Neuroscience and Neurobiology Commons^™

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.

Effect Of Nicotine On Body Composition, Laura O'Dell

Departmental Papers (Psych)

No abstract provided.

Evidence For Pit-Type (Slc20) And Napi-Ii-Type (Slc34) Transporters In The Rat Choroid Plexus, Hien M. Le

Honors Scholar Theses

: A major function of the brain choroid plexus (CP) is to regulate the exchange of solutes between the blood plasma and the cerebrospinal fluid (CSF) using selective transporters. CSF inorganic phosphate (P_i) concentration is maintained at about one-half that of plasma and is potentially important because of its regulatory, structural, and biochemical functions. Phosphate is critical for ATP and DNA formation, the linked regulation between phosphate and calcium, and as an intracellular buffer. The human body has two major P_i transporter gene families known as SLC34 (NaPi-II) and SLC20 (PiT), which have wide tissue distribution. Although …

Effects Of Maternal Low Protein Diet On Expression Of Drug Transporters In The Blood-Brain Barrier Of Adult Offspring, Bonnie L. Hastings

Senior Theses

Adverse uterine environment, manifested as low birth weight (LBW), has been shown to predispose individuals to hypertension, diabetes, and obesity by mechanisms that are just beginning to be understood. One of the mechanisms is the dysregulation of the expression or function of drug transport proteins, such as the organic anion transporter (OAT) family, which are crucial for the transport of various endogenous and exogenous compounds into and out of all organs, especially the brain. Hence, we examined the status of select drug transporters in the blood-brain barrier (BBB), using a LBW rat model. Maternal low protein diet (LPD) during gestation …

Structural Analysis Of The Drosophila Innexin Shakb: Role Of The N-Terminus In Rectifying Electrical Synapses, William Marks

Biology Theses

Gap junction channels mediate direct intercellular communication in all multicellular animals. They are comprised of the connexin family of proteins in vertebrates and the innexin family in prechordates. Connexins and innexins share many functional and structural similarities as orthologous proteins. Both types are capable of forming electrical synapses. Rectifying junctions are specialized electrical synapses found in neural systems that control escape responses. It has been shown that heterotypic gap junction channels mediate asymmetric properties of rectifying junctions. Shaking B N+16 and Shaking B lethal are variants of the ShakB locus in Drosophila and the organization of these innexins into heterotypic …

Parkinson’S Disease: Molecular Mechanisms And Treatments, Delia Vahey

Senior Honors Theses

Parkinson’s disease is a motor system disorder that is caused primarily by the loss of dopamine-producing brain cells. The most affected brain structure is the pars compacta of the substantia nigra. This area of the brain is essential to the control of voluntary movement, and so its impairment leads to symptoms such as tremors, rigidity, and impaired balance. The neuronal protein alpha-synuclein has been shown to be heavily involved in the pathogenesis of the disease at the cellular level. The currently available treatments for PD mainly target dopamine regulation, and there been no cure developed for the disease at present. …

Detection Of Sk2 Channels On Hippocampal Neurons, Jamie L. Maciaszek

Master's Theses

Calcium-activated small conductance potassium channels (SK) are crucial for synaptic plasticity, sleep, and learning and memory (Hammond, Bond et al. 2006; Cueni, Canepari et al. 2008; Lin, Lujan et al. 2008). Despite the recent progress on SK channel physiology, the precise spatial organization of SK channels in neurons has remained unknown. Such knowledge is critical as the subcellular distribution of SK channels is an important determinant of neuronal excitability. Currently, there are no techniques to image ion channel distribution quantitatively at the nanometer scale in living cells. Here, it is demonstrated that integration of natural toxins with single molecule atomic …

Angioarchitecture Of The Adult Rat Neuroendocrine Hypothalamus, Nicolas D. Silva^, Arshad M. Khan*

COURI Symposium Abstracts, Spring 2012

No abstract provided.

Stress-Induced Activation Of Distinct Subpopulations Of Neurons In The Basolateral Amygdala Of The Rat, Juan M. Bolanos^, Jameel N. Hamdan, Victor M. Rosales, Kristin L. Gosselink*

COURI Symposium Abstracts, Spring 2012

No abstract provided.

Integration Of Subthreshold And Suprathreshold Excitatory Barrages Along The Somatodendritic Axis Of Pyramidal Neurons, Hysell V. Oviedo, Alex D. Reyes

Publications and Research

Neurons integrate inputs arriving in different cellular compartments to produce action potentials that are transmitted to other neurons. Because of the voltage- and time-dependent conductances in the dendrites and soma, summation of synaptic inputs is complex. To examine summation of membrane potentials and firing rates, we performed whole-cell recordings from layer 5 cortical pyramidal neurons in acute slices of the rat’s somatosensory cortex. We delivered subthreshold and suprathreshold stimuli at the soma and several sites on the apical dendrite, and injected inputs that mimic synaptic barrages at individual or distributed sites. We found that summation of subthreshold potentials differed from …

Selective Serotonergic Excitation Of Callosal Projection Neurons, Daniel Avesar, Allan T. Gulledge

Dartmouth Scholarship

Serotonin (5-HT) acting as a neurotransmitter in the cerebral cortex is critical for cognitive function, yet how 5-HT regulates information processing in cortical circuits is not well understood. We tested the serotonergic responsiveness of layer 5 pyramidal neurons (L5PNs) in the mouse medial prefrontal cortex (mPFC), and found three distinct response types: long-lasting 5-HT_1A (1A) receptor-dependent inhibitory responses (84% of L5PNs), 5-HT_2A (2A) receptor-dependent excitatory responses (9%), and biphasic responses in which 2A-dependent excitation followed brief inhibition (5%). Relative to 5-HT-inhibited neurons, those excited by 5-HT had physiological properties characteristic of callosal/commissural (COM) neurons that project to the …

Pten Regulation Of Local And Long-Range Connections In Mouse Auditory Cortex, Qiaojie Xiong, Hysell V. Oviedo, Lloyd C. Trotman, Anthony M. Zador

Publications and Research

Autism spectrum disorders (ASDs) are highly heritable developmental disorders caused by a heterogeneous collection of genetic lesions. Here we use a mouse model to study the effect on cortical connectivity of disrupting the ASD candidate gene PTEN (phosphatase and tensin homolog deleted on chromosome 10). Through Cre-mediated recombination, we conditionally knocked out PTEN expression in a subset of auditory cortical neurons. Analysis of long-range connectivity using channelrhodopsin-2 revealed that the strength of synaptic inputs from both the contralateral auditory cortex and from the thalamus onto PTEN-cko neurons was enhanced compared with nearby neurons with normal PTEN expression. Laser-scanning photostimulation showed …

Domain Architecture Of A Calcium-Permeable Ampa Receptor In A Ligand-Free Conformation, Charles R. Midgett, Avinash Gill, Dean R. Madden

Dartmouth Scholarship

Ligand-gated ion channels couple the free energy of agonist binding to the gating of selective transmembrane ion pores, permitting cells to regulate ion flux in response to external chemical stimuli. However, the stereochemical mechanisms responsible for this coupling remain obscure. In the case of the ionotropic glutamate receptors (iGluRs), the modular nature of receptor subunits has facilitated structural analysis of the N-terminal domain (NTD), and of multiple conformations of the ligand-binding domain (LBD). Recently, the crystallographic structure of an antagonist-bound form of the receptor was determined. However, disulfide trapping of this conformation blocks channel opening, suggesting that channel activation involves …

Conditioned Response Evoked By Nicotine Conditioned Stimulus Preferentially Induces C-Fos Expression In Medial Regions Of Caudate-Putamen, Sergios Charntikov, Matthew E. Tracy, Changjiu Zhao, Ming Li, Rick A. Bevins

Department of Psychology: Faculty Publications

Nicotine has both unconditioned and conditioned stimulus properties. Conditioned stimulus properties of nicotine may contribute to the tenacity of nicotine addiction. The purpose of this experiment was to use neurohistochemical analysis of rapidly developing c-Fos protein to elucidate neurobiological loci involved in the processing of nicotine as an interoceptive conditioned stimulus (CS). Rats were injected (SC) in an intermixed fashion with saline or nicotine (16 sessions of each) and placed in conditioning chambers where they were given one of the three conditions depending on group assignment: (a) nicotine paired 100% of the time with intermittent access to sucrose (nicotine-CS condition), …

Structure-Function Analysis Of Nel, A Thrombospondin-1-Like Glycoprotein Involved In Neural Development And Functions, Masaru Nakamoto

Biology Faculty Publications

Nel (neural epidermal growth factor (EGF)-like molecule) is a multimeric, multimodular extracellular glycoprotein with heparin-binding activity and structural similarities to thrombospondin-1. Nel is predominantly expressed in the nervous system and has been implicated in neuronal proliferation and differentiation, retinal axon guidance, synaptic functions, and spatial learning. The Nel protein contains an N-terminal thrombospondin-1 (TSP-N) domain, five cysteine-rich domains, and six EGF-like domains. However, little is known about the functions of specific domains of the Nel protein. In this study, we have performed structure-function analysis of Nel, by using a series of expression constructs for different regions of the Nel protein. …

Investigating The Role Of Prion Protein Polymorphisms On Prion Pathogenesis, Eri Saijo

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are lethal and infectious neurodegenerative diseases of humans and animals. The misfolding of the normal, or cellular isoform of the prion protein (PrP^C) into the abnormal disease-associated isoform of PrP (PrP^Sc) could change the properties of PrP, consequently, PrP^Sc has lethal infectivity to transmit diseases. The proteinaceous infectious particle consisting mainly of PrP^Sc is called prion. Transmissibility of prions is strongly influenced by multiple factors including PrP polymorphisms, species barriers (PrP sequence specificity) and prion strains (conformational specificity) by unknown mechanisms. Even though the ability …

The Cellular Nucleic Acid Binding Protein Regulates The Alzheimer’S Disease Β-Secretase Protein Bace1, Christopher J. Holler

Theses and Dissertations--Molecular and Cellular Biochemistry

Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly population and is believed to be caused by the overproduction and accumulation of the toxic amyloid beta (Aβ) peptide in the brain. Aβ is produced by two separate enzymatic cleavage events of the larger membrane bound amyloid precursor protein, APP. The first, and rate-limiting, cleavage event is made by beta-secretase, or BACE1, and is thus an attractive therapeutic target. Our lab, as well as many others, has shown that BACE1 protein and activity are increased in late-stage sporadic AD. We have extended these findings to show that BACE1 …

Iptakalim Preferentially Decreases Nicotine-Induced Hyperlocomotion In Phencyclidine-Sensitized Rats: A Potential Dual Action Against Nicotine Addiction And Psychosis, Nick Volf, Gang Hu, Ming Li

Department of Psychology: Faculty Publications

Objective: Iptakalim is a putative ATP-sensitive potassium (KATP) channel opener. It is also a novel nicotinic acetylcholine receptor (nAChR) blocker and can antagonize nicotine-induced increase in dopamine release in the nucleus accumbens. Our recent work also shows that iptakalim exhibits a clozapine-like atypical antipsychotic profile, indicating that iptakalim may possess a dual action against nicotine addiction and schizophrenia.

Methods: The present study examined the potential therapeutic effects of iptakalim on nicotine use in schizophrenia. We created an animal model of comorbidity of nicotine addiction and schizophrenia by injecting male Sprague-Dawley rats with nicotine (0.40 mg/kg, subcutaneously［sc］) or saline, in combination …

A Proposal To Test The Effects Of Factor Ecat1 On Pluripotency, From Reprogramming To Differentiation Of Human Somatic Cells, Vritti R. Goel

CMC Senior Theses

The field of stem cell research has been growing more because of the interest in using stem cells to cure diseases and heal injuries. Human embryonic stem cells, because of the controversy surrounding them—and subsequently the difficulties in acquiring samples of the existing aging cell lines—can only be used in limited capacities. While the development of induced pluripotent stem cells in the last decade has allowed the field to progress closer to medical treatments, the low efficiency of reprogramming a somatic cell to a pluripotent state, and the vast molecular and genomic differences between human embryonic stem cells and human …

Map Kinases Couple Hindbrain-Derived Catecholamine Signals To Hypothalamic Adrenocortical Control Mechanisms During Glycemia-Related Challenges, Arshad Khan, Kimberly Kaminski, Graciela Sanchez-Watts, Todd Ponzio, J. Kuzmiski, Jaideep Bains, Alan Watts

Selected Works Temporary Series

No abstract provided.

Map Kinases Couple Hindbrain-Derived Catecholamine Signals To Hypothalamic Adrenocortical Control Mechanisms During Glycemia-Related Challenges, Khan, Kimberly Kaminski, Graciela Sanchez-Watts, Todd Ponzio, J. Kuzmiski, Jaideep Bains, Alan Watts

Departmental Papers (Biology)

No abstract provided.