Molecular and Cellular Neuroscience Commons^™

Oxidative Stress Mediated Glutamate Release And Nmda Receptor-Dependent Synaptic Remodeling In Radiation-Induced Cognitive Dysfunction, Thanh Lam

Dissertations and Theses (Open Access)

In children younger than 14 years old, the brain and other parts of the central nervous system are the most common sites for solid tumors. Radiotherapy is an effective treatment for central nervous system (CNS) tumors. However, it often causes a progressive decline in cognitive functions, which is especially devastating for pediatric patients. Although post-mitotic neurons are generally considered resistant to radiation-induced immediate cell death, ionizing radiation causes complex neurochemical and structural changes that damage synaptic integrity. In this study, we examined the molecular cascades following a 10 Gy radiation dose applied to mouse cortical neurons. We found that radiation-induced …

The Rpm-1/Phr Signaling Hub Modulates Tau-Induced Neurodegeneration Through Regulation Of Microtubule Stability And Mapk Pathways In C. Elegans, Xinxing Ding

Theses and Dissertations

Neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia, are characterized by the accumulation of pathological tau proteins and progressive neuronal loss. Although research regarding tau-mediated toxicity is extensive, the specific pathology that determine whether neurons maintain homeostasis or succumb to collapse under tau-induced stress remain incompletely elucidated. A central, yet still insufficiently understood, feature of these diseases is the disruption of the microtubule (MT) cytoskeleton . The PHR protein family is evolutionarily highly conserved; within this family, RPM-1 in C. elegans functions as an intracellular signaling hub that regulates axon development, synapse formation, axon termination, and various microtubule-associated processes. This …

Mapping The Neuroexposome: Integrative Analysis Of Dementia Risk Factors Through Multi-Omics And Environmental Profiling In The Egyptian Population., Mai Ahmed Saadzaghloul Othman

Theses and Dissertations

Background: Dementia represents one of the most pressing public health challenges of the twenty-first century, with the global burden projected to reach 153 million cases by 2050. Egypt, as the most populous Arab nation, faces a corresponding rise in age-related diseases, yet comprehensive data from low- and middle-income countries remain severely limited. The neuroexposome framework, integrating genetic susceptibility, environmental exposures, and metabolic alterations, offers a powerful strategy to characterize the complex interplay between internal and external risk factors for Alzheimer's disease (AD) and Alzheimer's disease Related Dementias (ADRD).

Objectives: This thesis aimed to: (1) examine the distribution of APOE alleles …

Investigation Of Environmental Influences On Multiple Sclerosis: A Study For Egypt’S Health, Noha Ezzaldin Alziny Ali

Theses and Dissertations

Background: Multiple sclerosis (MS) is a complex, chronic neuroinflammatory disease influenced by both genetic and environmental factors. While global research has identified potential environmental influences, most evidence comes from Western populations, creating a significant knowledge gap for regions like Egypt, which has witnessed a dramatic rise in MS prevalence over recent decades. This study hypothesized that Egyptian MS patients exhibit a distinct biological signature in their blood, characterized by an imbalance in essential and toxic trace elements (the metallome) and alterations in stress-response biomarkers associated with neuroaxonal injury and cellular stress. Objective: This study aimed to comprehensively profile and compare …

Rhythms Of Hippocampal Function And Memory After Moderate Prenatal Alcohol Exposure, Lilliana May Sanchez

Psychology ETDs

Fetal Alcohol Spectrum Disorders involve morphologic and neurobiological abnormalities in offspring subjected to prenatal alcohol exposure. Although not as well studied as high exposure, moderate prenatal alcohol exposure represents the most common and undetected form in humans. While learning and memory deficits have been well characterized at the behavioral level in humans with Fetal Alcohol Spectrum Disorders and in animal models of moderate prenatal alcohol exposure, few studies have determined the circuit or systems level mechanisms of the behavioral deficits. A complete understanding of the neural bases of memory deficits after moderate prenatal alcohol exposure is needed to ultimately identify …

Stromal Interaction Molecule (Stim) Proteins In Microglia And The Impact On Store-Operated Calcium Entry (Soce) And Spinal Cord Injury Recovery, Norah G. Hill

College of Arts & Sciences Senior Theses

In spinal cord injury (SCI), worsening functional outcomes are largely because of secondary injury processes and prolonged chronic inflammation. A major contributor of secondary injury is overload of intracellular calcium, causing neuronal overexcitation and persistent inflammatory responses. One of the primary mediators of calcium entry into the cell is store-operated calcium entry (SOCE). In SOCE, sensors detecting calcium depletion from the endoplasmic reticulum stores are called STIM proteins (1-2). When calcium is low in the cell, STIM proteins will activate Orai channels to open, allowing for the influx of calcium into the cell. The purpose of this study was to …

Using A Toxic Aging Coin To Assess Hexavalent Chromium Neurotoxicity: Impact Of Cr(Vi) On The Blood-Brain Barrier, Liam Buchanan

College of Arts & Sciences Senior Theses

The US population faces simultaneous public health threats from both aging and environmental pollutants. Chief among these is hexavalent chromium [Cr(VI)], whose toxic effects in peripheral tissues are well-established but its effects on the brain are still understudied. Following previous results indicating hippocampal metals dyshomeostasis after Cr(VI) exposure, we aim to assess Cr(VI)’s impact on the blood-brain barrier (BBB), a key structure for brain protection. We exposed young, middle-aged, and geriatric rats of both sexes to low levels of Cr(VI) in their drinking water for 90 days, after which we used immunofluorescence and confocal microscopy to analyze tissues for evidence …

Revised - The Role Of Gad67/65 In The Therapeutic Effects Of Ketamine And Fluoxetine In Fear-Conditioned Mice, Alex G. Ottimer

All NMU Master's Theses

Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder and the most common disorder following exposure to a traumatic event. The most commonly used drugs in PTSD treatment are selective serotonin reuptake inhibitors (SSRIs), though only about 50% of patients respond to this treatment. Previous work in our lab demonstrated the combination of chronic fluoxetine (FLX) and acute ketamine treatment decreased fear response in a contextual fear paradigm in male C57/BL mice. In rodents, fear conditioning (FC) is commonly used in the literature to induce behaviors related to PTSD. The mammalian central fear memory circuit involves a dynamic interplay between …

Establishment Of A Hek293t Cell Model System To Investigate Direct Intracellular Interactions Between Amyloid-Β (Aβ) And The Nlrp3 Inflammasome, Cristina Sinobas Pereira

Dissertations

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. While Amyloid-β (Aβ) aggregation is a defining pathological feature, increasing evidence highlights chronic neuroinflammation as a critical contributor to disease progression. Soluble Aβ assemblies can act as damage associated molecular patterns (DAMPs) including activation of the NLRP3 inflammasome, which links amyloid pathology to sustained inflammatory responses in the brain (Heneka et al., 2015; Nakanishi et al., 2018). However, the molecular mechanisms by which specific Aβ conformations influence inflammasome assembly remain incompletely understood.This study aimed to investigate whether distinct aggregation states of amyloid β42 (Aβ42) are …

The Role Of Pten Subcellular Localization In Neuronal Development And Autism Spectrum Disorder, Nicole Desmet

Dartmouth College Ph.D Dissertations

Autism spectrum disorders (ASD) are genetically heterogeneous neurodevelopmental conditions that nevertheless converge on altered neuronal connectivity and circuit function. A central unresolved problem in the field is how diverse genetic perturbations, acting at different biological levels and developmental stages, give rise to shared neurodevelopmental outcomes. This dissertation addresses this problem by examining how gene function, subcellular signaling, and developmental context interact to shape neuronal morphology and circuit-relevant phenotypes.

Cell-autonomous mechanisms regulating neuronal morphology are examined through the ASD risk gene Phosphatase and Tensin Homolog (PTEN) in developing dentate gyrus granule neurons. Selective biasing of PTEN to defined intracellular compartments in …

Situation Mouse All Floxed Up: Exploring Phenotypic Abnormalities In Bdnf Floxed Mice, Marissa A. Burkman

All NMU Master's Theses

Animal research is a contentious topic in both the scientific and general communities.  It is essential that our animal models accurately and predictably depict intended phenotypes, necessitating careful colony monitoring and maintenance.  Volunteer animal staff in the Ottem Laboratory became concerned when mice with LoxP sites flanking the BDNF gene depicted anxiety-like behaviors such as aggression, difficulty handling, and increased agitation.  Though many studies have noted behavioral and phenotypic abnormalities related to large gene inserts, few have noted abnormalities with small gene inserts such as the 34 bp LoxP site.  Brandt (2018) performed a three-stage behavioral protocol on these mice …

Local Angiotensin Converting Enzyme 2 (Ace2) Enzymatic Activity Modulates Cholinergic Interneuron Function In The Dorsolateral Striatum, Aria R. Walls

Dissertations, Theses, and Capstone Projects

The renin angiotensin system (RAS) is an ancestrally ancient peptidergic signaling pathway best known for its role regulating blood pressure in the periphery. However, its presence and importance in the central nervous system has more recently been identified and is less well understood. Previous work shows RAS is expressed in the nigrostriatal pathway of the basal ganglia and has been implicated in basal ganglia disorders including Parkinson’s disease (PD) and levodopa-induced dyskinesia (LID). Interestingly, the canonical and noncanonical arms of the RAS pathway produce opposite effects on PD disease vulnerability and progression. The shift from the neurodegenerative canonical RAS to …

Silver Nanoparticle-Induced Disruption Of Astrocytic Morphology And Synaptic Microarchitecture In Rat Brain, Elli Williams

Theses, Dissertations and Capstones

Silver nanoparticles (AgNPs) are widely incorporated into consumer and medical products due to their antibacterial properties, increasing the potential for chronic exposure. AgNPs can be released into the environment, enter the body through ingestion or inhalation, cross the blood-brain barrier (BBB), and bioaccumulate in brain tissue. Previous in vitro studies demonstrate that AgNP exposure disrupts cytoskeletal organization and induces neurite collapse in neural cells, suggesting vulnerability of cytoskeleton-dependent structures in vivo. Astrocytes, through their perisynaptic astrocytic processes (PAPs) and perivascular endfeet, play critical roles in maintaining synaptic and neurovascular architecture, both of which rely heavily on cytoskeletal integrity. This …

Metabolism As A Regulator Of Sleep And Cortical Activity In Health And Alzheimer’S Disease, Nicholas J. Constantino

Theses and Dissertations--Neuroscience

Metabolic flexibility is essential for maintaining normal physiological function, enabling an organism to sense, flux, utilize, and switch fuel sources in response to changing energetic availability, demand, and cellular needs. Energetic demands are state-dependent, with wake and sleep exhibiting distinct metabolic profiles. Sleep is highly sensitive to changes in metabolism and requires metabolic flexibility to both transition into and maintain sleep stability. Alzheimer’s disease (AD) is increasingly recognized as a disease of altered metabolism yet is often framed as a disease of energetic failure. We instead define AD as a disease of metabolic inflexibility, characterized not by insufficient energy availability, …

Design And Advancement Of Analytical Frameworks For In Vivo Single-Photon Calcium Imaging To Characterize Temporal- And Treatment-Dependent Neural Adaptations To Opioid Exposure And Withdrawal In The Medial Prefrontal Cortex, Alexia R. Alsum Dr.

Theses and Dissertations--Pharmacy

Despite the availability of several approved medications for opioid use disorder (OUD), it remains a significant public health concern characterized by persistent neurobiological adaptations that drive relapse and impede successful recovery. The medial prefrontal cortex (mPFC), a region critical for executive control and decision-making, undergoes pronounced functional changes during chronic opioid exposure and withdrawal, yet the cellular mechanisms underlying these adaptations remain poorly understood. This dissertation aims to investigate longitudinal alterations in mPFC neural activity across opioid exposure and withdrawal using in vivo single-photon calcium imaging and newly developed computational frameworks.

Following standard preprocessing to extract and normalize calcium traces, …

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 …

Microglial Apoe Across Alzheimer’S Disease-Relevant Pathologies, Georgia Nolt

Theses and Dissertations--Physiology

APOE exists as three common alleles (APOE2, APOE3, APOE4) that encode their corresponding protein isoforms (apoE2, apoE3, apoE4). Despite differing by only one or two single-amino acid substitutions, each APOE allele confers a distinct AD risk profile with APOE4 increasing risk by 28% and APOE2 decreasing risk by 14% compared to the most commonly expressed APOE3 allele. While traditionally considered “neutral,” APOE3 still accounts for ~36% of AD cases while APOE4 contributes ~57%, indicating that the majority of AD cases would not occur in the absence of the APOE3 and APOE4 alleles. Microglia, the resident phagocytic immune cells …

Manuka Honey Modulates Oxidative Stress In Neuro2-A Cells Through Mitochondrial Regulation, Rachel Abramovici

Honors Undergraduate Theses

Manuka honey is known for its vital usage in wound healing, being an agonist towards fighting infections, and is an acting antioxidant [32]. Its main constituents are flavonoids and phenolic compounds, with methyl syringate (MSYR) being a major active ingredient. The specific compounds responsible for these antioxidant effects, particularly in the CNS, remain unclear. It is hypothesized that pre-treatment of mouse neuroblastoma cells with MSYR followed by hydrogen peroxide exposure will activate the AMPK/SIRT1/PGC-1a pathway, due to MSYR’s phenolic structure, and thus reduce oxidative stress and improve mitochondrial biogenesis. Hydrogen peroxide is a standard reactive oxygen species (ROS) treatment to …

Disrupted Circadian Rhythms Affect Hallmark Pathologies In Alzheimer’S Disease-Related Mouse Models, Valeria Buzinova

Theses and Dissertations--Molecular and Cellular Biochemistry

Alzheimer’s Disease (AD) is a complex neurodegenerative disease with two hallmark pathologies: extracellular amyloid-b (Ab) and intracellular neurofibrillary tangles (NFTs). Ab is proteolytically processed from amyloid precursor protein (APP) by b-secretase and g-secretase as a monomeric peptide prone to aggregation. Eventually, the aggregate-prone monomers will form dense plaques that are difficult to break down and remove. These plaques begin to deposit into the cortex decades prior to the formation of NFTs and the onset of cognitive decline. NFTs are comprised of hyper-phosphorylated tau. Tau is a protein that serves to promote and stabilize the formation of microtubules. The formation of …

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, …

The Serotonin 1b Receptor In Psilocybin’S Therapeutic-Like Mechanisms: From Behavior To Network Reorganization, Sixtine Fleury

Dartmouth College Ph.D Dissertations

Mood disorders represent a substantial and growing global health crisis, with ~10 million adults in the US meeting criteria for a major depressive disorder (MDD). Current first-line treatments such as SSRIs require long-term daily administration and fail a significant proportion of patients, driving renewed interest in rapid-acting alternatives. Psilocybin, a serotonergic psychedelic, shows growing clinical evidence of efficacy in treating depressive and anxiety disorders, often producing therapeutic effects persisting weeks to months following a single dose. Yet, the neural mechanisms underlying these enduring effects remain poorly understood and have been largely attributed to the serotonin 2A receptor (5-HT2AR) based on …

Investigation Of Mono-Allelic Rack1 Deletion Effects On Cell Growth And Pkc Mrna Expression, Ashen Quiambao

Seton Hall University Dissertations and Theses (ETDs)

The µ-opioid receptor is a primary target of clinically used opioids, and RACK1 regulates its transcription by physically interacting with MOR transcription regulator PCBP1 in the cytosol to prevent its nucleus translocation. Two mono-allelic RACK1 knockout cell lines named RACKA and RACKB were generated by the CRISPR-Cas9 technique using WT NMB neuroblastoma cells. As RACK1 also contains a PKC-binding domain, this study aims to evaluate the impacts of mono-allelic deletion on cell growth rates and PKC isoform expression. Although a slight decreased tendency of growth rate in RACKA and RACKB cells was observed when compared to that of WT NMB …

Stress During Adolescence: A Characterization Of Anxiety-Like Behavior, And The Mrna Expression Of Neuroimmune Factors, Clock And Stress Genes In Corticolimbic Areas., Annette Fernandez Oropeza, Annette K. Fernandez Oropeza

Biomedical Sciences ETDs

Adolescence represents a critical window of frontal cortex (FC) maturation and corticolimbic circuit refinement that supports stress and emotion regulation. Disruption of these processes by early-life insults such as prenatal alcohol exposure (PAE) or adolescent stress increases vulnerability to anxiety and mood disorders, in part through circadian–immune dysregulation. The circadian transcription factor Bmal1 and the proinflammatory cytokine tumor necrosis factor-alpha (TNFα) have emerged as key regulators of neuroimmune signaling and synaptic communication, yet their interactions across developmental risk contexts remain poorly understood. This dissertation examined the effects of mild adolescent isolation stress, with and without PAE, on anxiety-like behaviors and …

Generating Predictive Gene Expression Signatures For Alzheimer's Disease Using Postmortem Brain Tissue, Ashley Duche

Pharmaceutical Sciences (PhD) Dissertations

Background: Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and tau protein aggregates. These pathological features develop in specific brain regions, but why some areas are more vulnerable to early AD-related changes remains unclear. To address this, predictive gene expression signatures were developed to explore the molecular mechanisms underlying regional susceptibility to AD pathology.

Methods: This was performed using postmortem brain (PMB) tissue from participants in the Religious Orders Study and Memory and Aging Project (ROSMAP), Mayo Clinic, and Mount Sinai Brain Bank (MSBB) to generate gene expression signatures from six brain …

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 …

Investigation Of Motor Neuronal And Circuit Level Mechanistic Determinants Of Spinal Excitability Following Cst Injury, Thelma Bethea

Dissertations, Theses, and Capstone Projects

The corticospinal tract (CST) is the primary descending motor pathway in mammals, essential for precise, dexterous movements, especially in humans and nonhuman primates. Damage to the CST, such as from spinal cord injury (SCI), impairs skilled motor function and triggers maladaptive changes including aberrant proprioceptive afferent sprouting and increased spinal excitability. These changes are closely linked to both muscle weakness and the development of hyperreflexia, compounding the functional deficits. Animal models of SCI are valuable for investigating mechanisms of injury and recovery, though traditional models often limit the ability to isolate circuit-specific contributions. To address this, I employed selective unilateral …

The Sonic Hedgehog Effector Smoothened Modulates Cholinergic Interneuron Activity, Physiology, And Striatum-Dependent Behaviors, Santiago Uribe-Cano

Dissertations, Theses, and Capstone Projects

The striatum is a central node in action selection and associative learning, integrating cortical, thalamic, and neuromodulatory input. Among its principal modulators, dopamine (DA) and acetylcholine (ACh) are known for their temporally coordinated yet mechanistically distinct influences on striatal output. However, the upstream signals that regulate their dynamic interplay, particularly within cholinergic interneurons (CINs)—the primary source of striatal ACh—remain incompletely characterized. This dissertation investigates the role of Smoothened (Smo), a G protein-coupled receptor (GPCR) effector of Sonic Hedgehog (Shh) signaling, in modulating ACh signaling dynamics in the striatum.

Building on evidence that midbrain DA neurons co-release Shh and that CINs …

Mechanistic Insights Into The Neuroprotective Effects Of The Antidepressant Agomelatine In Alzheimer's Disease, Grace Terry

Dissertations, Theses, and Capstone Projects

Alzheimer’s Disease (AD) is a complex neurodegenerative disease that has limited treatment options and no cure. AD is characterized by robust pathology including extracellular amyloid beta plaques, intracellular neurofibrillary tangles, neuronal and synaptic loss, neuroinflammation, and brain atrophy. AD presents with cognitive decline and memory loss but only years after neuropathology has started to accumulate. This robust pathology has made AD difficult to treat and highlights the need for therapeutics that modulate multiple pathways. Agomelatine (AGO) was selected by a high-throughput machine learning drug repurposing algorithm by our collaborator Dr. Lie Xie (Hunter College Dept. of Comp. Sci.) as having …

Repurposing Atractylenolide Iii, A Natural Anti-Inflammatory Compound, For Alzheimer’S Disease, Angela M. Steele

Dissertations, Theses, and Capstone Projects

Alzheimer’s disease (AD) is a debilitating neurological condition ranked as the fifth leading cause of death in adults over the age of 65. Despite the severity, 98% of drugs have failed as treatments for AD. Current novel drug development approaches have been unable to produce a disease-modifying treatment as they often have a one-target approach, not accounting for the complex nature of the disease. One of the hallmarks of the disease, inflammation, may provide a better target for treatment because it interacts with multiple facets of the disease. Drug repurposing to identify compounds that mitigate inflammation in AD could provide …

Detecting Sonic Hedgehog Expression In The Adult Mouse Brain Using A Gene Expression Tracer, Kendra Stephens-Jones

Dissertations, Theses, and Capstone Projects

Sonic Hedgehog (Shh) is best known for its role in development, yet evidence supports Shh signaling plays a functional role in the adult brain. Previous work demonstrated that Shh is expressed by dopamine (DA) neurons in the ventral midbrain and that loss of Shh from these neurons leads to late-onset motor and structural abnormalities resembling Parkinson’s disease. However, the extent of Shh expression and its connectivity to the striatum in the adult mouse brain remain unclear due to the lack of reliable antibodies for Shh detection. To address this gap, the present study employed Shh ^L/L and DAT-Cre^+/- mice …