an early onset LCA3 retinal disease gene, encodes a putative scaffold protein that is essential for the proper assembly of the connecting cilium (CC) complex in photoreceptors. Previous studies have shown that SPATA7 interacts with other photoreceptor-specific ciliary proteins, such as RPGR and RPGRIP1, and maintains the integrity of CC integrity. However, although it is known that Spata7 is required for early formation of the CC, it is unclear if Spata7 is also required for the maintenance of the CC. To investigate Spata7 function in the retina at the adult stage, loss of function was induced in the …

Targeting Notch3 With Crispr-Cas9 Technology In Zebrafish Retinal Degeneration Models, Emily Januck

Celebration of Scholarship 2022

Teleost fish such as zebrafish (Danio rerio) have shown the ability to regenerate damaged photoreceptors due to the robust activity of Müller glia [1]. Interestingly, the Müller glia in retinal disease model zebrafish such as bbs2, cep290, and eys do not respond like those in normal zebrafish, making these genotypes a good model to study treatment options in humans [2, 3, 4]. The Notch signaling pathway is a highly conserved cell signaling pathway in many organisms that plays a role in determining cell fates in developmental processes [5]. Specifically, the notch3 gene has been studied and shown to have effects …

Sex Differences In Hippocampal O-Glcnacylation Of The Adult Mouse Brain, Makenzie Johnson

Selected Honors Theses

The hippocampus is a structure in the brain crucial for learning and memory. This occurs by synaptic remodeling known as long term potentiation and long term depression. Modifications of proteins in the hippocampus can affect its function. One of these modifications is the addition of O-linked β-N-acetylglucosamine, also known as O-GlcNAc. This is a sugar produced from glucose by the hexosamine biosynthetic pathway that is reversibly added onto serine and threonine residues of proteins by O-GlcNAc Transferase, or OGT. It is reversibly removed from these residues by O-GlcNAcAse, or OGA. This modification has been implicated in diabetes, cardiac dysfunction, and …

An Unfinished Melody: Mental Illness, Worship Music, And The Tension Of The Pentecostal “Now” And “Not Yet, Brianna Turbeville

Masters of Theological Studies

According to the National Institute of Mental Health, it is estimated that nearly 20% of adults within the United States suffer from some form of mental illness.1 With roughly one-fifth, if not more, of the entire U.S. population facing a daily internal battle of some sort, this is an issue that is certainly elemental to the overarching purpose of the Church as an agent of reconciliation of creation with Creator. A prevalent problem requires prevalent solutions. What is something even more pervasive in every culture than mental health? Music. Melodies and lyrics are native to virtually every individual on earth. …

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 …