Neurosciences Commons^™

Population-Scale Sequencing Resolves Determinants Of Persistent Ebv Dna, Sherry S Nyeo, Erin M Cumming, Oliver S Burren, Meghana S Pagadala, Jacob C Gutierrez, Thahmina A Ali, Laura C Kida, Yifan Chen, Hoyin Chu, Fengyuan Hu, Xueqing Zoe Zou, Benjamin Hollis, Margarete A Fabre, Stewart Macarthur, Quanli Wang, Leif S Ludwig, Kushal K Dey, Slavé Petrovski, Ryan S Dhindsa, Caleb A Lareau

Duncan NRI Faculty and Staff Publications

Epstein–Barr virus (EBV) is an endemic herpesvirus implicated in autoimmunity, cancer and neurological disorders. Although primary infection is often subclinical, persistent EBV infection can drive immune dysregulation and long-term complications. Despite the ubiquity of infection, the determinants of EBV persistence following primary exposure remain poorly understood, although human genetic variation partially contributes to this phenotypic spectrum1–3. Here we demonstrate that existing whole genome sequencing (WGS) data of human populations can be used to quantify persistent EBV DNA. Using WGS and health record data from the UK Biobank (n = 490,560) and All of Us ( …

Harmonizing Neuropsychological Test Data Across Prospective Studies, Rosita Shishegar, James D. Doecke, Yen Ying Lim, Pierrick Bourgeat, Vincent Dore, Bhargav Tallapragada, Simon M. Laws, Tenielle Porter, Samantha Burnham, Azadeh Feizpour, Ashley Gillman, Michael Weiner, Jason Hassenstab, Christopher C. Rowe, Victor L. Villemagne, Colin L. Masters, Jurgen Fripp, Hamid Sohrabi, Paul Maruff

Research outputs 2022 to 2026

Introduction: Alzheimer's disease (AD) research relies on large datasets and advanced statistical models. However, individual population studies often lack sufficient sample size for conclusive results. Harmonizing cognitive test data across studies can address this gap, despite differences in testing protocols. This study harmonizes cognitive data from three major AD cohorts to support robust clinical–pathological modelling. Methods: Information from the Alzheimer's Disease Neuroimaging Initiative (N = 1446); Australian Imaging, Biomarkers and Lifestyle (N = 1764); and Open Access Series of Imaging Studies-3 (N = 440) were integrated, including cognitive scores, demographics, genetics, and clinical and neuroimaging data. Neuropsychological tests relevant to …

Novel Small-Molecule Analogues Of Iu1 Ameliorate Amyloid-Β Mediated Toxicity In Alzheimer’S Disease Cell And Worm Models, Ajish Ariyath, Fraulein Denise Arigo, Izhar Wallach, W. M.A.D.Binosha Fernando, Ralph N. Martins, Prashant Bharadwaj

Research outputs 2022 to 2026

Dysregulation of the deubiquitinating enzyme Ubiquitin-specific peptidase 14 (USP14) is implicated in several neurodegenerative diseases, and IU1, an allosteric inhibitor, has shown neuroprotective effects by reducing protein aggregate toxicity. This study aimed to develop new IU1 analogues and evaluate their ability to mitigate amyloid-β (Aβ) accumulation and toxicity in Alzheimer’s disease (AD) cell and Caenorhabditis elegans worm models. IU1 and 71 newly designed analogues identified using the AtomNet^® virtual screening platform were assessed in an amyloid precursor protein-C terminal fragment/amyloid-β (APP-C99/Aβ)-producing AD cell model using a high-throughput toxicity assay. Lead compounds were further evaluated for their effects on neurodegeneration, …

Plasma Biomarker Progression Across The Alzheimer's Disease Amyloid Beta And Tau Positron Emission Tomography Trajectories, Rodrigo Cánovas, Christopher J. Fowler, Azadeh Feizpour, Vincent Dóre, Pierrick Bourgeat, Ziad S. Saad, Gallen Triana-Baltzer, Hartmuth C. Kolb, Manu Vandijck, Gwendlyn Kollmorgen, Clara Quijano-Rubio, Jurgen Fripp, Simon Laws, Anthony W. Bannon, Kaj Blennow, Henrik Zetterberg, Stephanie Rainey-Smith, Sulantha Mathotaarachchi, Christopher C. Rowe, Colin L. Masters, James D. Doecke

Research outputs 2022 to 2026

Introduction: With increased uptake in disease-modifying treatments for amyloid beta (Aβ) removal, it is important to measure performance of highly sensitive plasma biomarkers to detect the presence of Aβ and tau in cognitively impaired populations. Methods: In this study, we investigated a large set of plasma biomarkers for their capability to predict Aβ and tau positron emission tomography (PET) and their association with increasing Aβ and tau burden. RESULTS: From the biomarkers assessed, tau phosphorylated at threonine 217 (pTau217) showed the largest increases across the full range of Aβ and tau levels. Furthermore, pTau217/Aβ42 had the smallest proportion of participants …

Regulation Of Autophagy-Mediated Pathways By Diet, Physical Activity, And Sleep In Alzheimer's Disease, Ajish Ariyath, Zoe Mputhia, Christopher Dougherty, Bushra Kaleelur Rahuman, W. M.A.D.Binosha Fernando, Belinda Brown, Samantha L. Gardener, Stephanie R. Rainey-Smith, Ralph Martins, Prashant Bharadwaj

Research outputs 2022 to 2026

Alzheimer's disease (AD) is a progressive, age-related, neurodegenerative disorder marked by cognitive decline, memory loss, and accumulation of amyloid beta (Aβ) plaques and tau tangles. A key feature of AD is impaired protein homeostasis, often driven by autophagy dysfunction. Autophagy, a cellular degradation and recycling process, plays a vital role in maintaining neuronal health and is increasingly recognized as a therapeutic target in AD. Lifestyle factors such as diet, physical activity, and sleep can positively influence autophagy and support cognitive function. Intermittent fasting (IF) and calorie restriction (CR) activate autophagy and promote longevity; physical activity enhances cerebral blood flow and …

Two Lysosomal Genes Atp13a2 And Gba1 Interact To Drive Neurodegeneration, Mingxue Gu, Jinghan Zhao, Mingxi Deng, Guang Lin, Xueyang Pan, Wenwen Lin, Mengqi Ma, Jinyong Kim, Seul Kee Byeon, Akhilesh Pandey, Lara M Lange, Chad A Shaw, Jonggeol Kim, Joanne Trinh, Christine Klein, Oguz Kanca, Joshua M Shulman, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Background: Parkinson’s disease (PD) is a genetically complex disorder in which combinations of heterozygous risk variants may contribute to pathogenesis. Many PD risk loci encode lysosomal genes, such as GBA1, a common and potent risk factor, conferring at least a 5-fold increase. However, the mechanisms of GBA1 penetrance remain poorly understood.

Methods: Using Drosophila melanogaster, we performed a genetic interaction screen of lysosomal storage disorder (LSD) genes to identify dominant modifiers of Gba1b (fly homolog of GBA1). Age-dependent locomotor assessments, electroretinograms (ERG), transmission electron microscopy (TEM) analyses and quantification of dopaminergic (DA) neurons were used to assess …

Integrated Proteomics To Understand The Role Of Neuritin-1 (Nrn1) As A Molecular Mediator Of Synaptic Resilience In Alzheimer’S Disease, Derian Pugh

ETDs from 2020-2029

Alzheimer’s disease (AD) is the leading cause of dementia in adults over the age of 65, and currently affects approximately 6.9 million people in the United States. By 2060, the number of people age 65 and older with AD is projected to reach 13.8 million, barring the development of disease-altering therapies to prevent, slow or cure AD. Thus, there is a need for progress in the understanding of AD pathophysiology, as well as in the development of diagnostic and therapeutic interventions. Approximately one-third of individuals without dementia at the time of death are found to harbor high levels of amyloid-beta …

Analysis Of The Effect Of Neuro-Developmental Treatment (Ndt) On Gross Motor Function In Children With Spastic Diplegic Cerebral Palsy: A Systematic Review, Haunan Naja Izdihar, Aditya Denny Pratama

Jurnal Vokasi Indonesia

Effectiveness of Neurodevelopmental Treatment (NDT) in Children with Spastic Diplegia Cerebral Palsy: A Systematic Review

Background:
Neurodevelopmental Treatment (NDT) is commonly used in pediatric rehabilitation to improve motor function in children with cerebral palsy, particularly those with spastic diplegia.

Methods:
This systematic review followed PRISMA 2020 guidelines. Seven studies published between 2018 and 2024 were identified through electronic databases, including PubMed, Scopus, ProQuest, ScienceDirect, SpringerLink, Cochrane Library, Google Scholar, and Crossref.

Results:
The included studies reported improvements in gross motor function, posture, balance, and daily functional independence following NDT, particularly when combined with other therapeutic interventions. However, outcome measures and …

Hiv Vpr Induces Demethylation Of The Snca Antisense Promoter, Leading To Neurocognitive Impairment, Maryline Santerre, Ying Wang, Daniel Kalamarides, Jin Park, Lynn G Kirby, Jeannie Chin, Jaroslav Jelinek, Natalia Shcherbik, Bassel E Sawaya

Faculty, Staff and Students Publications

Human immunodeficiency virus type 1 (HIV-1) alpha-synuclein (α-Syn) aggregation is a hallmark of neurodegenerative diseases. Accumulation and aggregation of α-Syn are often observed in individuals with HIV-1 cognitive impairments. The direct mechanistic link between α-Syn dysregulation and HIV-associated neurocognitive disorders (HAND) remains unclear. Emerging evidence suggests that epigenetic changes, particularly deoxyribonucleic acid (DNA) demethylation, influence α-Syn regulation. We show that the HIV-1 protein viral protein R (Vpr) demethylates the antisense promoter within intron 1 of the alpha-synuclein gene (SNCA), potentially contributing to increased α-Syn expression. Elevated α-Syn promotes aggregation, causing synaptic dysfunction and impaired mitochondrial transport. These processes contribute to …

Tead-Independent Mechanisms Of Yap Function In Cardiomyocyte Cell Cycle Reentry, Bing Xie, Jeffrey Steimle, Vaibhav Deshmukh, Lin Liu, Chang-Ru Tsai, Todd R Heallen, Wyatt Paltzer, Yuka Morikawa, Fansen Meng, Jun Wang, James F Martin

Faculty, Staff and Students Publications

Adult mammalian hearts exhibit limited regenerative capacity because of the restricted renewal of cardiomyocytes. Recent studies reveal that mammalian hearts exhibit transient regenerative potential within a short time frame after birth, suggesting a regulatory mechanism that prevents adult hearts from initiating a regenerative response to cardiac injury. Here, we discovered that an active form of YAP, named YAP6SA, which is not inhibited by the Hippo signaling pathway and does not interact with TEADs, induces cardiomyocyte cell cycle reentry. In addition, YAP6SA interacts with scaffold protein MPDZ to regulate Rho GTPases and promote cell cycle progression in cardiomyocytes (CMs). Importantly, YAP6SA …

Using The Linear References From The Pangenome To Discover Missing Autism Variants, Yang Sui, Jiadong Lin, Michelle D Noyes, Youngjun Kwon, Isaac Wong, Nidhi Koundinya, William T Harvey, Mei Wu, Kendra Hoekzema, Katherine M Munson, Gage H Garcia, Jordan Knuth, Julie Wertz, Tianyun Wang, Kelsey Hennick, Druha Karunakaran, Rafael A Polo Prieto, Rebecca Meyer-Schuman, Fisher Cherry, Davut Pehlivan, Bernhard Suter, Jonas A Gustafson, Danny E Miller, Human Pangenome Reference Consortium (Hprc), Hanna Berk-Rauch, Tomasz J Nowakowski, Aravinda Chakravarti, Huda Y Zoghbi, Evan E Eichler

Duncan NRI Faculty and Staff Publications

To better understand large-effect pathogenic variation associated with autism, we generated long-read sequencing (LRS) data to construct phased and near-complete genome assemblies (average contig N50 = 43 Mbp, QV = 56) for 189 individuals from 51 families with unsolved cases. We applied read- and assembly-based strategies to facilitate comprehensive characterization of de novo mutations, structural variants (SVs), and DNA methylation. Using LRS pangenome controls, we efficiently filtered >97% of common SVs exclusive to 87 offspring. We find no evidence of increased autosomal SV burden for probands when compared to unaffected siblings yet observe a suggestive trend toward an increased SV …

Early-Life Exposure To Pfas Affects Adolescent Neuroimmune Activity, Gia Marie Valdez

Theses and Dissertations from DePaul University

Per-/polyfluoroalkyl substances (PFAS) are persistent organic pollutants commonly used in non-stick, oil-resistant, and water-proof food packaging as well as textiles; they are detected in more than 99% of human serum. Perfluorooctane sulfonic acid (PFOS), one of the most ubiquitous PFAS, is associated with altered lipid metabolism, immunotoxicity, and neurodevelopmental disorders. These outcomes all implicate microglia, resident macrophages in the brain critical for development and sensitive to lipid signaling, as key mediators of toxicity. However, developmental effects of PFOS on microglia are not well-characterized, nor is it clear how PFOS alters microglial inflammatory responses. We hypothesized that early-life PFOS exposure alters …

Genome-Wide Association Study Identifies Novel Variants In Olfactory, Vitamin A, Vitamin B, And Cadherin Pathways Associated With Learning And Memory, Lloyd N. Hopkins, Nesli Avgan, Heidi G. Sutherland, Francesca E. Fernandez, Emma M. Knowles, Larisa M. Haupt, John Blangero, David C. Glahn, David H. K. Shum, Rod A. Lea, Lyn R. Griffiths

Human Genetics Publications

Learning and memory, as fundamental components of human cognition, are heritable traits that are highly variable between individuals and within populations. Investigation into the genetic basis of cognition is a prominent area of research, with genetic associations being previously reported for a wide range of cognitive phenotypes. Here we utilise a genome-wide association study (GWAS) approach to evaluate the contribution of genetic variation to learning and memory phenotypes in a comprehensively phenotyped, well-characterised, healthy, and unrelated cohort of individuals (n = 613). Cognitive phenotypes were assessed using nine comprehensive test batteries consisting of twenty-one cognitive performance assessments including IQ, five …

Rare Heterozygous De Novo Variants In Rapgef2 Are Associated With A Neurodevelopmental Disorder, Ali H Bereshneh, Kirkland A Wilson, Xueyang Pan, Shabab B Hannan, Megan A Cooper, Jullianne Diaz, Eyby Leon, Tiana M Moses, Mahshid S Azamian, Daryl A Scott, Ping Yee Billie Au, Juan Pablo Appendino, Ingrid E Scheffer, Antony Kaspi, Melanie Bahlo, Michael S Hildebrand, Angela T Morgan, Ekanem Ekure, Joshua M Shulman, Friedhelm Hildebrandt, Jennifer E Posey, Paul Kruszka, Eric Vilain, Shinya Yamamoto, Oguz Kanca, Seth Berger, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Purpose: RAPGEF2 encodes a guanine nucleotide exchange factor (GEF) that activates small GTPases and has not been linked to a Mendelian disorder. RAPGEF2 is highly intolerant to loss-of-function variants. We report 5 de novo heterozygous variants in RAPGEF2 in unrelated individuals with developmental delay, attention deficit hyperactivity disorder, epilepsy, dysmorphic features, or other manifestations. We used a Drosophila model to assess the functional impact of the identified human variants.

Methods: We generated a Kozak-GAL4 null allele of the Drosophila ortholog of RAPGEF2, PDZ-GEF, and used the allele to determine the gene expression pattern as well as the loss-of-function phenotypes. We …

The Role Of Isotocin In Female Zebrafish (Danio Rerio) Reproductive Behavior And Its Implication For Intranasal Oxytocin Therapy In Humans, Katelynn M. Benge

Masters Theses

In the past several decades, oxytocin has been colloquially termed the “cuddle hormone,” due to its role in pair-bonding and monogamy (Carter et al., 1992). In addition to being used experimentally for psychological disorder, it has also been used in couple’s counseling settings (Anagnostou et al., 2014; Domes et al., 2016). The outcomes of this research reveal mixed results, creating a need for further research in the topic to understand the exact mechanisms by which oxytocin works in the brain to induce this prosocial response. This study sought to address this deficit through the zebrafish animal model. The zebrafish serves …

Pathogenesis Of Polyglutamine Diseases: Piecing Together A Complex Molecular Puzzle, Esmeralda Villavicencio Gonzalez, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Polyglutamine (polyQ) diseases, caused by a CAG repeat expansion encoding a glutamine tract in nine distinct proteins, present a complex molecular puzzle in which each piece contributes to neurodegeneration. While each of the causative proteins has a distinct function, the downstream consequences of polyQ toxicity are often similar, including protein accumulation, transcriptional dysregulation, somatic CAG repeat instability, disrupted energy homeostasis, compromised synaptic function, and selective neuronal death. This review summarizes emerging insights into how proteins with an expanded polyQ tract disrupt distinct cellular functions, and we examine a multitude of discoveries that are inspiring and reshaping novel therapeutic strategies.

Task-Optimized Brain Parcellations Reveal Latent Functional Organization For Enhanced Connectivity-Based Neuroimaging Classification, Andrew Hannum, Mario A. Lopez

Computer Science: Faculty Scholarship

Brain parcellation schemes are fundamental to neuroimaging, yet general-purpose atlases may obscure the specific functional architecture relevant to a given cognitive task or clinical condition. This reflects a growing consensus that the “optimal” brain map is context-dependent. Here, we introduce a novel framework that validates this principle by generating task-optimized human brain parcellation maps directly from supervised learning objectives. Our method defines functional parcels by grouping brain regions based on the similarity of their contributions to a classifier's decision boundary for a specific goal (e.g., cognitive state decoding or clinical group separation). This approach prioritizes a region's discriminative role over …

Dark And Camouflaged Genomic Regions Remain Challenging In Chm13, Mark E. Wadsworth, Madeline L. Page, Bernardo Aguzzoli Heberle, Justin B. Miller, Cody J. Steely, Mark T. W. Ebbert

Sanders-Brown Center on Aging Faculty Publications

Comprehensive genomic analysis is essential for advancing our understanding of human genetics and disease. However, short-read sequencing technologies are inherently limited in their ability to resolve highly repetitive, structurally complex, and low-mappability genomic regions, previously coined as “dark” regions. Long-read sequencing technologies, such as PacBio and Oxford Nanopore Technologies (ONT), offer improved resolution of these regions, yet they are not perfect. With the advent of the new Telomere-to-Telomere (T2T) CHM13 reference genome, exploring its effect on dark regions is prudent. In this study, we systematically analyze dark regions across four human genome references—HG19, HG38 (with and without alternate contigs), and …

Data-Driven Thresholds For Standardized Classification Of Severe Alzheimer’S Disease Neuropathology Using Digital Neuropathology, Ryan K. Shahidehpour, Allison M. Neltner, Mitchell A. Klusty, Cole Corbett, Angelique D. Gonzalez, David A. Gutman, David W. Fardo, Adam D. Bachstetter, Cody Bumgardner, Margaret E. Flanagan, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Alzheimer's disease neuropathological changes (ADNC)—operationalized with semi-quantitative parameters—represent the consensus-based gold standard for diagnostic evaluation of disease severity. Although useful, ADNC diagnostic frameworks have limitations, particularly in advanced disease stages where pathological severity varies widely within a given diagnostic category. Further, some individuals lacking cognitive impairment are inappropriately categorized as having severe ADNC. In this study, quantitative pathology metrics and alternative tissue sampling schemes were integrated with data about premortem cognitive status, in order to derive clinically informed neuropathologic diagnostic thresholds. Specific goals of the current study were to generate data-driven, standardized diagnostic cut-points, with the most severe stages of …

Clonal Expansion Of Cytotoxic Cd8⁺ T Cells In Lecanemab-Associated Aria, Lance A. Johnson, Kai Saito, Akhil V. Pallerla, Jessica L. Funnell, Ashley R. Ezzo, Chelsea M. Song, Douglas A. Harrison, Noah J. Norton, Lauren C. Moore, Linda J. Van Eldik, David W. Fardo, Greg E. Cooper, Josh M. Morganti

Sanders-Brown Center on Aging Faculty Publications

Amyloid-related imaging abnormalities (ARIA) are the principal safety concern limiting anti-amyloid therapies for Alzheimer’s disease, yet their biology remains unclear. Here we show, through multi-omic profiling of peripheral blood from three ARIA+ patients and matched controls, that ARIA is associated with coordinated reprogramming of CD8 + T cells. CD8+ effector memory (TEM) and terminally differentiated (TEMRA) subsets were expanded, clonally enriched, and transcriptionally primed for cytotoxicity and vascular trafficking. Transcription factor inference and metabolomics converged on glycolytic reprogramming favoring short-lived effector function. Ligand-receptor modeling revealed enhanced monocyte-to-T cell signaling through antigen presentation, adhesion, and chemokine axes, while integration with a …

From Fog To Function: An Occupational Therapist's Guide To Evaluating And Treating Cancer-Related Cognitive Impairments, Lauren E. Toner

Entry-Level Occupational Therapy Doctorate - Doctoral Capstone Symposium

Cancer – related cognitive impairment (CRCI) is a common side effect of cancer treatment that interferes with cancer survivors’ occupational performance, independence, and quality of life. Despite its high prevalence, CRCI remains under recognized and inconsistently addressed within oncology care. About 70% of individuals diagnosed with cancer report cognitive changes during or after treatment, yet many do not receive treatment. Occupational therapists are clinically trained to evaluate and treat functional cognition, activities of daily activities, instrumental activities of daily living, and client centered goals, positioning them as key providers in addressing CRCI. However, limited occupational therapy specific resources have hindered …

Nicotine Self-Administration And The Impacts On Medial Habenula And Interpeduncular Nucleus Neurophysiology, Nathan Alexander Olszewski

Theses, Dissertations and Capstones

Nicotine use is a tremendous public health issue in the United States, with over 23 million people being dependent on the substance. Low cessation rates associated with nicotine use are largely attributed to the withdrawal and craving symptoms that occur after abstinence of use from nicotine. The medial habenula (MHb) and interpeduncular nucleus (IPN) are two brain regions heavily associated and linked with nicotine withdrawal. Here, I sought to understand how these brain regions are altered in their physiology during nicotine intake. Utilizing E-Vape self-administration, mice were first taught to selfadminister nicotine of various, clinically relevant, dosages which correlate to …

Apoe4 Drives Maladaptive Heterogeneity And Immunometabolic Responses Of Astrocytes, Danielle S. Goulding, Holden C. Williams, Amy A. Gorman, Nicholas A. Devanney, Douglas A. Harrison, Adeline E. Walsh, Tony Tuck, Diana J. Zajac, Shannon L. Macauley, Steven Estus, Julia Tcw, Lance A. Johnson, Josh M. Morganti

Sanders-Brown Center on Aging Faculty Publications

Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimer’s disease (AD). Across the CNS, astrocytes are the predominant expressor of APOE while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional inflammation and metabolic processes, yet insights into the molecular constituents driving these responses remain unclear. Utilizing complementary approaches across humanized APOE mice and isogenic human iPSC astrocytes, we demonstrate that ApoE4 alters the astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings show that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at single-cell and spatially-resolved domains, which …

Sox11 Overexpression Restores Embryonic Pro-Growth Transcription In Mature Corticospinal Tract Neurons, Eliazbeth Batsel, Zimei Wang, Elizabeth Otten, Syed Roshan, Rabia Mohammad, Paula Pascual, Darby O'Shea, Jose Rosas, Pantelis Tsoulfas, Murray G. Blackmore

Biomedical Sciences Faculty Research and Publications

Neurons in the central nervous system (CNS) display a high capacity for axon growth during early development but lose this ability at a pivotal differentiation stage marked by synaptic maturation, circuit integration, and a profound shift in gene transcription. Once mature, most CNS neurons fail to reverse this transcriptional switch after axon injury, fundamentally constraining their intrinsic capacity for axon regeneration. Here, we show with single-nucleus RNA sequencing that forced expression of the transcription factor Sox11 in mature corticospinal tract (CST) neurons produces large-scale and stable changes in gene expression that are highly enriched for growth-relevant processes, and which strongly …

The Effects Of Stress-Related Hormones On Excitatory Synapse Formation, Autumn C. Garvey

Honors Undergraduate Theses

Stress profoundly influences brain function through neuromodulatory hormones that regulate synaptic plasticity, yet how temporal patterns of hormone exposure shape excitatory synapse formation remains poorly understood. This study investigates how exposure to stress hormones, norepinephrine and cortisol, affects excitatory synapse development. While existing research primarily compares concentration models, real-world stress occurs in variable patterns that may produce distinct neural outcomes. To address this gap, differentiated Neuro2A neuronal cells are exposed to norepinephrine or cortisol under a continuous treatment paradigm designed to model chronic stress conditions. Following treatment, immunofluorescence imaging is utilized to quantify excitatory synapse formation through analysis of presynaptic …

The Role Of P2y1 And P2y2 Receptors In Human Neural Stem Cell Proliferation, Daria Sokolova

Honors Undergraduate Theses

Endogenous neural stem cells (NSCs) are located in specialized niches of the adult brain and play a vital role in both neurogenesis and neuronal repair. However, declines in NSC proliferation and metabolism associated with age and pathology make these cells less efficient at responding to neurodegenerative disease. Understanding signaling pathways that regulate NSC function is therefore essential for the understanding and development of treatments for these conditions. P2Y receptors are G-protein-coupled purinergic receptors that are activated by extracellular nucleotides and regulate cellular metabolism and proliferation. Among the eight known P2Y subtypes, P2Y1 and P2Y2 have been linked to neuronal signaling …

Exploring Anticholinergic Neurotoxicity: Diphenhydramine's Impact On Neuro-2a Cell Morphology, Expression, And Viability, Jordan B. Mcintyre

Honors Undergraduate Theses

Anticholinergic medications, such as diphenhydramine (commonly known as Benadryl), are increasingly recognized for their association with cognitive impairment and neurodegenerative disease. These medications, which inhibit the action of acetylcholine, a neurotransmitter essential for the formation and utilization of the central and peripheral nervous system, have been implicated in conditions such as dementia and may impact fundamental cellular processes like neurogenesis and cell proliferation. This study investigates the effects of diphenhydramine on neurogenesis when introduced to Neuro-2a cells during differentiation. For all studies cells were plated on coverslips or in 6-well plates with differentiation media containing 0 ng/mL, 50 ng/mL, …

Dual Orexin Receptor Antagonism With Lemborexant Enhances Microglial Clearance Of Β-Amyloid In Mice, Ashish Sharma, Emiko Segawa, Xiaoying Chen, Sohui Park, Shoutang Wang, Riley E. Irmen, Nicholas J. Constantino, Chanung Wang, Michael F. Kanan, Marco Colonna, Shannon L. Macauley, Jocelyn Y. Cheng, Ken Hatanaka, Margaret Moline, Erik S. Musiek

Sanders-Brown Center on Aging Faculty Publications

Background: Sleep disturbances elevate brain amyloid-beta (Aβ) levels and represent a modifiable risk factor for Alzheimer’s disease (AD). The orexin/hypocretin system regulates sleep–wake behavior and has emerged as a therapeutic target in AD; however, the effects of FDA-approved dual orexin receptor antagonists (DORAs) on amyloid pathology remain unclear. We compared lemborexant, an FDA-approved DORA, to doxepin, an antihistaminergic sleep medication, on amyloid pathology and microglial responses in PSAPP mice.

Methods: PSAPP mice received lemborexant (10 or 30 mg/kg/day), doxepin (35 mg/kg/day), or vehicle for 6 weeks beginning prior to plaque onset or 4 weeks after established pathology. Sleep was assessed …

Age-Related Ultrastructural Differences In The Dorsal Cortex Of The Inferior Colliculus In The Fischer Brown Norway Rat, Kylee M. Tenney, Dakota Smallridge, Gillian Barach, Gurveer Singh, Erin Beskitt, Justine Busby, Syllissa Duncan, Alexa Wawrzyniak, Brenda Vega, Nick Tokar, Andrew Ohl, Jesse Young, Jeffrey Mellott

Williams Honors College, Honors Research Projects

The inferior colliculus is a nucleus in the auditory midbrain that plays an important role in sound and speech processing through how it encodes temporal precision. Temporal precision depends on the balance of inhibition and excitation within the IC. This balance degrades during aging. Age-related changes in synapses have been described in the lemniscal IC as a contributing factor for this imbalance. However, it is unknown if aging affects synapses throughout the non-lemniscal IC in a similar manner. We sought to determine this by examining the dorsal cortex of the IC. The ICd is a non-lemniscal nucleus that is well …

A Balancing Act: Amyloid-Β, Tau, And Excitation-Inhibition In Alzheimer's Disease, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

A growing body of evidence shows that epileptic activity is frequently observed in patients with Alzheimer's disease (AD), implicating underlying excitatory–inhibitory imbalance. The distinction of whether the AD-epileptic phenotype represents a subset of patients or an underdiagnosed manifestation holds major therapeutic implications. Here, we quantified the excitatory–inhibitory imbalance in AD patients using magnetoencephalography and examined the relationships to AD pathophysiology—amyloid-beta and tau, and to epileptic activity. We used two metrics to quantify regional excitatory–inhibitory imbalance distinguishing between local hyperexcitability (Neural excitability, quantified by regional aperiodic spectral slope) and aberrant long-range synaptic input integration (Neural fragility, quantified by …