Cell Biology Commons^™

Novel Psychoplastogen Dm506 Reduces Cue-Induced Heroin-Seeking And Inhibits Tonic Gaba Currents In The Prelimbic Cortex, Kassandra Looschen, Shailesh N. Khatri, Malabika Maulik, Colin Salisbury, Alaina F. Carman, Katilyn Corriveau, Colton Smith, Dina Manetti, Maria Novella Romanelli, Hugo R. Arias, Cassandra D. Gipson, Swarup Mitra

Markey Cancer Center Faculty Publications

Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior …

Unraveling The Role Of Hid-1: Insights Into Sgii Regulation, Breanna L. Sellers

Electronic Theses and Dissertations

The regulated secretory pathway is important for the secretion of hormones and neuropeptides from large dense core vesicles (LDCVs). Dysregulation of the biogenesis of LDCVs can result in metabolic and neurological diseases. Recent studies have suggested that the peripheral membrane protein HID-1 plays a role in the sorting and storage of granins which contribute to LDCV biogenesis. To further understand how HID-1 influences the regulation of granins, we investigated potential HID-1 interactors. We determined that while HID-1 is likely functioning in the same pathway as USP25, a deubiquitinating enzyme (DUB), the cause of reduced cellular SgII levels is likely not …

Deciphering The Contribution Of Microglia To Neurodegeneration In Friedreich's Ataxia, Sydney N. Gillette

Master's Theses

Friedreich's ataxia (FRDA) is the most prevalent inherited ataxia, affecting one in every 50,000 individuals in the United States. This hereditary condition is caused by an abnormal GAA trinucleotide repeat expansion within the first intron of the frataxin gene resulting in decreased levels of the frataxin protein (FXN). Insufficient cellular frataxin levels results in iron accumulation, increased reactive oxygen species production and mitochondrial dysfunction. Tissues most heavily impacted are those most dependent on oxidative phosphorylation as an energy source and include the nervous system and muscle tissue. This is evident in the clinical phenotype which includes muscle weakness, ataxia, neurodegeneration …

Towards A New Role Of Mitochondrial Hydrogen Peroxide In Synaptic Function, Cliyahnelle Z. Alexander

Student Theses and Dissertations

Aerobic metabolism is known to generate damaging ROS, particularly hydrogen peroxide. Reactive oxygen species (ROS) are highly reactive molecules containing oxygen that have the potential to cause damage to cells and tissues in the body. ROS are highly reactive atoms or molecules that rapidly interact with other molecules within a cell. Intracellular accumulation can result in oxidative damage, dysfunction, and cell death. Due to the limitations of H₂O₂ (hydrogen peroxide) detectors, other impacts of ROS exposure may have been missed. HyPer7, a genetically encoded sensor, measures hydrogen peroxide emissions precisely and sensitively, even at sublethal levels, during …

Unveiling The Nexus Of Cellular Quality Control: Exploring The Interplay Between Ribosome-Associated Protein Quality Control And Mitochondrial Quality Control Pathways, Foozhan Tahmasebinia

Biological Sciences Theses and Dissertations

In eukaryotic cells, the intricate interplay between cellular quality control mechanisms is crucial for maintaining homeostasis and safeguarding the integrity of vital processes, spanning from macromolecule synthesis to the renewal of entire cellular organelles.

Disruption of these networks can lead to severe diseases such as metabolic disorders, underscoring the interconnected nature and feedback control mechanisms inherent in biological systems, including cellular quality control systems. This interconnectedness extends to the intricate communication between organelles, enabling coordinated functioning and adaptation to changing cellular conditions, particularly in response to stressors.

While the exact mechanisms governing these communications within cellular quality control systems remain …

Investigating The Antibacterial And Immunomodulatory Effects Of Resolvin D2 On Monocytes And Macrophages, Cristina Maria Padovani

Theses and Dissertations

In the late phase of sepsis, immunosuppression occurs, where the host is unable to clear the pre-existing infection and is susceptible to secondary infections. It is believed that the ideal treatments for sepsis should attenuate immunosuppression so that the host can get back to homeostasis. Specialized Pro-resolving Mediators (SPMs) are endogenously- produced fatty acids that resolve infectious inflammation without being immunosuppressive. We hypothesize that an SPM – Resolvin D2 (RvD2) – can augment exhausted macrophage function during the immunosuppressive phase of sepsis. We developed a two-hit model to establish macrophage exhaustion in vitro, and found that RvD2 increased NF-κB activity, …

Intra-Accumbens Microinfusion Of The Dopamine D3 Receptor Partial Agonist (±)Vk4-40 Does Not Affect Basal Locomotion In Mice, Yeonwoo Sim, Nicole M. Hinds, Amy Hauck Newman, Daniel F. Manvich

Rowan-Virtua Research Day

The opioid epidemic remains a pressing public health crisis, prompting the search for alternative pharmacotherapies for Opioid Use Disorder (OUD). This study explores the potential of the dopamine D3 receptor (D3R) partial agonist, (±)VK4-40, as a novel treatment option. We investigated the impact of intra-nucleus accumbens (NAc) microinfusion of VK4-40 on basal locomotion in mice. Results indicate that VK4-40 did not significantly alter basal locomotion, suggesting that its therapeutic effects may not be mediated through disruptions in generalized motor function. Future research will focus on elucidating the neuropharmacological mechanisms underlying VK4-40's therapeutic actions and exploring its effects on psychostimulant-induced hyperlocomotion. …

Microglial Dynamics And Mechanisms Underlying The Phagocytosis Of Dying Oligodendrocytes, Genaro E. Olveda

Dartmouth College Ph.D Dissertations

Myelin is a complex multilamellar structure, generated by oligodendrocytes, that ensheaths axons and is a vital component for neural processing. Degeneration of both oligodendrocytes and their myelin sheaths is a common pathological feature associated with aging and neurodegenerative diseases. Efficient removal of the cellular and myelin debris is crucial for remyelination and prevention of further degeneration. Microglia, the primary phagocytes of the CNS, are thought to play a key role in this process. To investigate the cellular dynamics underlying microglia-mediated clearance of degenerating oligodendrocytes and myelin sheaths, at the single cell level, we developed a novel model for inducible cortical …

Atlas-Based Analysis Of The Neural Projections From The Lateral Hypothalamic Area To The Lower Brainstem In The Adult Male Rat, Jessica Valeria Salcido Padilla

Open Access Theses & Dissertations

Within the last decade, the number of diseases associated with dysregulation of the neural circuits responsible for energy balance, glucosensing, and feeding control has increased. One brain region containing these circuits is the lateral hypothalamic area (LHA), which plays an important role in the sleep/wake cycle, energy balance, and motivated behavior. Although the LHA has been termed a â??feeding centerâ??, other regions within the hindbrain are known for the regulation of similar functions including energy balance, glucosensing, and feeding control. While many studies have explored and reported projections from the LHA to the hindbrain, few have further investigated the interconnections …

Development Of Vasculature Patterns In A Mouse Model Of Supratentorial Ependymoma, Jackson Ayers

Honors Scholar Theses

Supratentorial Ependymoma (ST-EPN) is a subtype of ependymoma, a primary solid tumor found throughout the nervous system. ST-EPN are most commonly caused by an oncogenic fusion between the zinc finger gene ZFTA and the RELA, and this distinct ependymoma subtype is readily modeled in mice by conditional expression of ZFTA-RELA in radial glial cells. ST-EPN are known to have a distinctive arrangement of tumor cells and vasculature forming pseudo-rosettes in which polarized tumor cells surround blood vessels within the tumors. It is not known how these pseudo-rosettes or the tumor vasculature form and develop in ST-EPN, so in this study …

Methamphetamine-Induced Dna Double-Stranded Breaks: The Impact Of The Dopamine Transporter And Insights Into The Mechanisms Of Dna Damage In Mouse Neuro 2a Cells, Lizette Couto

Dissertations, Theses, and Capstone Projects

Methamphetamine (METH) abuse remains a global health concern, with emerging evidence highlighting its genotoxic potential. In the central nervous system METH enters dopaminergic cells primarily through the dopamine transporter (DAT), which controls the dynamics of dopamine (DA) neurotransmission by driving the reuptake of extracellular DA into the presynaptic neuronal cell. Additional effects of METH on the storage of DA in synaptic vesicles lead to the dysregulated cytosolic accumulation of DA. Previous studies have shown that after METH disrupts intracellular vesicular stores of DA, the excess DA in the cytosol is rapidly oxidized. This generates an abundance of reactive oxygen species …

Calcium And Proteasomal Regulation Of Er-To-Golgi Protein Transport In Neurons, Samuel A. Galindo

Undergraduate Theses, Professional Papers, and Capstone Artifacts

Regulatory mechanisms of protein trafficking from the endoplasmic reticulum (ER) are critical to understand since neurodegenerative diseases involve defects in this process leading to chronic ER stress and cell death. This study aimed to better understand the calcium regulatory mechanisms of ER-to-Golgi trafficking in hybrid neuroglioblastoma cells (NG108). Specifically, we asked whether proteasomal degradation of transport machinery was involved in the previously demonstrated upregulation of ER-to-Golgi transport evoked by calcium signaling. Based upon previous literature, we believe that the calcium induced increase in transport is due to the activation of the calcium sensitive regulatory protein apoptosis linked gene 2 (ALG-2) …

Aberrant Lipid Accumulation And Retinal Pigment Epithelium Dysfunction In Prcd-Deficient Mice, Sree Indrani Motipally

Graduate Theses, Dissertations, and Problem Reports (ETD)

Progressive Rod-Cone Degeneration (PRCD) is a peripheral membrane protein predominantly expressed in photoreceptor outer segment (OS) disc membranes with an unknown function. Several mutations in Prcd are implicated in Retinitis pigmentosa (RP) in humans. The most common “cysteine to tyrosine” (C2Y) mutation in Prcd leads to progressive retinal atrophy in multiple dog breeds and RP in humans. Canine models harboring the C2Y mutation in Prcd show disorganized OS structure with greatly attenuated photoreceptor OS renewal rates. Recent studies show defects in the photoreceptor nascent disc flattening in the absence of Prcd. However, it is unclear how OS discs eventually …

Regulation Of Er To Golgi Transport By Alg-2 And Peflin In Response To Calcium Signaling, And A Review Of Relevant Genetically-Encoded Fluorescent Tools, Danette M. Kowal Seiler

Graduate Student Theses, Dissertations, & Professional Papers

The endoplasmic reticulum performs multiple functions in the eurkaryotic cell: biomolecule synthesis, protein folding, cargo sorting and secretion, and helping to maintain cellular calcium homeostasis. Though much has been discovered about these processes and the myriad proteins, enzymes, transcription factors, ions and other factors that play their own parts, much is still left to learn. To facilitate continued study of ER-to-Golgi transport, an array of genetically-encoded fluorescent tools are available to researchers. The featured review in Chapter 1 details the history of these tools and highlights some of the newest, which also incorporate information from the fields of synthetic chemistry …

Examining The Effects Of Artemisia Annua On Neuro2a Cells, Wesley Lim

Honors Undergraduate Theses

Artemisia annua L. is a well-known medicinal herb used in Traditional Chinese Medicine for many centuries and contains artemisinin, which exhibits antimalarial properties [1] and is a potential treatment for SARS-CoV-2 [2]. However, the neurological effect of A. annua and its compounds are poorly understood. We hypothesize that A. annua extracts and artemisinin will provide protection against oxidative stress in mouse neuronal Neuro2A cells. Superoxide dismutase 1 (SOD1) is an anti-oxidant enzyme that protects against oxidative damage [3]. Growth Arrest and DNA Damage-inducible 45 alpha (Gadd45a) is involved in DNA repair and is a common biomarker for DNA damage[4]. SOD1 …

Evaluating Reactive Gliosis In The Brain Of Adult Zebrafish Following The Ingestion Of Nanopolystyrene., Hannah A. Kelehear

College of Graduate Studies: Theses & Dissertations

Polystyrene nanoplastics are one of the most pervasive environmental contaminants and have been shown to infiltrate multiple organ systems following ingestion. Studies in several animal models and humans have demonstrated that nanoplastics can cross the blood-brain barrier. Additionally, there is evidence that plastics will induce an inflammatory response in the brain involving reactive gliosis of microglia and astrocytes. This process has yet to be thoroughly investigated in the zebrafish model system in the context of micro-/nanoplastic ingestion. In the current study, we examined microglial and astrocytic phenotypes in the adult zebrafish telencephalon after consuming food contaminated with 44 nm polystyrene …

Nucleus Accumbens Core Single Cell Ensembles Bidirectionally Respond To Experienced Versus Observed Aversive Events, Oyku Dinckol, Noah Harris Wenger, Jennifer E Zachry, Munir Gunes Kutlu

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Fear learning is a critical feature of survival skills among mammals. In rodents, fear learning manifests itself through direct experience of the aversive event or social transmission of aversive stimuli such as observing and acting on conspecifics' distress. The neuronal network underlying the social transmission of information largely overlaps with the brain regions that mediate behavioral responses to aversive and rewarding stimuli. In this study, we recorded single cell activity patterns of nucleus accumbens (NAc) core neurons using in vivo optical imaging of calcium transients via miniature scopes. This cutting-edge imaging methodology not only allows us to record activity patterns …

Short Chain Fatty Acid Combination Treatment Protects Against 6-Ohda And Wt Α-Synuclein Induced Decreases In Neurite Growth In In Vitro Models Of Parkinson’S Disease., Alex Morris

ORBioM (Open Research BioSciences Meeting)

Background

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron degeneration. This degeneration is partly driven by over expression of α-synuclein (α-syn) and development of α-syn aggregates known as Lewy bodies throughout the substantia nigra. As well as motor dysfunction, PD presents with several chronic gastrointestinal comorbidities, which cause a decline of gut microbial diversity and microbially derived short chain fatty acids (SCFAs). Recent in vivo studies have shown SCFAs to be neuroprotective in various degenerative disease states, suggesting that SCFAs may protect against dopaminergic degeneration.

Methods

Human neuroblastoma SH-SY5Y cells were used as a model of human …

Inhibition Of Mitochondrial Fission Activates Glycogen Synthesis To Support Cell Survival In Colon Cancer, Sumati Raj Hasani, Lyndsay E. A. Young, Warren Van Nort, Moumita Banerjee, Dylan R. Rivas, Jinhwan Kim, Xiaopeng Xiong, Ramon C. Sun, Matthew S. Gentry, Hiromi Sesaki, Tianyan Gao

Markey Cancer Center Faculty Publications

Metabolic reprogramming has been recognized as one of the major mechanisms that fuel tumor initiation and progression. Our previous studies demonstrate that activation of Drp1 promotes fatty acid oxidation and downstream Wnt signaling. Here we investigate the role of Drp1 in regulating glycogen metabolism in colon cancer. Knockdown of Drp1 decreases mitochondrial respiration without increasing glycolysis. Analysis of cellular metabolites reveals that the levels of glucose-6-phosphate, a precursor for glycogenesis, are significantly elevated whereas pyruvate and other TCA cycle metabolites remain unchanged in Drp1 knockdown cells. Additionally, silencing Drp1 activates AMPK to stimulate the expression glycogen synthase 1 (GYS1) mRNA …

Cyclophosphamide And Epirubicin Induce Apoptotic Cell Death In Microglia Cells, Rafael De La Hoz-Camacho

Research Symposium

Background. Chemotherapy Related Cognitive Impairment’s (CRCI), diminish patient’s quality life, being breast cancer (BC) patients the most affected. Microglia is described to play a major role in CRCI; hence, the aim of this research was to describe the cytotoxicity of cyclophosphamide (CTX) and Epirubicin (EPI), on microglia (SIM-A9), compared to BC cells (4T1).

Methods. We assessed cell viability (Resazurin) and cell death (AnnV), as well as nuclear damage with γ-H2AX, p53, p16 and cell cycle analysis (PI staining) by flow cytometry (FC). Furthermore, we evaluated ΔΨm (DIOC6), ROS (DCFDA) and NO (DAF-FM) production. Finally, caspase activation (TF2-VAD-FMK) and autophagy (CYTO-ID). …

Oligodendrocyte 2phatal Reveals Dynamics Of Myelin Degeneration And Repair, Timothy W. Chapman

Dartmouth College Ph.D Dissertations

Oligodendrocytes are responsible for producing myelin in the central nervous system. This lipid-rich coating along axons helps to increase action potential velocity, provide metabolic support to axons, and facilitate fine-tuning of neuronal circuitry. Demyelination and/or myelin dysfunction is widespread in neurodegenerative diseases and aging. Despite this, we know very little about how individual oligodendrocytes, or the myelin sheaths they produce, degenerate. Myelin repair, carried out by resident oligodendrocyte precursor cells (OPCs), is known to occur following myelin damage in certain contexts. We sought to investigate the cellular dynamics of oligodendrocyte degeneration and repair by developing a non-inflammatory demyelination model, combining …

Changes In The Epigenetic Landscape Of Oligodendrocyte Progenitor Cells With Time, David K. Dansu

Dissertations, Theses, and Capstone Projects

Most neonatal oligodendrocyte progenitors (nOPCs) give rise to myelinating oligodendrocytes during development, while a proportion are retained as proliferative undifferentiated cells in the adult brain (aOPCs). Previous studies have reported distinct properties for those two populations but the molecular mechanisms underlying these intrinsic differences are not well understood. Using RNA-sequencing and unbiased histone proteomics analysis, we identify transcripts and histone marks that are higher in aOPCs than nOPCs. The genome-wide ChIP-sequencing analysis of chromatin from aOPCs compared to nOPCs detects greater occupancy of the H4K8ac mark at loci corresponding to the higher transcript levels of oligodendrocyte-specific transcription factors and lipid …

Nanoscale Modeling Of Membrane Systems Under Mechanical Deformation In Traumatic Brain Injury Using Molecular Dynamics, Anh Thi Ngoc Vo

Theses and Dissertations

Neuronal membrane disruption and mechanoporation are nanoscale damage mechanisms that critically affect brain cell viability during traumatic brain injury (TBI). These nanoscale cellular impairments are elusive in experiments and necessitate in silico approaches such as molecular dynamics (MD) simulations. Implementing MD, this research aims to investigate the effects of different key factors related to membrane deformation and damage, including force field resolutions, lipid compositions, and loading conditions.

To examine the impact of force field resolution, MD deformation simulations were conducted on 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) lipid bilayer membranes, using all-atom (AA), united-atom (UA), and coarse-grained Martini (CG-M) force fields. The mechanical responses …

A Comparison Of Pm-Nato3’S Influence On Neural Progenitors And Mature Dopamine Neurons, Mary E. West

Masters Theses

This thesis presents significant findings regarding the role of PM-Nato3 in its interaction with developing neurons in the context of Parkinson's disease (PD) and regenerative medicine. We investigated the effects of PM-Nato3 on dopamine (DA) neurogenesis under different culture conditions, both in vitro and in vivo. In the standard dopaminergic culture condition, PM-Nato3 potentially increased the speed of DA neuron production but did not significantly increase the yield of DA neurons. In a minimal culture condition, there was no notable difference between the control and PM-Nato3 conditions, suggesting minimal impact on DA neurogenesis. In vivo studies using a mouse model …

Role Of Chronic Stress-Induced Neuroinflammation In Rodent Locus Coeruleus Physiology And Anxiety-Like Behaviors, Arthur Anthony Alfonso Reyes

Graduate School of Biomedical Sciences Theses and Dissertations

The locus coeruleus (LC), the primary site of brain norepinephrine (NE), is a key anatomical brain region implicated in the stress response. Stress is a neuroendocrine physiologic response to a stressor that promotes organism survival through adaptive change and restoration of homeostasis. The central stress response, which drives behavioral and physiological change, is primarily mediated by activating the hypothalamic-pituitary-adrenal (HPA) axis. While advantageous in the short term, chronic stress exposure can lead to HPA axis and LC dysregulation, which are thought to contribute to the etiology of anxiety disorders. Previous studies demonstrate the effects of acute stress in increasing LC …

Swallowing Disrupts Tongue-Jaw Coordination During Chewing In A Rat Model Of Parkinson's Disease, Meejan Palhang, N. Charles, Francois Gould

Rowan-Virtua Research Day

The primary motor symptoms of Parkinson’s disease, including bradykinesia, rigidity, and tremor, are associated with difficulties regulating transitions between motor behaviors due to basal ganglia dysfunction. Chewing and swallowing, which are disordered in most patients with Parkinson’s disease, are two complex motor behaviors which overlap in time and share some neuromuscular components. The objective of this study is to identify how Parkinson’s disease affects the coordination of chewing and swallowing. We hypothesize that as a result of impaired regulation of shift between motor patterns, chewing cycles that occur with a swallow will be more affected that chewing cycles occurring in …

Extravasated Brain-Reactive Autoantibodies Perturb Neuronal Surface Protein Expression In Alzheimer's Pathology, Wardah Bajwa, Mary Kosciuk, Randel L. Swanson, Anuradha Krishnan, Venkat Venkataraman, Robert Nagele, Nimish Acharya

Rowan-Virtua Research Day

Background: Increased blood-brain barrier (BBB) permeability is reported in both the neuropathological and in vivo studies in both Alzheimer’s Disease (AD) and age matched cognitively normal, no cognitive impairment (NCI), subjects. Impaired BBB allows various vascular components such as immunoglobulin G (IgG) to extravasate into the brain and specifically bind to various neuronal surface proteins (NSP), also known as brain reactive autoantibodies (BrABs). This interaction is predicted to further enhance deposition of amyloid plaques.

Hypothesis: Interaction between extravasated BrABs and its cognate NSPs lower the expression of that NSPs in AD patients.

Methods: We selected Western blotting technique to study …

Validating A New In Vivo Model To Study Als, Izabela J. Cimachowska

Student Theses and Dissertations

Buildup of oxidative stress and mitochondrial dysfunction are well known characteristics of both sporadic and hereditary amyotrophic lateral sclerosis (ALS). While both forms of the disease seem to arise from common cellular dysfunction, the genetic disease is studied to a much greater extent. Engineering novel animal models of the sporadic form of the disease is crucial for development of druggable targets to treat ALS and understand the underlying mechanisms. Interestingly, accumulation of oxidative stress by exacerbated emission of reactive oxygen species (ROS) from presynaptic mitochondria is a hallmark of both hereditary and sporadic ALS. Previous work by our laboratory showed …

Understanding The Expression And Role Of Pros-1 In The Male Gonad Of C. Elegans, Jack Bozik

Undergraduate Theses

The gene pros-1 is a transcription factor that is highly expressed within neuronal sheath cells, glial cells, and excretory canal cells. pros-1 plays a role in cell determination of those cell types in the nematode C. elegans, which promotes organismal development. But the degree to which pros-1 presence is important is still not fully understood, because there are many genes involved in development that when mutated or damaged can result in unexpected phenotypes or even total loss of function to a certain developmental mechanism. What makes pros-1 valuable to research is that it is a functional homologue to a …

The Role Of Schwann Cells In Nerve Injury: Forskolin-Mediated Camp Activation Upregulates Tnfα Expression Despite Nf-Κb Downregulation In Lps-Treated Schwann Cells, Caitlyn E. Henry, Angela L. Asirvatham Ph.D.

Student Research Poster Presentations 2023

Although Schwann cells are known to play a role in axonal regeneration following nerve injury and inflammation, the exact mechanism is unknown. This study explores two potential mechanisms: the NF-κB and cAMP pathways. The NF-κB pathway produces cytokines, such as TNFα, to regulate inflammation, whereas the cAMP pathway is anti-inflammatory and regulates Schwann cell proliferation via AKAP95 and cyclin D3. Although it is well-known that NF-κB and cAMP are involved in inflammation, not much is known regarding the effects of forskolin-mediated cAMP activation on LPS-mediated NF-κB activation in Schwann cells. In this study, RT4-D6P2T immortalized rat Schwann cells were treated …