Neurosciences Commons^™

Restoration Of Sfrp3 Preserves The Neural Stem Cell Pool And Spatial Discrimination Ability In A Mouse Model Of Alzheimer's Disease, Chia-Hsuan Fu, Jin Park, Umberto Tosi, Francisco A Blanco, Manuel Silva-Pérez, Kavitha Muralidharan, Jason C You, Minjung Lee, Gabriel S Stephens, Xiaohong Zhang, Yi Zheng, Helen Scharfman, Kimberley F Tolias, Jeannie Chin

Faculty, Staff and Students Publications

Individuals with Alzheimer's disease (AD) have an increased incidence of seizures, which worsen cognitive decline. Using a transgenic mouse model of AD neuropathology that exhibits spontaneous seizures, we previously found that seizure activity stimulates and accelerates depletion of the hippocampal neural stem cell (NSC) pool, which was associated with deficits in neurogenesis-dependent spatial discrimination. However, the precise molecular mechanisms that drive seizure-induced activation and depletion of NSCs are unclear. Here, using mice of both sexes, we performed RNA-sequencing on the hippocampal dentate gyrus and identified differentially expressed regulators of neurogenesis in the Wnt signaling pathway that regulates many aspects of …

The Perspectives And Experiences Of Prospective Parents Declining Diagnostic Prenatal Genome Sequencing In Continuing Pregnancies With Fetal Structural Anomalies, Lisa S Weingarten, Allison Rosenbaum, Jessica De Voest, Stephanie Galloway, Jessica L Giordano, Samantha Stover, Lauren E Westerfield, Grant Bonesteele, Kelly L Gilmore, Leandra Tolusso, Beatrix Wong, A Theresa Wittman, Daniel T Swarr, Nancy Leslie, Anthony Johnson, Ignatia B Van Den Veyver, Neeta L Vora, Rebecca G Clifton, Aaron B Caughey, Ronald J Wapner, Wendy K Chung

Duncan NRI Faculty and Staff Publications

Objective: This study evaluates an understudied perspective: the experiences of prospective parents who decline prenatal genome sequencing (pGS) for continuing pregnancies with fetal structural anomalies.

Method: We recruited a total cohort of 300 parents of 150 pregnancies who declined pGS, including 33 individuals who underwent an invasive procedure. These parents were invited to participate in a semi-structured interview between 1 and 15 months post-partum. We used Thematic Analysis to code and analyze interviews.

Results: We interviewed 22 parents of 16 pregnancies. Reasons for declining testing included risks of invasive procedures (n = 19, 86%), lack of prenatally actionable findings (n …

A Distinct Pp2a Subunit Regulates Local Protein Phosphorylation At The Axon Initial Segment, Andrew P Anderson, Sanghyun Kim, Allison J Melton, Xiaoyun Ding, Wei Zhang, Alexander B Saltzman, Anna Malovannaya, Matthew N Rasband, Yudong Gao

Faculty, Staff and Students Publications

Protein phosphorylation plays a crucial role in regulating the cytoskeletal and membrane proteins at the axon initial segment (AIS). However, our knowledge of AIS-specific kinases and phosphatases is very limited. Here, we report the identification of a protein phosphatase 2A (PP2A) B55 regulatory subunit enriched at the AIS in mice: Ppp2r2c. Our results demonstrate that PP2A-B55 subunits exhibit substantial heterogeneity in their subcellular localization and function. Notably, the Ppp2r2c subunit is selectively concentrated at the AIS, and this enrichment is driven by its unique structure. Utilizing a microelectrode array system (MEA), we show that Ppp2r2c modulates neuronal activity during in …

Activation Of Pro-Regenerative Gene Programs In The Mature Central Nervous System, Elizabeth Carlisle Batsel

Dissertations (1934 -)

Spinal cord injury (SCI) affects millions of people worldwide. Damage to the spinal cord disrupts the long-distance axon tracts of central nervous system (CNS) neurons. These axons fail to regenerate, leading to permanent dysfunction. Past work has shown that CNS neurons lose the capacity to elongate their axons as they mature. Conversely, after injury, embryonic and peripheral nervous system (PNS) neurons can elongate axons towards target cells, driven by the growth cone at the growing tip of the axon. Previous research has identified transcription factor (TF) families, such as the SoxC family, that contribute to embryonic and peripheral neurons’ high …

Targeting Tet3 Suppresses Group 3 Medulloblastoma Stemness And Progression Via Impairing Hypomethylation Of Otx2 Super-Enhancer, Xuan Chen, Ziwei Wang, Yan Song, Yu Su, Yahui Zhao, Jiankang Li, Wei Wang, Jiao Zhang, Craig Daniels, Xiaochong Wu, Olivier Saulnier, Yanan Wang, Fei Liu, Kaiwen Deng, Dongming Han, Zijia Liu, Meiyu Li, Liam D Hendrikse, Alexandra Rasnitsyn, Evan Y Wang, Dongyang Wang, Zhaoyang Feng, Yanong Li, Zitong Zhao, Hongyu Yuan, Youliang Sun, Yifei Jiang, Yanfeng Shi, Tao Yang, Xueling Qi, Yong Hou, Chunde Li, Yong-Qiang Liu, Yu Tian, Shuaicheng Li, Xiaoguang Qiu, Michael D Taylor, Guo Liang Li, Tao Jiang, Hailong Liu

Faculty, Staff and Students Publications

Medulloblastoma (MB), particularly Group_3 (G3-MB), remains the most aggressive subgroup due to strong stemness and therapeutic resistance. Through genome-wide DNA methylation and transcriptomic analysis of human MB samples, we identify enhancer hypomethylation as a key feature sustaining G3-MB stemness and tumor progression. Notably, hypomethylation of the Otx2 super-enhancer (SE) is a prognostic marker and potential therapeutic target for G3-MB patients. We demonstrate that disrupting Otx2 SE activity effectively reduces tumor growth in vivo, highlighting its critical role in G3-MB maintenance. TET3, recruited by OTX2, demethylates the Otx2 SE, promoting chromatin opening and sustaining tumor proliferation and stemness. To translate these …

High Test-Retest Reliability Of Nucleus Accumbens Activity During Reward Anticipation, Nathaniel Bouton

Graduate Theses and Dissertations

Recent research has questioned the reliability of Functional Magnetic Resonance Imaging (FMRI). The findings suggest poor test-retest reliability of FMRI measures across brain areas and tasks, and specifically in subcortical brain areas during reward-related tasks. Further, data from the Adolescent Brain Cognitive Development (ABCD) study showed low reliability and low stability of the fitted coefficients from whole-brain regression analyses of the Monetary Incentive Delay (MID) task. However, optimizing methods might improve reliability, for example: (1) acquiring single-band rather than multi-band FMRI sequences, (2) extracting raw activity rather than fitted coefficients, and (3) honing analyses to target brain areas during specific …

Capsinoids, Non-Pungent Trpv1 Agonists, Induce A Mild Hypothermia That Provides Short- And Long-Term Neuroprotection After Ischemic Stroke, Alexander Andersohn, Alexander Andersohn

Dissertations and Theses (Open Access)

Therapeutic hypothermia (TH) has demonstrated neuroprotection in instances of cardiac arrest and neonatal hypoxia/ischemia but faces different challenges in application to stroke due to the activation of cold defense mechanisms in conscious patients. This dissertation examines the efficacy and specificity of capsinoids (a purified mixture of capsiate and dihydrocapsiate) to induce a sustained mild hypothermia in conscious mice that is neuroprotective after stroke. Capsinoids function as TRPV1 agonists. However, unlike capsaicin, capsinoids are vulnerable to esterase-mediated breakdown, thus significantly restricting their action to the site of delivery. We showed that capsinoids delivered intraperitoneally (IP) to mice induced a TRPV1-dependent drop …

Improved Model For Neurodegeneration In C. Elegans, Jean-Pierre Arditi

Graduate Theses and Dissertations (2019 - present)

During Alzheimer's disease (AD), insoluble amyloid beta (AP) peptides accumulate to form extracellular aggregates (plaques). The direct cause of neuronal dysfunction observed in AD has been broadly investigated. The amyloid hypothesis states that AP plaques are neurotoxic, but recent studies support the AP oligomer hypothesis, which states that intracellular AP (iAP) is neurotoxic. To test this hypothesis, I used CRISPR-Cas9 gene editing to generate two transgenic Caenorhabditis elegans (C. elegans) strains. I generated a strain (RSLl 11) using the rab-3 promoter to co-express GFP in neurons, which showed no gross behavioral changes but had a 50% reduced egglaying rate. RSLl …

How Patients With Amyotrophic Lateral Sclerosis Perceive Respiratory Interventions: A Mixed-Methods Study To Inform Implementation Efforts, Jason Ackrivo, Danny Bracy, Lauren B. Elman, John Hansen-Flaschen, Zachary Simmons, Piera Pasinelli, Terry Heiman-Patterson, Steven M. Kawut, Meghan B. Lane-Fall

Department of Neuroscience Faculty Papers

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that commonly leads to respiratory failure. Early respiratory interventions that may improve symptoms and outcomes are underused when prescribed. We sought to characterize patient perspectives and preferences for respiratory care to enable identification of implementation strategies to improve the uptake of ALS respiratory interventions.

METHODS: A prospective multicenter mixed-methods observational study was conducted using semistructured interviews of participants recently diagnosed with ALS at 4 academic centers in the United States. Eligible patients were those with an ALS diagnosis in the previous 12 months, forced vital capacity < 80% predicted normal, or presence of dyspnea or orthopnea.

RESULTS: Twenty-four patients …

A Transdiagnostic, Multi-Modal Approach To Understanding Apathy: Methodological And Analytical Framework, Yunglin Gazes, Hideo Suzuki, Lee-Anne Morris, Seonjoo Lee, Zekai Jin, Edward D Huey, Bryan B Chen, Campbell Le Heron, Sarah R Heibronner, Nora Vanegas-Arroyave

Faculty, Staff and Students Publications

Apathy is characterized by loss of motivation and manifests as a reduction of goal-directed behavior. Apathy is highly prevalent across neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD), and is an important contributor to the disability and reduce quality of life in these conditions. The treatment of apathy remains challenging due to a lack of specific therapies, largely attributed to an incomplete understanding of its cognitive and neuroanatomical underpinnings, crucial for developing targeted interventions. Apathy can be mechanistically studied through effort-based decision-making (EBDM) paradigms, where individuals choose between low- and high-effort tasks for varying reward magnitudes. Anatomically, apathy …

Exploration Of Zileuton Protective Mechanisms Against Vancomycin-Associated Nephrotoxicity, Cole S Hudson, James E Smith, Rongjin Sun, Linh T Vuong, Luan D Truong, David Sheikh-Hamad, Masayuki Nigo, Ming Hu, Vincent H Tam

Faculty, Staff and Students Publications

Vancomycin is one of the most commonly used parenteral antibiotics for treating drug-resistant bacterial infections, however, it is hindered by nephrotoxicity. We previously demonstrated that zileuton could delay the onset of vancomycin-associated nephrotoxicity in rats. Here, we sought to understand the mechanism(s) of zileuton renal protection. Sprague-Dawley rats were administered vancomycin (200 mg/kg) and zileuton (1 and 4 mg/kg) daily for 10 days. After 3 days, kidneys were collected from select animals for histopathological analysis of renal injury. Single-dose vancomycin serum pharmacokinetics and renal tissue spatial distribution with adjuvant zileuton were evaluated. In vitro, proximal tubular cells were exposed …

From Bladder To Brain: How You Know When It’S Time To Go, Anne M J Verstegen, Kara L Marshall

Duncan NRI Faculty and Staff Publications

The decision to urinate relies on assessing bladder fullness and context to determine an appropriate time and place to go. Any disruption in this interoceptive process results in frequent and sometimes debilitating consequences in daily life. Recent work has uncovered key pathways and brain regions that contribute to the sense of bladder stretch and the control of urinary reflexes, but many open questions remain. Here, we review the known mechanisms that convey sensory information from the bladder to the brain and back down again, and we highlight the knowledge gaps and opportunities for better understanding this system, which will be …

Loss Of The Lysosomal Protein Cln3 Triggers C-Abl-Dependent Yap1 Pro-Apoptotic Signaling, Neuza Domingues, Alessia Calcagni', Sofia Freire, Joana Pires, Ricardo Casqueiro, Ivan L Salazar, Niculin Joachim Herz, Tuong Huynh, Katarzyna Wieciorek, Tiago Fleming Outeiro, Henrique Girão, Ira Milosevic, Andrea Ballabio, Nuno Raimundo

Duncan NRI Faculty and Staff Publications

Batten disease is characterized by early-onset blindness, juvenile dementia and death within the second decade of life. The most common genetic cause are mutations in CLN3, encoding a lysosomal protein. Currently, no therapies targeting disease progression are available, largely because its molecular mechanisms remain poorly understood. To understand how CLN3 loss affects cellular signaling, we generated human CLN3 knock-out cells (CLN3-KO) and performed RNA-seq analysis. Our multi-dimensional analysis reveals the transcriptional regulator YAP1 as a key factor in remodeling the transcriptome in CLN3-KO cells. YAP1-mediated pro-apoptotic signaling is also increased as a consequence of CLN3 functional loss in retinal pigment …

A Molecular Renaissance In Alzheimer's Disease Research: The Rise Of Systems Biology And Spatial Omics, Lucia M. Perez-Navarro, Juan Lopez-Alvarenga

School of Medicine Publications

Recent advances in multi-omics and spatial proteomics are reshaping our understanding of Alzheimer's disease. Guo et al.1 applied integrative multi-omics to stratify mild cognitive impairment into biologically distinct subtypes with divergent progression trajectories: one metabolically impaired and slow-progressing, the other immune-activated and rapidly declining. Current techniques such as STC-DESI, LCM-MS, and machine learning enhance regional proteomic resolution, supporting biomarker discovery and spatially targeted interventions. This work exemplifies a broader shift toward precision medicine and a systems-level molecular framework in neurodegenerative disease research.

Summarizing Attributable Factors And Evaluating Risk Of Bias Of Mendelian Randomization Studies For Alzheimer’S Dementia And Cognitive Status: A Systematic Review And Meta-Analysis, Xiaoni Meng, Xiaochun Li, Meiling Cao, Jing Dong, Haotian Wang, Weijie Cao, Di Liu, Youxin Wang

Research outputs 2022 to 2026

Background: No effective treatment is available to delay or reverse the onset and progression of Alzheimer’s dementia (AD). Mild cognitive impairment, a clinical state between normal aging and AD, may offer the proper window for AD intervention and treatment. This systematic review aimed to summarize evidence from Mendelian randomization (MR) studies exploring factors attributable to AD and related cognitive status and to assess its credibility. Methods: We searched PubMed, Embase, MEDLINE, and the Cochrane Library to identify MR studies investigating the associations between any factor and AD and related cognitive status. The risk of bias in MR studies was evaluated …

Cross-Species Standardised Cortico-Subcortical Tractography, Stephania Assimopoulos, Shaun Warrington, Davide Folloni, Katherine Bryant, Ali-Reza Mohammadi-Nejad, Wei Tang, Saad Jbabdi, Sarah R Heilbronner, Rogier B Mars, Stamatios N Sotiropoulos

Faculty, Staff and Students Publications

Despite their importance for brain function, cortico-subcortical white matter tracts are under-represented in diffusion magnetic resonance imaging tractography studies. Their non-invasive mapping is more challenging and less explored compared to other major cortico-cortical bundles. We introduce a set of standardised tractography protocols for delineating tracts between the cortex and various deep subcortical structures, including the caudate, putamen, amygdala, thalamus, and hippocampus. To enable comparative studies, our protocols are designed for both human and macaque brains. We demonstrate how tractography reconstructions follow topographical principles obtained from tracers in the macaque and how these translate to humans. We show that the proposed …

Diaphragm Resuspension To Titanium Neo-Ribs: A Technique For Chest-Wall Reconstruction Involving The Costal Margin, Patrick Mcgeoghegan, Vuong-Lam Pham, Cristian Medina, Sebastian Winocour, Robert Taylor Ripley, Ramiro Fernandez

Faculty, Staff and Students Publications

No abstract provided.

Relationship Between Cytomegalovirus Antibody Levels And Cognitive Performance Is Dependent On Age And Genetic Risk, Michael Vacher, Silvia Lee, Patricia Price, Phuongnhi Ha, Shelley Waters, Simon M. Laws

Research outputs 2022 to 2026

Human cytomegalovirus (CMV) is endemic worldwide. It is often acquired in childhood and persists throughout adult life. CMV is linked with several diseases of aging, but associations with cognitive performance are not consistent. Here we address whether this may reflect a dependence on putative genetic determinants, Apolipoprotein E (APOE) ε4 and Tumour Necrosis Factor (TNF), and/or the age of the subjects tested. CMV-reactive antibodies were quantitated in 419 individuals aged 71.7 [53.2—89.1] years, drawn from the Australian Imaging, Biomarker & Lifestyle (AIBL) study. Cognitive composite scores, covering five domains, a global score of cognitive performance, brain amyloid-β (Aβ) burden and …

Alzheimer’S Disease Biological Pet Staging Using Plasma P217+Tau, Azadeh Feizpour, Vincent Doré, Natasha Krishnadas, Pierrick Bourgeat, James D. Doecke, Ziad S. Saad, Gallen Triana-Baltzer, Simon M. Laws, Rosita Shishegar, Kun Huang, Christopher Fowler, Larry Ward, Colin Masters, Jurgen Fripp, Hartmuth Kolb, Victor Villemagne, Christopher Rowe

Research outputs 2022 to 2026

Background: Plasma phospho-tau biomarkers, such as p217+tau, excel at identifying Alzheimer’s disease (AD) neuropathology. However, their ability to substitute for tau PET to identify AD biological stage is unclear. Methods: Participants included 248 cognitively unimpaired (CU) and 227 cognitively impaired (CI) individuals, with Janssen plasma p217+tau Simoa® assay, 18F-NAV4694 Aβ-PET (A) and 18F-MK6240 tau-PET (T) data. Biological PET stages were defined according to the Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease (2024): Initial (A + T-), Early (A + TMTL +), Intermediate (A + TMOD +), and Advanced (A + THIGH +). The threshold for A+ was 25 …

Caveolin 1 And 2 Enhance The Proliferative Capacity Of Bcam-Positive Corneal Progenitors, Yuzuru Sasamoto, Shoko Kiritoshi, Catherine A.A. Lee, Yoshiko Fukuda, Gabrielle Martin, Bruce R. Ksander, Markus H. Frank, Natasha Y. Frank

Research outputs 2022 to 2026

Caveolin (CAV) 1 and 2 are integral membrane proteins that constitute major components of small membrane pouches termed caveolae. While several functions have been described in other tissues, the roles of CAV1 and CAV2 in the ocular surface have remained unknown. In the current study, we investigated the expression and function of CAV1 and CAV2 in the human cornea. We found CAV1 and CAV2 to be preferentially expressed by proliferative Basal Cell Adhesion Molecule (BCAM)-positive progenitor cells along the entire limbal and corneal basal epithelial layer. Functional gene knockdown studies reveal that BCAM, BCAM co-expressed Laminin α5 (LAMA5) and Laminin …