Molecular and Cellular Neuroscience Commons^™

Involvement Of The Sigma-1 Receptor In Methamphetamine-Mediated Changes To Astrocyte Structure And Function, Richik Neogi

Theses and Dissertations--Medical Sciences

Methamphetamine is a highly addictive psychostimulant drug. There are currently no FDA-approved pharmacological treatments for methamphetamine addiction. Pharmacologically, (+)-methamphetamine is a dopamine releasing agent and dopamine transporter substrate that redistributes dopamine from intracellular vesicles via the vesicular monoamine transporter 2 (VMAT2) and reverses the direction of dopamine transport in the dopamine transporter. Methamphetamine, cocaine, and other drugs of abuse are also sigma-1 receptor ligands, and previous studies have demonstrated the role of the sigma-1 receptor in modulating the behavioral and cellular effects of these drugs. However, almost all these studies were conducted in cell culture systems or with emphasis on …

Combination Of Investigational Cell-Based Therapy And Deep Brain Stimulation To Alter The Progression Of Parkinson’S Disease, Nader El Seblani

Theses and Dissertations--Pharmacy

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the motor symptoms are caused by progressive loss of midbrain dopamine neurons. There is no current treatment that can slow or reverse PD. Our current “DBS-Plus” clinical trial (NCT02369003) features the implantation in vivo of autologous Schwann cells (SCs) derived from a patient’s sural nerve into the substantia nigra pars compacta (SNpc) in combination with Deep Brain Stimulation (DBS) therapy for treating patients with advanced PD.

The central hypothesis of our research is that transdifferentiated SCs within conditioned nerve tissue will deliver pro-regenerative factors to enhance the survival of …

Divergence In Neuronal Calcium Dysregulation In Brain Aging And Animal Models Of Ad, Adam Ghoweri

Theses and Dissertations--Pharmacology and Nutritional Sciences

Neuronal calcium dysregulation first garnered attention during the mid-1980’s as a key factor in brain aging, which led to the formulation of the Ca²⁺ hypothesis of brain aging and dementia. Indeed, many Ca²⁺-dependent cellular processes that change with age, including an increase in the afterhyperpolarization, a decrease in long-term potentiation, an increased susceptibility to long-term depression, and a reduction in short-term synaptic plasticity, have been identified. It was later determined that increased intracellular Ca²⁺ with age was due to increased Ca²⁺ channel density, elevated release from intracellular Ca²⁺ stores, and decreased Ca²⁺ buffering …

Apoe As A Metabolic Regulator In Humans, Mice, And Astrocytes, Brandon C. Farmer

Theses and Dissertations--Physiology

Altered metabolic pathways appear to play central roles in the pathophysiology of late-onset Alzheimer’s disease (AD). Carrier status of the E4 allele of the APOE gene is the strongest genetic risk factor for late-onset AD, and increasing evidence suggests that E4 carriers may be at an increased risk for neurodegeneration based on inherent metabolic impairments. A new appreciation is forming for the role of APOE in cerebral metabolism, and how nutritional factors may impact this role. In chapter 1, the literature on nutritional interventions in E4 carriers aimed at mitigating disease risk is reviewed. Studies investigating the mechanism by which …

Intracellular Localization Of The Novel Polyq Protein Fam171b, Dulanjani Rajaguru

All Graduate Theses, Dissertations, and Other Capstone Projects

FAM171B is a relatively uncharacterized protein that contains fourteen consecutive glutamine residues within its primary amino acid sequence; thus it is a polyglutamine (polyQ) protein. PolyQ proteins are interesting because mutations within the polyQ tract have been linked to a number of severe neurodegenerative diseases including Huntingtons Disease (HD). To date, there are minimal published data regarding FAM171B and its molecular function, such that both expression levels and intracellular localization have yet to be definitively determined. Using immunohistochemical and in situ hybridization analyses, our lab has recently found that FAM171B is expressed throughout the mouse brain. This current study attempts …

Targeting The Nt17 Of The Huntingtin Protein Via Natural And Chemical Modifications: Impact On Aggregation And Membrane Interactions, Faezeh Sedighi

Graduate Theses, Dissertations, and Problem Reports (ETD)

Huntington Disease (HD) is a fatal neurodegenerative disorder caused by an expanded polyglutamine domain (polyQ) in the first exon of the huntingtin protein (htt-exon1). The major hallmark of HD is the accumulation of aggregates into proteinaceous inclusion bodies. PolyQ expansion in huntingtin promotes self-assembly into a variety of toxic aggregates such as oligomers, fibrils, and amorphous aggregates. The resulting heterogeneous mixture of distinct species makes it difficult to assign a toxic function to specific aggregate structures. In addition, htt interacts with a variety of membranous surfaces. The first 17 amino acids (Nt17) of htt directly flanking the polyQ domain functions …

Characterizing The Requirements For The Matricellular Protein, Dccn, In Nervous System Function, Elizabeth L. Catudio Garrett

Graduate Student Theses, Dissertations, & Professional Papers

The brain is organized as a complex network of specialized neurons that communicate via a combination of electrical and chemical signals. Our brains function to generate movement, control organ function, or direct complex behaviors; all of which requires the ability to regulate the flow of communication between circuits and networks. Work in this thesis addresses two areas of neuron communication: first, how does the release of more than one neurotransmitter from a single neuron impact behavior, and second, are matricellular proteins (MCPs) key contributors to synaptic transmission and neuron function? The conserved CCN family of MCPs have a …

Neuroanatomy Of The Blackspotted Rockskipper, Entomacrodus Striatus, Pooja Dayal

Williams Honors College, Honors Research Projects

Here I characterized the central neuroanatomy of the Blackspotted Rockskipper, Entomacrodus striatus, native to French Polynesia. The neuroanatomy of E. striatus has not been studied prior to this paper. I used several histology and antibody staining techniques to accomplish this, including Crystal Violet, immunohistochemistry, immunofluorescence, and Bielschowsky’s Silver Nitrate staining. This paper describes the most successful techniques used, identifies major structures in the species’ neuroanatomy, and also explains why studying E. striatus is important in the future of vertebrate research.

Non-Invasive Method For Leptin Supplementation In Zebrafish (Danio Rerio), Regan Mcnamara

Williams Honors College, Honors Research Projects

I tested the hypothesis that recombinant leptin protein can be introduced to zebrafish in vivo through non-invasive soaking in a solution containing the protein. One way to study various molecules’ effects in vivo is through intraperitoneal or intracerebroventricular injections during the embryonic or larval stage, which is invasive, difficult to administer, and can have a high mortality rate. 48 hours post fertilization (hpf) zebrafish were soaked in a His-tagged recombinant leptin protein solution at 10 nM and 100 nM concentrations (produced by Genscript). After soaking, zebrafish larvae were washed extensively to remove all recombinant protein on their exterior before homogenization. …

Assessing Morphology Of Iprgcs After Traumatic Brain Injury, Brian Foresi, Matt Smith

Williams Honors College, Honors Research Projects

ipRGCs are retinal ganglion cells that project to visual processing centers of the brain for nonimage forming visual functions. The relation of ipRGCs to tramatic brain injury (TBI) is emerging as data has been published describing ipRGC functional changes in TBI affected military veterans. Major symptomologies of concussions, a mild form of TBI, also overlap with the function governed by sites in the brain with major ipRGC projection percentages. Assesing if a morphological change is occuring in the ipRGCs after a TBI could support the idea of a pathological mechanism of the injury. This study could also indicate further relevance …

Optimization And Validation Of The Neurolux Wireless Optoelectronics System For Optogenetics, Karis Courey, Su Hyun Lee Ph.D., Adam Smith Ph.D., Nicholas Cilz Ph.D., Sarah K. Williams Avram Ph.D., Adi Cymerblit-Sabba Ph.D., June Song, Nicholas Leipzig Ph.D., W. Scott Young M.D., Ph.D.

Williams Honors College, Honors Research Projects

Utilizing light and genetic engineering, optogenetics permits the manipulation of events within cells via light using the light-sensitive properties of single-component microbial opsins. Microbial opsins are activated by a light source, such as lasers, light-emitting diodes, and incandescent sources that deliver light to the region of interest either directly or indirectly, such as through fiberoptics. In classical in vivo optogenetics, the wiring of optic fibers necessitates tethering of animals by the optic fiber to the light source. The novel NeuroLux wireless optoelectronic system for optogenetics circumvents issues pertaining to classical optogenetics by utilizing near-field power transfer via magnetic coil antennae …

Understanding How Sequence Differences Among Glutamate Transporters Might Contribute To Their Differential Function In Glutamate Clearance In C. Elegans, Irving Estevez

Dissertations and Theses

In the nervous system, high circuit resolution requires efficient post-signaling clearance of the neurotransmitter. Glutamate-mediated neurotransmission involves the release of glutamate (Glu) into the synaptic cleft by the presynaptic cell and binding to glutamate receptors (GluR) on the postsynaptic cell, leading to activation of a signal transduction cascade. Neurotransmission is eventually terminated by Glu uptake via glutamate transporters (GluT). Inefficient Glu clearance is detrimental to precise rapid signaling, can lead to blurring of circuit resolution by inadvertent Glu spillover to nearby circuits, and may even be neurotoxic. While classical views depict synapses as insulated by glia, recent technological advances show …

Effects Of Weak Electric Fields On Long-Term Synaptic Plasticity, Gregory Kronberg

Dissertations and Theses

Transcranial direct current stimulation (tDCS) is a technique where a weak direct electrical current is applied to the scalp with the goal of stimulating the brain. There is tremendous interest in the use of tDCS for treating brain disorders and improving brain function. However, the effects of tDCS have been highly variable across studies, leading to a debate over its efficacy. A major challenge is therefore to design tDCS protocols that yield predictable effects, which will require a better understanding of its basic mechanisms of action. One commonly discussed mechanism is that tDCS may alter synaptic plasticity, but the biophysics …

Biomechanics And Neural Control Of Movement: Cmi's Effects On Downstream Motor Processing And Gait In Forwards And Backwards Walking, Christopher Choi

CMC Senior Theses

Analyzing the effects of cognitive motor interferences (CMI) on walking is usually done in patients with neurological comorbidity or during forward walking (FW). However, there are few studies that examine gait differences between FW and backward walking (BW) under the presence of CMI when speed is kept constant on a treadmill. In this study we examined how CMI would disrupt sensory feedback and affect the descending motor pathway. We hypothesized that subjects that walked backwards and were given a cognitive task would show the greatest differences in gait due to a lack of visual input and the presence of CMI. …

Novel Post-Translational Modification And Function Of Fus: The Relevance To Amyotrophic Lateral Sclerosis, Alexandra Arenas

Theses and Dissertations--Toxicology and Cancer Biology

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the preferential death of motor neurons. Approximately 10% of ALS cases are familial and 90% are sporadic. Fused in Sarcoma (FUS) is a ubiquitously expressed RNA binding protein implicated in familial ALS and frontotemporal dementia (FTD). FUS is ubiquitously expressed in cells and has a variety of functions in the nucleus and cytoplasm. FUS mutations in the nuclear localization sequence (NLS) causes mislocalization of FUS in the cytoplasm, where it can undergo liquid-liquid phase separation and become stress granules or protein inclusions. Although FUS inclusion bodies can be found in …

The Wiring Logic Of Identified Serotonergic Neurons Across Olfactory Networks In Drosophila, Kaylynn E. Coates

Graduate Theses, Dissertations, and Problem Reports (ETD)

Serotonin is a ubiquitous neuromodulator that confers flexibility in networks to modulate a wide array of behavioral and physiological processes. However, due to the complexity and heterogeneity of serotonergic systems, it has been challenging to determine the patterns of connectivity as well as the physiological contexts that influence individual serotonin neurons. In this dissertation, I use two serotonergic neurons which innervate the Drosophila olfactory system, the CSDns, as a model to explore these broad questions comprehensively using anatomical approaches. I first show that the CSDns have distinct connectivity relationships with populations of antennal lobe principal olfactory neurons and that their …

Cerebrovascular Dysfunction And Degeneration In Alzheimer’S Disease Pathophysiology, Dominic Dimitri Quintana

Graduate Theses, Dissertations, and Problem Reports (ETD)

Alzheimer’s disease (AD) is a terminal illness and the most common form of dementia, which disproportionately affects the aged population. The pathophysiology of AD is characterized by neurodegeneration that slowly progresses, affecting regions of the brain that are involved in learning, memory, language, and executive function. In patients with the disease, early symptoms include non-disruptive forgetfulness that evolves into the inability to form new memories and ultimately the loss of autonomy at late stages. Histopathological hallmarks in the brain from patients with AD is the presence of amyloid-β (Aβ)-plaques and neurofibrillary tangles (NFT) deposited in the parenchyma. Since the discovery …

The Interplay Of Progestins, Matrix Metalloproteinases, And The Aging Brain, Keyana Nicole Porter

Graduate Theses, Dissertations, and Problem Reports (ETD)

Progestins are synthetic hormones that are designed to mimic the biological actions of progesterone. They, however, possess other pharmacological actions and properties, in addition to their progestational activities. Medroxyprogesterone Acetate (MPA) is a progestin used globally in the hormonal contraceptive, Depo Provera®, by women in their reproductive prime and is a major compound found in hormone therapy (HT) formulations used by menopausal women. MPA is used by approximately 1 in 5 adolescents and adult women in the United States who are sexually active. Globally, nearly 48 million women utilize injectable contraceptives to prevent pregnancy, with most users utilizing MPA as …

A Kinesin Adapter Directly Mediates Dendritic Mrna Localization During Neural Development In Mice, Hao Wu, Jing Zhou, Tianhui Zhu, Ivan Cohen, Jason Dictenberg

Publications and Research

Motor protein-based active transport is essential for mRNA localization and local translation in animal cells, yet how mRNA granules interact with motor proteins remains poorly understood. Using an unbiased yeast two–hybrid screen for interactions between murine RNA-binding proteins (RBPs) and motor proteins, here we identified protein interaction with APP tail-1 (PAT1) as a potential direct adapter between zipcode-binding protein 1 (ZBP1, a β-actin RBP) and the kinesin-I motor complex. The amino acid sequence of mouse PAT1 is similar to that of the kinesin light chain (KLC), and we found that PAT1 binds to KLC directly. Studying PAT1 in mouse …

Factors Influencing Huntingtin Aggregation At Surfaces: Implications For Huntington’S Disease, Sharon E. Groover

Graduate Theses, Dissertations, and Problem Reports (ETD)

Huntington’s Disease (HD) is a genetic, neurodegenerative disease characterized by an abnormal polyglutamine (polyQ) expansion in the first exon of the huntingtin protein (htt). The polyQ domain facilitates aggregation and initiates the formation of a diverse collection of aggregate species, including fibrils, oligomers and annular aggregates. The first 17 amino acids of htt (Nt17) directly flank the polyQ domain and is a key factor in htt’s association to membranous structures. In addition to Nt17 being an amphipathic αhelix, it also promotes aggregation through self-association and contains numerous posttranslational modifications (PTMs) that can modulate toxicity and subcellular localization. For in depth …