Molecular and Cellular Neuroscience Commons^™

The Triggering Receptor Expressed On Myeloid Cells 2: “Trem-Ming” The Inflammatory Component Associated With Alzheimer's Disease, Troy T. Rohn

Biology Faculty Publications and Presentations

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by a progressive loss of memory and cognitive skills. Although much attention has been devoted concerning the contribution of the microscopic lesions, senile plaques, and neurofibrillary tangles to the disease process, inflammation has long been suspected to play a major role in the etiology of AD. Recently, a novel variant in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has been identified that has refocused the spotlight back onto inflammation as a major contributing factor in AD. Variants in TREM2 triple one's risk of developing late-onset AD. …

Rescuing Acetylcholinesterase From Nerve Agent Inhibition: Protein Dynamics Driven Drug Discovery, Aiyana M. Emigh, Brian Bennion

STAR Program Research Presentations

Severe morbidity and mortality consequences result from irreversible inhibition of human acetylcholinesterase by organophosphates (OPs). Oxime-based reactivators are currently the only available treatments but lack efficacy in the central nervous system (CNS) where the most damage occurs. Computational docking and molecular dynamics (MD) simulations reveal complex structural barriers that may reduce oxime efficacy. These results may guide future drug designs of more effective countermeasures.

Aβ Alters The Dna Methylation Status Of Cell-Fate Genes In An Alzheimer’S Disease Model, Gary D. Isaacs, Noor Taher, Courtney Mckenzie, Rebecca Garrett, Matthew Baker, Nena Fox

Faculty Publications and Presentations

Alzheimer’s disease (AD) is characterized by neurofibrillary tangles and extracellular amyloid-β plaques (Aβ). Despite ongoing research, some ambiguity remains surrounding the role of Aβ in the pathogenesis of this neurodegenerative disease. While several studies have focused on the mutations associated with AD, our understanding of the epigenetic contributions to the disease remains less clear. To that end, we determined the changes in DNA methylation in differentiated human neurons with and without Aβ treatment. We isolated the DNA from neurons treated with Aβ or vehicle, and digested the two samples with either a methylation-sensitive (HpaII) or a methylation-insensitive (MspI) restriction endonuclease. …

Peripheral Nerve Injury Is Associated With Chronic, Reversible Changes In Global Dna Methylation In The Mouse Prefrontal Cortex, Maral Tajerian, Sebastian Alvarado, Magali Millecamps, Pascal Vachon, Cecilia Crosby, M. Catherine Bushnell, Moshe Szyf, Laura S. Stone

Publications and Research

Changes in brain structure and cortical function are associated with many chronic pain conditions including low back pain and fibromyalgia. The magnitude of these changes correlates with the duration and/or the intensity of chronic pain. Most studies report changes in common areas involved in pain modulation, including the prefrontal cortex (PFC), and pain-related pathological changes in the PFC can be reversed with effective treatment. While the mechanisms underlying these changes are unknown, they must be dynamically regulated. Epigenetic modulation of gene expression in response to experience and environment is reversible and dynamic. Epigenetic modulation by DNA methylation is associated with …

Changes In Sleep Architecture And Cognition With Age And Psychosocial Stress: A Study In Fischer 344 Rats, Heather M. Buechel

Theses and Dissertations--Pharmacology and Nutritional Sciences

Changes in both sleep architecture and cognition are common with age. Typically these changes have a negative connotation: sleep fragmentation, insomnia, and deep sleep loss as well as forgetfulness, lack of focus, and even dementia and Alzheimer’s disease. Research has shown that psychosocial stressors, such as isolation from family and friends or loss of a loved one can also have significant negative effects on sleep architecture and cognitive capabilities. This leaves the elderly in a particularly vulnerable situation: suffering from cognitive decline and sleep dysregulation already, and more likely to respond negatively to psychosocial stressors. Taking all of these factors …

Diet-Induced Obesity: Dopaminergic And Behavioral Mechanisms As Outcomes And Predictors, Vidya Narayanaswami

Theses and Dissertations--Pharmacy

Obesity and drug abuse share common neural circuitries including the mesocoticolimbic and striatal dopamine reward system. In the current study, a rat model of diet-induced obesity (DIO) was used to determine striatal dopamine function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. For the outcome study, rats were randomly assigned a high-fat (HF) or a low-fat (LF) diet for 8 wk. Following the 8-wk HF-diet exposure, rats were segregated into obesity-prone and obesity-resistant groups based on maximum and minimum body weight gain, respectively, and neurobehavioral outcomes were evaluated. For the predictor study, neurobehavioral antecedents were evaluated prior to …

Injury Establishes Constitutive Μ-Opioid Receptor Activity Leading To Lasting Endogenous Analgesia And Dependence, Gregory F. Corder

Theses and Dissertations--Physiology

Injury causes increased pain sensation in humans and animals but the mechanisms underlying the emergence of persistent pathological pain states, which arise in the absence of on-going physical damage, are unclear. Therefore, elucidating the physiological regulation of such intractable pain is of exceptional biomedical importance. It is well known that endogenous activation of µ-opioid receptors (MORs) provides relief from acute pain but the consequences of prolonged endogenous opioidergic signaling have not been considered. Here we test the hypothesis that the intrinsic mechanisms of MOR signaling promote pathological sensitization of pain circuits in the spinal cord. We found that tissue inflammation …

Olanzapine Sensitization And Clozapine Tolerance: From Adolescence To Adulthood In The Conditioned Avoidance Response Model, Jing Qiao, Hong Li, Ming Li

Department of Psychology: Faculty Publications

Disruption of conditioned avoidance response (CAR) in rodents is one trademark feature of many antipsychotic drugs. In adult rats, repeated olanzapine (OLZ) treatment causes an enhanced disruption of avoidance response (sensitization), whereas repeated clozapine (CLZ) treatment causes a decreased disruption (tolerance). The present study addressed (1) whether OLZ sensitization and CLZ tolerance can be induced in adolescent rats, and (2) the extent to which OLZ sensitization and CLZ tolerance induced in adolescence persists into adulthood. Male adolescent Sprague–Dawley rats (approximate postnatal days (BP) 43–47) were first treated with OLZ (1.0 or 2.0 mg/kg, subcutaneously (sc)) or CLZ (10 or 20 …

The Cellular Nucleic Acid Binding Protein In Aging And Disease, Robin Webb

Theses and Dissertations--Molecular and Cellular Biochemistry

The ZNF9 gene on chromosome 3 encodes the cellular nucleic acid binding protein (CNBP), a ubiquitously expressed, 177 amino acid (≈19.5kDa) protein that is highly conserved among vertebrates. The function of the protein is largely unknown, however an expansion in the first intron of the protein results in myotonic dystrophy type 2 (DM2), a multisystemic disease featuring cardiac arrhythmia, muscle wasting, cataracts, and a range of neuropathologies. Remarkably, we recently discovered that CNBP is involved in regulating the activity of β-secretase, the enzyme that produces the first cleavage event in the generation of the amyloid-β peptide (Aβ). The progressive fibrillization …

A Dna Computer For Glioblastoma Multiforme Diagnosis And Drug Delivery, Sumaiya F. Hashmi

CMC Senior Theses

Glioblastoma multiforme (GBM) is a debilitating malignant brain tumor with expected patient survival of less than a year and limited responsiveness to most treatments, often requiring biopsy for diagnosis and invasive surgery for treatment. We propose a DNA computer system, consisting of input, computation, and output components, for diagnosis and treatment. The input component will detect the presence of three GBM biomarkers: vascular endothelial growth factor (VEGF), caveolin-1α (CAV), and B2 receptors. The computation component will include indicator segments for each of these genes, and ensure that output is only released if all the biomarkers are present. The output component …

Doxorubicin-Induced, Tnf-Α-Mediated Brain Oxidative Stress, Neurochemical Alterations, And Cognitive Decline: Insights Into Mechanisms Of Chemotherapy Induced Cognitive Impairment And Its Prevention, Jeriel T. Keeney

Theses and Dissertations--Chemistry

The works presented in this dissertation provide insights into the mechanisms of chemotherapy-induced cognitive impairment (CICI or “ChemoBrain”) and take steps toward outlining a preventive strategy. CICI is now widely recognized as a complication of cancer chemotherapy experienced by a large percentage of cancer survivors. Approximately fifty percent of existing FDA-approved anti-cancer drugs generate reactive oxygen species (ROS). Doxorubicin (Dox), a prototypical ROS-generating chemotherapeutic agent, produces the reactive superoxide radical anion (O₂^-•) in vivo. Dox treatment results in oxidation of plasma proteins, including ApoA-I, leading to TNF-α-mediated oxidative stress in plasma and brain. TNF-α elevation in brain …

Cellular And Molecular Mechanisms Underlying The Interaction Of Apoe And Estrogen In Olfactory Neuronal Growth-Potential Relevance To Alzheimer's Disease, Minh Luong

Masters Theses

In recent years, there have been many studies looking at estrogen therapy (ET) as a treatment for Alzheimer's disease. Literature review suggests a close relationship between estrogen and apolipoprotein E (apoE) in the central nervous system. The mechanism underlying the interaction of apoE genotype with estrogen in the nervous system is not yet known. Therefore, the objectives of this research are 1) to determine the effects of estradiol treatment on basal cell proliferation and neuronal differentiation and 2) to identify the estrogen receptor subtype (ERα and ERβ) that mediates the increase of apoE levels, neurite outgrowth and neuronal numbers.

Results …

Validation Of Interaction Between The Glyt2 And The Nsf, David Quispe Escudero, Hector Cuevas, Luciana Girotto Gentil, Manuel Miranda

COURI Symposium Abstracts, Summer 2012

The Glycine Transporter 2 (GlyT2) is a presynaptic membrane transporter in charge of re-uptake of glycine from the synaptic cleft back into the presynaptic neuron. GlyT2 is present only in vertebrate neurons and possesses a 200 amino- acid long N-terminal tail of unknown function. We hypothesize that such domain serve as a docking site for a network of presynaptic proteins, such as NSF that plays a pivotal role during vesicle transport. Therefore, our goal in this project is to analyze protein-protein interaction between GlyT2 and NSF. We have used co-immunoprecipitation experiments from rat brainstem with GlyT2 and NSF antibodies as …

Inhibitors Of Polyisoprenylated Methylated Protein Methyl Esterase (Pmpmease) Cause Neurodegeneration By Altering Microtubules And Gβγ In Pc12 Cells, Jose A. Rivas Jr., Rebekah M. Bach, Jessica Martinez-Jurado, Jorge A. Siera-Fonseca, Sukla Roychowdhury

COURI Symposium Abstracts, Summer 2012

Neurodegeneration, a progressive loss of nerve cells (neurons), occurs in many neurological disorders including Alzheimer’s disease, Parkinson’s disease, Schizophrenia and drug addiction. Disruption of Microtubules (MTs), a major component of cytoskeleton and aggregation of proteins associated with them is the hallmark of neurodegeneration. Gβγ, an important component of G protein signaling has been shown to induce neurite outgrowth of PC12 cells by interacting with microtubules. The goal of the present study is to understand whether interfering with Gβγ-MT mediated pathway causes neurodegeneration. Because prenylation of γ subunits is important for the interaction of Gβγ with MTs, we used inhibitors (L-23 …

Gβγ-Microtubule Interaction And Neurodegeneration, Jane K. Martinez, Jorge Sierra, Sukla Roychowdhury Ph.D.

COURI Symposium Abstracts, Summer 2012

Aberrant organization of microtubules (MTs) is known to be a feature of neurodegeneration, which occurs in many neurological disorder including Alzheimer’s disease, Parkinson’s disease, neuropsychiatric illness such as schizophrenia, and drug addiction. Previously, Gβγ, an important component of G protein-coupled signaling pathways, has been shown to regulate neurite outgrowth by interacting with MTs. The aim of the present study is to understand the Gβγ regulation of MT assembly and its relation to neurodegeneration, using GRK-ct peptide (consists of the carboxy terminus of G protein-coupled-receptor kinase) which is known to inhibit Gβγ-dependent signaling by binding to and sequestering Gβγ. PC12 cells …

Characterization And Localization Of Glycinergic Neurons From The Mouse Brain Stem, Astrid M. Rodriguez, Alejandra C. Camacho, Manuel Miranda

COURI Symposium Abstracts, Summer 2012

The neurotransmitter glycine functions as the major inhibitory neurotransmitter in the brain stem, cerebellum and spinal cord, where is contained in synaptic vesicles within glycinergic neurons. However the location of cell bodies, neuronal projections and connections are undefined to date. While the presence of glycine, the glycine transporters GlyT1, GlyT2 and the vesicular glycine transporter VIAAT may define a glycinergic neuron, little efforts have been made to investigate these neurons. To better identify and characterize these glycinergic neurons, we prepared primary cultures from the brain stem and the retina, using a transgenic mouse that expresses the green fluorescent protein (GFP) …

The Regulation Of The Glycine Transporter 1 By Phosphorylation, Alejandro A. Acuna, Qi Zhang, Vicente Castrejon, Luciana Girotto Gentil, Manuel Miranda

COURI Symposium Abstracts, Summer 2012

The plasma membrane glycine transporters 1 (GlyT1) is the carrier molecule responsible for the fast removal of the inhibitory neurotransmitter glycine from the synaptic cleft back into the presynaptic terminals of glycinergic neurons by an electrogenic, Na⁺-Cl^- transport couple mechanism maintained by the Na⁺,K⁺-ATPase. GlyTs belong to SLC6 family that includes other neurotransmitter transporters, such as the dopamine, norepinephrine, serotonin, and GABA transporters. In order to determine the role of PKC-dependent phosphorylation on GlyT1, we have analyzed the effect of PKC activation by phorbol ester (PMA) on the activity, post-translational modifications and the …

Insights Into The Role Of The N-Terminus Of The Neuronal Glycine Transporter 2, Diego A. Escobar-Garcia, Ana Garibay, Miryam Pando, Manuel Miranda

COURI Symposium Abstracts, Summer 2012

Hyperekplexia is distinguished by exaggerated muscle tension, sudden shock and even death in response to touch/acoustic stimuli. Genetic analysis showed that mutations on glycinergic proteins on the presynaptic neurons are responsible for the attacks. Mutations in the Glycine Transporter 2 (GlyT2) have been suggested to be the second major cause of hyperekplexia. The GlyT2 consist of twelve transmembrane domains, a 201 amino acid long N-terminus and a shorter C-terminus, both intracellular. Dysfunction of this transporter prevents the intake of glycine from the synapse back to the presynaptic neuron. Our goal is to better understand the role of N-terminus on protein …

Dynamic Gene Expression In The Human Cerebral Cortex Distinguishes Children From Adults, Kirstin N. Sterner, Amy Weckle, Harry T. Chugani, Adi L. Tarca, Chet C. Sherwood, Patrick R. Hof, Christopher W. Kuzawa, Amy M. Boddy, Asad Abbas, Ryan L. Raaum, Lucie Grégoire, Leonard Lipovich, Lawrence I. Grossman, Monica Uddin, Morris Goodman, Derek E. Wildman

Publications and Research

In comparison with other primate species, humans have an extended juvenile period during which the brain is more plastic. In the current study we sought to examine gene expression in the cerebral cortex during development in the context of this adaptive plasticity. We introduce an approach designed to discriminate genes with variable as opposed to uniform patterns of gene expression and found that greater inter-individual variance is observed among children than among adults. For the 337 transcripts that show this pattern, we found a significant overrepresentation of genes annotated to the immune system process (pFDR>0). Moreover, genes known to …

Effect Of Nicotine On Body Composition, Laura O'Dell

Selected Works Temporary Series

No abstract provided.