Molecular and Cellular Neuroscience Commons^™

Mitochondrial Aspects Of Neuronal Pathology In Triple-Transgenic Alzheimer’S Disease Mice, John Zachary Cavendish

Graduate Theses, Dissertations, and Problem Reports

Alzheimer’s disease (AD) is a fatal, progressive neurodegenerative disease afflicting millions of people in the United States alone and is the only one of the top leading causes of morbidity and mortality with no effective disease-modifying therapies. It is the most common form of dementia, affecting one in three people over the age of 85. While the hallmarks of the disease include accumulation of beta-amyloid-based extracellular plaques and hyperphosphorylated tau-based intracellular neurofibrillary tangles, treatment strategies centered on removing or mitigating these components of AD have all failed in humans. Mitochondrial dysfunction has been increasingly recognized as an early and ...

Hiv-1 Tat Interactions With Opioids Are Modulated By Progesterone And Estradiol, Dejun Jackson

Honors Theses

HIV infection and combined substance abuse are comorbid epidemics. Previous studies show that concurrent opioid drug use may potentiate HIV-1-mediated neurotoxicity partly via interactions with opioids. Preclinical studies suggest that the HIV-1 trans-activator of transcription (Tat), an HIV regulatory protein, can synergize with opioids to exacerbate its already neurotoxic effects. However, its interactions with clinical opioids, such as oxycodone, have yet to be elucidated. Additionally, Tat disrupts a number of systems including the dopaminergic system, which contribute to its capacity to potentiate the rewarding effects of abused drugs. Although the neurotoxic effects of Tat may be inhibited by gonadal steroids ...

The Current Neuroscientific Understanding Of Alzheimer's Disease, Rachel A. Brandes

Pursuit - The Journal of Undergraduate Research at the University of Tennessee

Alzheimer’s disease is a degenerative neurological illness characterized by the deterioration of brain regions implicated in memory and cognitive function. While researchers have yet to find a cure or effective treatment, they have gained a better understanding of its pathology and development. Through years of neuroscience research, scientists have discovered much of what happens in the brain during Alzheimer’s disease onset and how this causes its symptoms; many hypotheses regarding this aspect of the illness involve temporal lobe atrophy, neurofibrillary tangles, and amyloid plaques. Although Alzheimer’s disease affects millions of people every day, it seems that most ...

Neurocognitive Risk Factors And Current Intervention Strategies For Survivors Of Pediatric Acute Lymphoblastic Leukemia, Abigail Taber

Senior Honors Theses

The improved survival rate for pediatric cancer patients is one of the greatest triumphs of recent medicine, but the late effects faced by these survivors have been uncovered through this new population of survivors. Many survivors of pediatric acute lymphoblastic leukemia (ALL) experience cognitive deficits in areas such as attention, memory, processing speed, and academic achievement following cancer treatment. Recent research has pointed to chemotherapeutic agents, host risk factors, and genetic predispositions as perpetrators of these deficits, although other factors are also under investigation. Consequently, the search for appropriate interventions for the amelioration of these deficits has dominated the literature ...

The Functional Role Of Mitochondria In Neural Progenitor Cells, Alyssa Luz-Ricca

Undergraduate Honors Theses

Neurodevelopment is a complex process that requires the precise spatiotemporal control of cellular differentiation. As cells differentiate, they undergo metabolic changes that make them increasingly reliant on their mitochondria for energy production. Beyond playing a central role in the bioenergetic support of newborn neurons, functional changes in mitochondria regulate the processes of cellular differentiation. Importantly, mitochondrial function extends beyond energy production. Mitochondria in neural stem cells play an essential role in both producing intermediates for biosynthesis and regulating calcium levels. In this thesis, I review the functional role of mitochondria in stem cell fate decisions, differentiation, and proliferation during neurodevelopment ...

A Study Of Matr3 And Its Effects On The Neural Progenitor Cells Of Xenopus Laevis Tadpoles, Kendall Branham

Undergraduate Honors Theses

Understanding the genes and mechanisms that regulate the highly important process of neurogenesis in the developing nervous system is crucial to uncovering why disease arises when this system is disrupted. Neural progenitor cells and their multipotent nature allow for the growth of a large pool of stem cells in the early stages of development, but the signal that leads these cells to the irreversible fate of becoming a neuron is unclear. The gene matr3 has been implicated in having a role in the maintenance of undifferentiated neural stem cells but its role needs further investigation to fully reveal how its ...

The Role Of Dopamine In Decision Making Processes In Drosophila Melanogaster, Michelle C. Bowers

Undergraduate Honors Theses

Understanding the neural processes that mediate decision making is a relatively new field of investigation in the scientific community. With the ultimate goal of understanding how humans decide between one path and another, simpler models such as Drosophila Melanogaster, the common fruit fly, are often utilized as a way of determining the neural circuits involved in these decision-making processes. One of the most important decisions flies make is the decision of where to lay their eggs (oviposit). Choosing the proper substrate upon which to lay eggs is a crucial decision that can ultimately impact their fecundity. This paper investigates the ...

Beta-Endorphin Expression And Sex Affect The Ability Of Alcohol To Alter Tyrosine Hydroxylase Immunoreactivity In The Reward Pathway In Mice, Hannah Kelly-Quigley

Senior Scholars Day

Alcohol has sexually dimorphic effects on the brain, and the endogenous opioid, beta-endorphin (BE), mediates many effects of alcohol. In the mesolimbic dopamine reward pathway, alcohol stimulates neurons to enhance dopaminergic signaling, but the exact mechanism underlying this phenomenon is unknown. Alcohol could impact dopaminergic signaling in the reward pathway by affecting the production and localization of tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis. Therefore, we hypothesized that acute alcohol intoxication would increase c-fos expression and tyrosine hydroxylase immunoreactivity (TH-ir) in the ventral tegmental area (VTA) and nucleus accumbens (NAc) in a sex- and BE-dependent manner. In this ...

The Role Of Diet In The Onset Of Depression: A Biochemical Connection Between Nutrition And Mental Health, Katlin Wildeman

Senior Honors Theses

Depression is a major clinical concern, having a complex onset and the presence of multiple, often unidentifiable causes. Depression affects millions of individuals worldwide, with a high prevalence in regions of the world with a Western-style diet as compared to regions with a Mediterranean diet. A Western-style diet consists of foods high in sugar, fat, and processed meats and grains, whereas the Mediterranean diet contains significantly more vegetables, fruits, lean meats, and whole grains. The link between diet and mental health disorders has implications for individuals of all ages who are hesitant to turn to medication. In addition to presenting ...

Effect Of Reduced Neurogenesis On Microglial Activation, Amelia Smith

Honors Theses

The geriatric population of America has grown exponentially in the past century. Health degradations and expensive medical care are characteristic of this population with many of these costs due to age-related cognitive decline. It is essential to completely understand the mechanisms of normal and abnormal aging in the search for treatments for cognitive decline. A reduction of neurogenesis is a common factor in aging, but this reduction is even more drastic in individuals experiencing cognitive decline. It is unclear what effect reduced neurogenesis has on the extracellular environment, including glial cells. In particular, changes in microglial activation could be related ...

The Expression Of Mtor And Trib3 In Oligodendrocyte Lineage Cells, Katie Lazur

Senior Theses and Projects

Oligodendrocytes are a type of glial cell in the central nervous system that are responsible for producing the myelin sheath which allows for faster neuronal firing rates. Myelin production is a metabolically expensive process, which requires the oligodendrocytes to be aware of the nutrients are available to them. It has been demonstrated that the mammalian target of Rapamycin (mTOR) is required for the later stages of maturation in oligodendrocytes. However, when mTOR is inhibited by Rapamycin in the early stages of oligodendrocyte development, the oligodendrocytes are still able to fully differentiate. Tribbles Homolog 3 (Trib3) is a pseudo kinase that ...

Amino Acid Sensing Ability By The Mechanistic Target Of Rapamycin In Oligodendrocytes, Emma England

Senior Theses and Projects

Oligodendrocytes (OLs) are a type of glial cell in the central nervous system that require substantial nutrients such as lipids and amino acids to create the extensive, metabolically expensive myelin sheath surrounding the axons of neurons. The mammalian target of rapamycin (mTOR) is a regulatory kinase that is necessary for the maturation of progenitor OLs through their distinct oligo-lineage phases. Amino acids are vital for the functioning of cells. The focus of this study was to determine if mTOR activity is dependent on the availability of leucine, methionine, and alanine. This was assessed by examining the phosphorylation level of the ...

Beta-Amyloid Clustering Around Asc Fibrils Boosts Its Toxicity In Microglia, Lea L. Friker, Hannah Scheiblich, Inga V. Hochheiser, Rebecca Brinkschulte, Dietmar Riedel, Eicke Latz, Matthias Geyer, Michael T. Heneka

Open Access Articles

Alzheimer's disease is the world's most common neurodegenerative disorder. It is associated with neuroinflammation involving activation of microglia by beta-amyloid (Abeta) deposits. Based on previous studies showing apoptosis-associated speck-like protein containing a CARD (ASC) binding and cross-seeding extracellular Abeta, we investigate the propagation of ASC between primary microglia and the effects of ASC-Abeta composites on microglial inflammasomes and function. Indeed, ASC released by a pyroptotic cell can be functionally built into the neighboring microglia NOD-like receptor protein (NLRP3) inflammasome. Compared with protein-only application, exposure to ASC-Abeta composites amplifies the proinflammatory response, resulting in pyroptotic cell death, setting free ...

Premature Termination Codon Readthrough Upregulates Progranulin Expression And Improves Lysosomal Function In Preclinical Models Of Grn Deficiency, Jonathan Frew, Fen-Biao Gao, Haakon B. Nygaard

Open Access Articles

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a devastating and progressive disorder, and a common cause of early onset dementia. Progranulin (PGRN) haploinsufficiency due to autosomal dominant mutations in the progranulin gene (GRN) is an important cause of FTLD (FTLD-GRN), and nearly a quarter of these genetic cases are due to a nonsense mutation. Premature termination codons (PTC) can be therapeutically targeted by compounds allowing readthrough, and aminoglycoside antibiotics are known to be potent PTC readthrough drugs. Restoring endogenous PGRN through PTC readthrough has not previously been explored as a therapeutic intervention in FTLD.

METHODS: We studied whether the aminoglycoside G418 ...

A Chromosomal Connectome For Psychiatric And Metabolic Risk Variants In Adult Dopaminergic Neurons, Sergio Espeso-Gil, Tyler M. Borrman, Zhiping Weng, Schahram Akbarian

Open Access Articles

BACKGROUND: Midbrain dopaminergic neurons (MDN) represent 0.0005% of the brain's neuronal population and mediate cognition, food intake, and metabolism. MDN are also posited to underlay the neurobiological dysfunction of schizophrenia (SCZ), a severe neuropsychiatric disorder that is characterized by psychosis as well as multifactorial medical co-morbidities, including metabolic disease, contributing to markedly increased morbidity and mortality. Paradoxically, however, the genetic risk sequences of psychosis and traits associated with metabolic disease, such as body mass, show very limited overlap.

METHODS: We investigated the genomic interaction of SCZ with medical conditions and traits, including body mass index (BMI), by exploring ...

Mushroom Body-Specific Gene Regulation By The Swi/Snf Chromatin Remodeling Complex, Kevin Cj Nixon

Electronic Thesis and Dissertation Repository

Over the lifetime of an organism, neurons must establish, remodel, and maintain precise connections in order to form neural circuits that are required for proper nervous system functioning. Disruptions in these processes can lead to neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder. Mutations in genes encoding subunits of the SWI/SNF chromatin remodeling complex have been implicated in ID, yet the role of this complex in neurons is poorly understood. In this project, I established cell-type specific methods to examine the effect of SWI/SNF subunit knockdowns on gene transcription and chromatin structure in the memory-forming ...

Tamalin/Gras-1 Connects Glutamate Receptor Activity To The Insulin/Igf Signaling Cascade To Regulate Neuroprotection In A Nematode Model Of Excitotoxicity, Ayesha Chowdhury

All Dissertations, Theses, and Capstone Projects

Brain ischemia is a major cause of debilitation and death in the United States. Excitotoxicity, a condition that arises from the accumulation of glutamate (Glu) in the synapse that leads to overactivation of Glu receptors (GluRs), is the major mechanism of neuronal damage in brain ischemia / stroke. Although it is commonly acknowledged that over activation of GluRs leads to neurodegeneration, it has been recently shown that even during excitotoxicity Glu has a concurrent important role in regulating neuroprotection. GluR-activated transcription factors seem to mediate this neuroprotection, but it remains unclear which signaling cascades and transcription factors are regulated by GluRs ...

Integrated Mirna-/Mrna-Seq Of The Habenulo-Interpeduncular Circuit During Acute Nicotine Withdrawal, Alison P. Casserly, Junko Tsuji, Rubing Zhao-Shea, Ciearra B. Smith, Susanna Molas-Casacuberta, Andrew R. Tapper, Zhiping Weng, Paul D. Gardner

Open Access Articles

Tobacco use is the leading preventable cause of mortality in the world. The limited number of smoking cessation aids currently available are minimally effective, highlighting the need for novel therapeutic interventions. We describe a genome-wide approach to identify potential candidates for such interventions. Next-generation sequencing was performed using RNA isolated from the habenulo-interpeduncular circuit of male mice withdrawn from chronic nicotine treatment. This circuit plays a central role in the nicotine withdrawal response. Differentially expressed miRNAs and mRNAs were validated using RT-qPCR. Many of the differentially expressed mRNAs are predicted targets of reciprocally expressed miRNAs. We illustrate the utility of ...

Epigenetic Alterations At Synaptic Plasticity Genes In A Genetically Heterogeneous Rat Model Of Neuropsychiatric Disorders, Doan M. On

Theses and Dissertations

Sensorimotor gating impairments are observed across a range of neuropsychiatric conditions. The prepulse inhibition of the acoustic startle response (PPI) is a validated measure of sensorimotor gating. Genetic and pharmacological manipulations in rodents have shown PPI is regulated by specific brain monoaminergic systems. Using genetically heterogeneous NIH-HS rats, we stratified individuals by %PPI. In low PPI animals, we observed elevated mRNA levels of certain neurotransmitter receptors, including metabotropic glutamate receptor Grm2, dopamine receptors Drd1 and Drd2, serotonin receptors Htr1a and Htr2a, and scaffolding protein Homer1, in the frontal cortex (FC) and striatum (STR). We found Drd2 mRNA levels were significantly ...

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 ...