Molecular and Cellular Neuroscience Commons^™

The Role Of Semaphorins In Response To Injury In C. Elegans Neurons, Maria Belen Harreguy Alfonso

Dissertations

When neural tissue is injured by trauma, delicate neuronal processes such as axons and dendrites are prone to lesion damage and often disconnect. The molecular, cellular, and circuit mechanisms that underlie the regrowth and reconnection of these processes and the recovery of behavior are major challenges in the fields of neuroscience, regeneration, and resilience. At the molecular and cellular levels, signaling pathways that mediate neuronal growth cone guidance during development can play a role in neuronal regeneration and recovery from injury. One family of signaling proteins involved in this process comprises the highly conserved semaphorins and their receptors, the plexins. …

Role Of The Anti-Viral Immune Response In Neural Cell Modulation And Neurological Sequelae Of Childhood Viral Infections, Yashika Kamte

Electronic Theses and Dissertations

Viral infections of the central nervous system (CNS) often result in neurological sequelae and are considered a risk factor for the development of neurological disease. Moreover, the outcomes of a viral infection are largely dependent on the age of the host, with younger hosts developing more profound neuropathology. Perhaps the developing brain coupled with an immature immune system contributes to worse outcomes in the very young. Children suffering from brain infections are more prone to develop enduring neurological impairments even after recovery from the infection. Although majority of the brain growth occurs in utero, neurodevelopment continues throughout the juvenile …

Cardiac Vagal Dysfunction And Ventricular Arrhythmogenesis In Type 2 Diabetes Mellitus After Myocardial Infarction, Dongze Zhang

Theses & Dissertations

Diabetes is the eighth leading cause of death in the United States. Every eight seconds a person dies from diabetes around the world. Among various types of diabetes, type 2 diabetes mellitus (T2DM) is the most common form, representing 90% to 95% of all diabetes populations. The leading cause of mortality and morbidity in T2DM patients is cardiovascular disease, among which acute myocardial infarction (MI)-induced ventricular arrhythmia is the major cause of death in T2DM. Patients with T2DM are two to four times more likely to die from MI than non-diabetic patients. Although well-known therapies including better glycemic control have …

Jun Upregulation Drives Aberrant Transposable Element Mobilization, Associated Innate Immune Response, And Impaired Neurogenesis In Alzheimer’S Disease, Chiara Scopa, Samantha Barnada, Maria Cicardi, Mo Singer, Davide Trotti, Marco Trizzino

Farber Institute for Neuroscience Faculty Papers

Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer's disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death …

Central Activation Of Orl-1 Receptors In Heart Failure Models, Jeffrey Angell

Theses & Dissertations

Heart failure is a prevalent and debilitating disease associated with high morbidity and mortality rates worldwide and is the leading cause of death in the United States. While various therapeutic strategies have been developed and approved to manage heart failure, exploration of novel targets and mechanisms are essential for improving patient outcomes. This thesis investigates the therapeutic potential of the central activation of opioid receptor-like 1 (ORL-1) by nociceptin in a rodent heart failure model.

Furthermore, this study aims to elucidate the central mechanisms underlying nociceptin induced cardiovascular and renal effects in heart failure. This involves investigating neuronal pathways and …

Deciphering The Role Of Huntingtin In Endosomal Functions, Yue Yu

Dissertations and Theses (Open Access)

Huntington's disease (HD), a neurodegenerative disorder, is a result of an abnormal expansion of CAG trinucleotide repeat encoding an extended polyglutamine (polyQ) tract in the coding region of Huntingtin (HTT) gene. While antisense oligonucleotide (ASO) strategies aimed at lowering mutant HTT levels seemed promising, recent clinical trials were unsuccessful due to worsening patient outcomes in the ASO treatment group compared to the placebo. This may be attributed to potential adverse effects resulting from decreased levels of normal HTT, which could play a pivotal role in brain functions and HD progression. The impact of reduced HTT levels on cellular functions and …

Identification And Delineation Of Neuronal Pathways Underlying Hypophagia, Jing Cai

Dissertations and Theses (Open Access)

In terms of metabolism, eating disorders manifest in two extreme directions: overnutrition, which can lead to obesity, and malnutrition, which can result in underweight or even starvation. Both extremes compromise the quality of life. According to the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) standard, eating disorders affect up to 17.9% of young women and 2.4% of young men. Although eating disorders are primarily defined as mental disorders rather than metabolic disorders, they are intertwined with complex emotions and sensory perceptions. However, in contemporary animal research related to eating disorders and feeding behaviors, the majority of neuroscientists still examine …

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 …

Assessing The Potentiation Of The (Alpha4)3(Beta2)2 Nicotinic Acetylcholine Receptor By Analogs Of The Allosteric Agonist Cmpi, Josue Gaona, Marcos Bermudez, Wilder Felix, Amaya Rolling, Ganesh Thakur, Ayman K. Hamouda

School of Medicine Student Publications and Presentations

The (α4)3(β2)2 nicotinic acetylcholine receptor (nAChR) is the major heteromeric nAChR isoform expressed in the cortex and is believed to play a role in memory, cognition, and neuronal survival during aging. As such, selective potentiators of the (α4)3(β2)2 nAChR have potential therapeutic benefits in conditions associated with decline in the output of nAChR in the brain. In previous work, we have studied the pharmacology of the allosteric agonist CMPI (3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)- 1H-pyrazol-4-yl) isoxazole) at the (α4)3(β2)2 nAChR and identified its binding site at the α4:α4 subunit extracellular interface. As part of our ongoing efforts to define structural features that confer CMPI …

Synapse-Associated Protein 102 – A Highly Mobile Maguk Predominate In Early Synaptogenesis, Dominique Alexandra De Los Reyes, Mohammad Yaman Karkoutly, Yonghong Zhang

School of Integrative Biological & Chemical Sciences Faculty Publications

Neurodevelopmental and neurodegenerative disorders are primarily characterized by serious structural and functional changes in excitatory glutamatergic synapses in the brain, resulting in many synaptic deficits and aberrant synapse loss. It is a big challenge to reverse these synaptic impairments as a treatment for neurological diseases in the field. Extensive research on glutamate receptors as therapeutic targets has been done but with little success shown in human trials. PSD-95-like MAGUK proteins perform a pivotal role in regulating the trafficking and stability of glutamate receptors that are important to postsynaptic structure and function. MAGUK and MAGUK-modulated synaptic pathways are becoming promising candidates …

A Blunted Th17 Cytokine Signature In Women With Mild Cognitive Impairment: Insights From Inflammatory Profiling Of A Community-Based Cohort Of Older Adults, Adam D. Bachstetter, Jenny Lutshumba, Edric D. Winford, Erin L. Abner, Barbra J. Martin, Jordan P. Harp, Linda J. Van Eldik, Frederick A. Schmitt, Donna M. Wilcock, Ann M. Stowe, Gregory A. Jicha, Barbara S. Nikolajczyk

Markey Cancer Center Faculty Publications

People with dementia have an increase in brain inflammation, caused in part by innate and adaptive immune cells. However, it remains unknown whether dementia-associated diseases alter neuro-immune reflex arcs to impact the systemic immune system. We examined peripheral immune cells from a community-based cohort of older adults to test if systemic inflammatory cytokine signatures associated with early stages of cognitive impairment. Human peripheral blood mononuclear cells were cultured with monocyte or T-cell-targeted stimuli, and multiplex assays quantitated cytokines in the conditioned media. Following T-cell-targeted stimulation, cells from women with cognitive impairment produced lower amounts of TH17 cytokines compared with cells …

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 …

Proteasome Inhibition Protects Blood–Brain Barrier P-Glycoprotein And Lowers Aβ Brain Levels In An Alzheimer’S Disease Model, Milica Vulin, Yu Zhong, Bryan J. Maloney, Björn Bauer, Anika M. S. Hartz

Markey Cancer Center Faculty Publications

Background Loss of P-glycoprotein (P-gp) at the blood–brain barrier contributes to amyloid-β (Aβ) brain accumulation in Alzheimer’s disease (AD). Using transgenic human amyloid precursor protein (hAPP)-overexpressing mice (Tg2576), we previously showed that Aβ triggers P-gp loss by activating the ubiquitin–proteasome pathway, which leads to P-gp degradation. Furthermore, we showed that inhibiting the ubiquitin-activating enzyme (E1) prevents P-gp loss and lowers Aβ accumulation in the brain of hAPP mice. Based on these data, we hypothesized that repurposing the FDA-approved proteasome inhibitor, bortezomib (Velcade®; BTZ), protects blood–brain barrier P-gp from degradation in hAPP mice in vivo.

Methods We treated hAPP mice with …

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). …

Palmitoylation As A Regulator Of Maguk Proteins Postsynaptic Localization, Rozena Shirvani-Arani, Santiago Balderas, Yonghong Zhang, Xioaqian Fang

Research Symposium

Synaptic plasticity is the ability of the brain to make changes and the changes occur at synapses. To achieve the complicated functions, a good number of proteins are present at synapse and are called synaptic proteins. To stabilize these proteins at synapses, proteins are modified through posttranslational modifications (PTMs). The most studied PTMs include phosphorylation, acetylation, ubiquitination, glycosylation, palmitoylation, etc. Palmitoylation is a type of lipid modification and has received more attention recently for its contribution to protein trafficking, localization, and interaction in various synaptic plasticity. The membrane-associated guanylate kinase (MAGUK) family includes PSD-95, PSD-93 (also known as chapsyn-110), SAP102, …

Prenatal Cafeteria Diet Exposure Promotes Lymphocyte Infiltration Into The Brain And Autism-Like Behavior In The Offspring Of C57bl6 Mice, José Alfredo Castillo Luna, Martín García Juárez, Diana Reséndez Pérez, Alberto Camacho Morales

Research Symposium

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an array of etiological causes, including environmental, genetic, and immunological triggers. High-energy diets activate the immune system during prenatal stages favoring infiltration of peripheral immune cells and cytokines into the brain by the choroid plexus and circumventricular regions and altering microglial activity. Accumulation of immune entities and microglia activation in brain have been reported to disrupt social behavior. However, the interplay between prenatal exposure to high-energy diets, neuroinflammation and defective social behavior has not been reported.

Methods: Female C57BL6 mice were exposed to cafeteria diet during pregnancy and lactation. The …

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 …

A Novel Therapeutic Strategy For Alzheimer’S Disease: Sex-Dependent Mechanisms Altered By The Hdac Inhibitor Rg2833 In A Transgenic Rat Model, Kelechi Ndukwe

Dissertations, Theses, and Capstone Projects

Alzheimer’s disease (AD) is the most common cause of dementia. In the United States, AD affects about 6.2 million Americans and is projected to reach 13.8 million by 2050. Currently, there are no effective therapies for AD and therapies targeting epigenetic mechanisms have shown to be effective in improving cognitive performance in animal models of AD. However, until now no study has reported sex-dependent mechanisms leading to differential expression of genes that contribute to changes in AD pathology. From our in silico studies, we identified an FDA-approved drug, RG2833 (N-[6-(2-aminoanilino)-6-oxohexyl]-4-methylbenzamide) that penetrates the blood brain barrier and can potentially ameliorate …

Characterization Of Pathological Tau Mutants, Charles J. Mcdonald

Dissertations, Theses, and Capstone Projects

Tau is a protein expressed exclusively in glia and neurons in the central nervous system and implicated in several neurogenerative diseases called “tauopathies”. Among all the tauopathies, one third is characterized by the presence of genetic mutations leading to the synthesis of tau proteins with single amino acid substitutions at specific locations and affecting protein function. While most of the initial studies have emphasize the functional role of tau as modulator of the axonal cytoskeleton, it has recently been well accepted that tau is also an intrinsically disordered protein that tends to form membraneless organelles called coacervates, due to a …