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Dissecting The Neural Circuits Mediating Pain-Induced Negative Affect And Drug-Seeking Behaviors, Tamara Markovic

Arts & Sciences Graduate Student Theses and Dissertations

Understating the function of neural circuits and the state-depended adaptations within them is one of the fundamental aims in the field of neuroscience. With recent technical developments in monitoring circuit dynamic, such as calcium (Ca2+) imaging, visualizing synaptic connections using viral approaches and manipulating neuronal activity in cell-specific manner such as optogenetic and chemogenetics, we are now able to mechanistically link the activity and function of neural circuits with behavioral outcomes.Using the above-mentioned techniques, I demonstrate that pain induces somatic adaptations in the Ventral Tegmental Area (VTA) dopamine (DA) neurons to drive anhedonia-like behaviors. Pain is a complex phenomenon composed …

The Role Of Soil Microbes In Improving Tallgrass Prairie Restoration And Rare Plant Reintroduction, Rachel Ellen Becknell

Arts & Sciences Graduate Student Theses and Dissertations

We are currently in the midst of an ecological crisis with many species and ecosystems threatened with extinction. Less than 1% of the original extent of the incredibly biodiverse tallgrass prairie ecosystem remains and other grassland ecosystems such as the limestone cedar glade complex that is home to many endemic plant species are threatened by development, woody plant encroachment, and trash dumping. Restoration practitioners have been acting to restore these degraded ecosystems for over a century and rare plant reintroductions have steadily increased over the past few decades, yet many plant restorations and reintroductions are often not successful. Prairie restorations …

Gut Reactions: Quantitative Predictions Of The Responses Of Human Gut Microbiota To Medical Interventions, Amy Elizabeth Langdon

Arts & Sciences Graduate Student Theses and Dissertations

The collection of microbes known as the human microbiome perform vital functions for their host, and when this community becomes unhealthy, its dysbiosis is implicated in a myriad of diseases. The gut microbiota in particular are known to suppress colonization of opportunistic pathogens, regulate the immune system, aid in nutrient breakdown, produce vitamins, and a growing number of other functions. In order to intervene in a dysbiotic microbial ecology, we can try to remove unwanted microbes or try to recolonize the gut with microbes expected to be beneficial. This dissertation provides an overview of the state of medical interventions for …

Stem Cell Models To Study The Regulation Of Human Cortical Development And Its Disruption In Neurodevelopmental Disorders, Emily Megan Alexandra Lewis

Arts & Sciences Graduate Student Theses and Dissertations

Abstract of the DissertationStem Cell Models to Study the Regulation of Human Cortical Development and Its Disruption in Neurodevelopmental Disorders by Emily M. A. Lewis Doctor of Philosophy in Biology and Biomedical Sciences Developmental, Regenerative, and Stem Cell Biology Washington University in St. Louis, 2021 Professor Kristen L. Kroll, ChairThe cell state transitions that occur during complex processes, such as development of the human brain, require precisely controlled changes in gene expression. Major regulators of these developmental events include transcription factors (TFs), which bind the genome in a sequence-specific manner, as well as chromatin modifying proteins and complexes that alter …

Retinal Ganglion Cells Underlying Visual Perception And Predation In Mice, Keith Patrick Johnson

Arts & Sciences Graduate Student Theses and Dissertations

The spike trains of retinal ganglion cells (RGCs) are the sole source of visual information to the brain. In mice, more than 40 RGC types send signals to more than 50 brain areas. RGCs that perform nonlinear operations to extract specific visual features (e.g., the motion of an object against a background) are called feature detectors. Those that linearly integrate local changes in light inten-sity are known as pixel encoders. Most mouse RGC types are feature detectors. In the first part of my dissertation, I discovered a pixel encoder RGC type in mice, the PixON-RGC. I revealed how the unique …

Etv2/Myct1 Axis In The Regulation Of Tumor Angiogenesis And Anti-Tumor Immunity, Ashraf Ul Kabir

Arts & Sciences Graduate Student Theses and Dissertations

Angiogenesis is a critical determinant of neoplastic growth and metastatic spread. As such, anti-angiogenic approaches have long been tried to throttle down tumor progression. However, current anti-angiogenic treatments so far have produced modest clinical benefits. Further in-depth research has provided rationales behind these disappointing and apparent perplexing clinical outcomes. It is now established that VEGF (vascular endothelial growth factor) and other prominent current angiogenic targets are neither specific to the vascular system nor the pathological conditions explaining the sub-optimal angiogenic control following the existing treatments. This suggests that anti-angiogenesis could still be a viable strategy for cancer patients should there …

Characterizing A Novel Metabolic Pathogenic Mechanism In Familial Hemiplegic Migraine, Sarah Elizabeth Smith

Arts & Sciences Graduate Student Theses and Dissertations

Migraine, an episodic neurological disorder, afflicts about 1 in 10 people at least monthly, yet the underlying pathophysiological mechanisms remain poorly understood. The prototypical monogenic migraine disorder, Familial Hemiplegic Migraine, theoretically presents an excellent opportunity for preclinical modeling, but thus far animal models of migraine have failed to recapitulate the severe migraine aura symptoms of episodic paralysis and ataxia. Mutations that cause Familial Hemiplegic Migraine occur in one of three genes, two neuronal ion channels, and interestingly, the astrocytic α2-Na/K ATPase. In the case of α2-Na/K ATPase, mutations primarily result in loss of protein function. As migraine is thought to …

Polygenic And Transcriptomic Studies In Neurodegeneration: Towards More Precise Medicine., Umber Dube

Arts & Sciences Graduate Student Theses and Dissertations

Precision medicine defines both health and disease in terms of high dimensional data. In my thesis work, I apply current knowledge and tools of precision medicine to better understand the etiopathogenesis of neurodegenerative diseases (NDs).Genome-wide association studies (GWAS) have demonstrated that genetic susceptibility for NDs and other diseases is mediated by many common genetic variants of modest effect size which contribute to disease risk in a polygenic or even omnigenic manner. These complex genetics render prioritizing genes to better understand the disease and potentially identify therapeutic targets, challenging. In the first half of this thesis, I address this challenge by …

Regulation Of Genome Architecture By Chromatin Remodeling In The Brain, Jared Vega Goodman

Arts & Sciences Graduate Student Theses and Dissertations

Brain development requires exquisite control of gene expression to establish and refine the proper circuitry of the nervous system. Gene expression control is under the purview of several cellular processes, including chromatin regulation in the form of DNA modification, histone modification, and nucleosome remodeling. Chromatin remodeling enzymes are the major effectors of nucleosome remodeling. These enzymes are clearly involved in brain development – mutations in chromatin remodeling enzymes are likely causative for neurodevelopmental disorders of cognition. Chromatin remodeling enzymes have discrete molecular functions and binding profiles and similarly control distinct phases of nervous system maturation. Chd4 is a Chd family …

Single-Cell Resolution Mechanistic Analyses Of Direct Lineage Reprogramming, Chuner Guo

Arts & Sciences Graduate Student Theses and Dissertations

End-stage organ failures remain a clinical challenge with an unmet need for medical therapies, with transplantation often being the only curative option. Despite advances in transplantation outcomes, organ shortage continues to limit the availability of cures to patients in need. The direct lineage reprogramming of one cell type to another is a promising avenue for therapy with the following advantages: (1) patient-specific cell sources, (2) direct conversion without reverting to pluripotency and the associated risk of teratoma formation, and (3) utilization of the cell type responsible for fibrotic scar formation for the engineering towards the desired cell fate. Nonetheless, many …

Dissecting The Role And Regulation Of Transcription Factor Zeb2 In Hematopoiesis, Xiao Huang

Arts & Sciences Graduate Student Theses and Dissertations

A potent immune response requires crosstalk and collaboration between the innate and adaptive immune systems, both of which contain highly specialized immune lineages. All immune lineages arise during adult life are generated from the differentiation of hematopoietic stem cells (HSCs) in the process of hematopoiesis. Normal hematopoiesis under steady state and emergency hematopoiesis during immune response are orchestrated precisely by transcriptional networks formed by transcription factors (TFs) to direct multipotent progenitors into specific fate. TFs required for the development of single or multiple lineages within the hematopoietic system has been identified, such as Irf8 for type I classical dendritic cells …

Dedicated Interneuronal Microcircuits Regulated By Behavioral State, Moises William Arriaga

Arts & Sciences Graduate Student Theses and Dissertations

The hippocampus is a critical brain structure for learning and memory. Neuronal inhibition within the hippocampus, performed by a wide variety of inhibitory interneuron subtypes, is required to organize and regulate the cell activity and circuit operations which underly memory formation. Despite the importance of inhibitory interneurons to the function of the hippocampus, detailed descriptions of the role of interneurons in the regulation of network activity have been limited by difficulties associated with identifying and recording from these cells using traditional electrophysiology techniques, especially in awake, behaving animals. To better investigate the function of hippocampal interneurons in awake, behaving animals, …

Glial Inflammatory Responses Regulate Neurocognitive Recovery Following Viral Encephalitis, Allison Luen Soung

Arts & Sciences Graduate Student Theses and Dissertations

The concept of the brain as an immune privileged organ has been slowly shifting as an in-creasing number of studies have demonstrated that even under homeostatic conditions, commu-nication between the nervous and immune system is essential for proper brain function. Given their roles in innate and adaptive immunity, glial cells and infiltrating immune cells have been placed at the center of this communication axis. Microglia, astrocytes, and T cells have all been shown to receive and convey information to all neural cell types in a coordinated effort to re-spond to injury and infection and initiate reparative mechanisms as well as …

Deep Learning Deleterious Small Molecule Biochemistry From The Lab To The Clinic, Matthew Matlock

Arts & Sciences Graduate Student Theses and Dissertations

Small molecules are key tools in biology and medicine. In biology, small molecules are used to probe biological systems and gain insight into their structure and function. In medicine, this role is further refined to reverse the biological conditions that contribute to human disease. Developing new small molecules into biological probes or drugs can be a daunting scientific task. These projects often begin with many thousands of potential candidates, which are progressively screened and eliminated from consideration by high-throughput experimental assays. Those molecules that emerge from this process as candidate drugs are also subject to extensive in vitro, in vivo, …

Modeling Small Molecule Metabolism In Human Liver Microsome To Better Predict Toxicity Risk, Na Le Dang

Arts & Sciences Graduate Student Theses and Dissertations

Adverse drug reactions (ADRs) are a serious problem with increasing morbidity, mortality, and health care costs worldwide. In the U.S., ADRs are responsible for more than 50% of acute liver failure cases and are the fourth most common cause of death, costing 100,000 lives annually.Idiosyncratic adverse drug reactions (IADRs) are immune-mediated hypersensitivity ADRs that are difficult to foresee during drug development. IADRs are often caused by reactive metabolites produced during drug metabolism. These reactive metabolites covalently attach to cellular components, and the resulting conjugates may provoke toxic immune response. Because reactive metabolites are short-lived, they can be difficult to detect. …

Rhoa Mediated Juxtacrine Regulation Of Glucagon Secretion, Yong Hee Chung

Arts & Sciences Graduate Student Theses and Dissertations

Glucagon is secreted from pancreatic islet alpha-cells in response to hypoglycemia. The regulation of this secretion likely involves multiple interacting molecular pathways. There are three general types of proposed models for glucose-dependent regulation of glucagon secretion: direct regulation by glucose mediated modulation of cell electrophysiology, paracrine regulation by other endocrine cell types within the islets of Langerhans, and juxtacrine regulation by surface protein interactions from neighboring beta-cells. This work is focused on one pathway of juxtacrine regulation that occurs through signaling from EphA4 receptors on the surface of α-cells upon interaction with ephrin-A5 ligands on the surface of beta-cells. In …

The Phylogeography Of Rare Central Tennessee Glade Endemics Trifolium Calcaricum And Viola Egglestonii, Rachel Ann Lyman

Arts & Sciences Graduate Student Theses and Dissertations

Endemic species are range-restricted to a particular type of habitat and generally occur in a few small populations. Often endemic species are threatened or endangered due to their geographic isolation and limited habitat breadth. Despite the fact that understanding factors that may have shaped the evolutionary history of a species with a narrow distribution can provide important insights for their management and conservation, little is known about the historical forces that gave rise to many endemic species. Endemic species can arise because of factors such as variation in climate, geographic barriers, and habitat specificity, or the combination of several of …

The Role Of Cd53 In Hematopoietic Development, Stress, And Malignancy, Zev Joshua Greenberg

Arts & Sciences Graduate Student Theses and Dissertations

For a cell to function properly, it must be able to interact with and respond to environmental cues; however, expression of surface molecules, proteins, and receptors is not always sufficient to execute a cellular response. Proper organization of the plasma membrane is necessary to facilitate these highly regulated protein interactions, such that a cell can respond to stressors, growth factors, and other signaling molecules. Tetraspanins are a family of transmembrane proteins which help correctly orient surface molecules on the cell membrane, often through tetraspanin enriched microdomains, a membrane structure similar to lipid rafts. As a family, tetraspanins are known to …

Apolipoprotein E Immunotherapy For The Preclinical Treatment Of Alzheimer Disease And Cerebral Amyloid Angiopathy, Monica Xiong

Arts & Sciences Graduate Student Theses and Dissertations

The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD), a neurodegenerative disorder that leads to cognitive dysfunction and dementia. One copy of APOE ε4 increases AD risk by 3.7-fold and two copies by 12-fold, whereas APOE ε2 is protective relative to the more prevalent ε3 allele. APOE4 accelerates the progression of AD by markedly impairing amyloid-β (Aβ) clearance and promoting excess Aβ aggregation, ultimately resulting in downstream neuroinflammation, tau pathology, and neurodegeneration. Aggregated Aβ can co-deposit with the APOE protein in the brain parenchyma as neuritic plaques and in …

Sex Differences In The Role Of Cornichon Homolog-3 On Spatial Memory And Synaptic Plasticity, Hannah Elizabeth Frye

Arts & Sciences Graduate Student Theses and Dissertations

Cornichon homolog-3 (CNIH3) is an AMPA receptor (AMPAR) auxiliary protein highly expressed in the dorsal hippocampus (dHPC), a region where AMPARs are critical for spatial memory and synaptic plasticity. A 2016 genome-wide association study (GWAS) by Nelson et al. identified single nucleotide polymorphisms (SNPs) in the gene CNIH3 to be associated with reduced individual risk for the development of opioid use disorder (OUD) in individuals with prior opioid exposure. We previously demonstrated a key role for AMPARs in the dHPC in opioid-associated learning and memory, therefore we hypothesized that CNIH3 in the dHPC may mediate learning and memory processes through …

Social Communication Across Reproductive Boundaries: Hormones And The Auditory Periphery Of Songbirds And Frogs, M. D. Gall, Alexander T. Baugh, J. R. Lucas, M. A. Bee

Biology Faculty Works

Most animals experience reproductive transitions in their lives; for instance, reaching reproductive maturity or cycling in and out of breeding condition. Some reproductive transitions are abrupt, while others are more gradual. In most cases, changes in communication between the sexes follow the time course of these reproductive transitions and are typically thought to be coordinated by steroid hormones. We know a great deal about hormonal control of communication behaviors in birds and frogs, as well as the central neural control of these behaviors. There has also been significant interest in the effects of steroid hormones on central nervous system structures …

Effect Of Nitrogen Addition On Selection Of Germination Trait In An Alpine Meadow On The Tibet Plateau, Kun Liu, Yang Liu, Zhilong Zhang, Shiting Zhang, Carol C. Baskin, Jerry M. Baskin, Ting Liang, Haiyan Bu, Shuxia Li, Tingting Zhang, Xianliang Cui, Sa Xiao

Biology Faculty Publications

Seed germination requirements may determine the kinds of habitat in which plants can survive. We tested the hypothesis that nitrogen (N) addition can change seed germination trait-environmental filter interactions and ultimately redistribute seed germination traits in alpine meadows. We determined the role of N addition on germination trait selection in an alpine meadow after N addition by combining a 3-year N addition experiment in an alpine meadow and laboratory germination experiments. At the species level, germination percentage, germination rate (speed) and breadth of temperature niche for germination (BTN) were positively related to survival of a species in the fertilized community. …

Nest Site Selection And Nesting Behavior Of The Mud Turtle Kinosternon Scorpiodes (Testudines, Kinosternidae) In Palo Verde National Park, Costa Rica: Implications For Management, José M. Mora, Franklin E. Castañeda

Biology Faculty Publications and Presentations

Habitat selection is the process whereby individuals preferentially use, or occupy, a non-random set of available habitats. At the same time, nest site selection is defined as the placement of eggs by females at sites differing from random sites within a delimited area. We located 59 nests of the mud turtle Kinosternon scorpioides in Palo Verde National Park (PVNP) in Northwestern Costa Rica. We compared eight microhabitat variables at nest sites against those at random sites. Females significantly placed their eggs at sites with more understory, leaf litter cover, and greater leaf litter depth than in random sites. Additionally, females …

The Spread Of Batrachochytrium Dendrobatidis And Its Effect On The Global Amphibian Ecosystem, Mars Pinkelman

COD Library Student Research and Award Symposium

The Spread of Batrachochytrium Dendrobatidis and its Effect on the Global Amphibian Ecosystem, discusses the deadly amphibian pathogen Batrachochytrium Dendrobatidis. My work aimed to answer the question, "How did the spread of batrachochytrium dendrobatidis, affect amphibian populations from its discovery in 1993 to modern day, and how could it affect biodiversity in the future?" It first covers a brief history of the disease and its discovery as well as the impacts it has on individual hosts. I then discuss the effects that the parasitic fungus has on biodiversity, concluding with ways for individuals and communities to mitigate the impacts that …

Physiological And Metabolic Strain Differences In Response To Constant Light In Male Mice, Hannah V. Deane

Honors Program Theses and Projects

Circadian rhythms, located in all organisms, is an innate natural clock system driving daily cycles in behavior and metabolism. This clock entrains to daily cycles via regular exposure to light:dark cycles. When light exposure is altered, it is known to cause alterations behavior and metabolism because of its role in regulating bodily function. Constant light (LL) is emerging as a predominant circadian disruption due to prolonged exposure to light at night during night-shift work, and the use of TVs and smartphones at night and throughout the night. To understand how different organisms respond to constant light, two comparative studies were …

Soil Macroinvertebrates Responses To Wildfires In The Blue Ridge Mountains, Usa, Madeline Olliff

Biology Theses

Fire has been a prevalent disturbance on Earth for millions of years. Around the globe there are several regions that have become fire adapted, including the Southeastern United States. There have been few studies examining the effects of wildland fires on soil macroinvertebrates in the Blue Ridge Mountains, in spite of the importance of these animals to soil processes and their contributions to the biodiversity of these ecosystems. During the fall of 2016, the Southeastern USA experienced numerous, large wildfires. These fires offered an opportunity to study the effects of wildland fire on soil macroinvertebrates. We sampled sites from three …

Selenium Burdens In Painted Turtles (Chrysemys Picta), Holly A. Gerberding

Honors Thesis

Tile drain systems are a critical advancement in agriculture that move excess water from crop fields to streams, ditches, and wetlands. Selenium is a necessary mineral but is considered toxic at high levels. Previous research indicates that wetlands with tile drains are at a higher risk for elevated selenium concentrations. Selenium enters the aquatic ecosystem via these tile systems and us taken up by invertebrates and continues to bioaccumulate mainly via direct transfer in higher trophic level taxa such as fish, amphibians, reptiles, birds, and mammals. For this study, painted turtles (Chrysemys picta) served as a model organism to …

Serum Biochemical Profile Of Captive-Bred Philippine Crocodiles (Crocodylus Mindorensis Schmidt, 1935) Sub-Adults, Janice A. Ragaza, Stephanie F. Velasquez, Marian Samantha M. Asuncion, Elyssa Marie F. Torres, Rainier Manalo, Hendrik Freitag

Biology Faculty Publications

The Philippine crocodiles Crocodylus mindorensis Schmidt; 1935 are a critically endangered species that necessitate minimally invasive diagnostic tools for their physiological state and health assessment. In the current study; we determined the reference ranges for the serum biochemistry of male and female captive-bred C. mindorensis sub-adults. We collected blood samples from the post-occipital venous sinus of six male and seven female captive-bred crocodile sub-adults at the Palawan Wildlife Rescue and Conservation Center and quantified the serum biochemical values for cholesterol; triglycerides; uric acid; glucose; creatinine; aspartate aminotransferase (AST); alanine aminotransferase (ALT); albumin; total protein; and globulin. We defined reference ranges …

Optimizing The Delivery Of A Gfp Gene Via A Biocompatible Nanocarrier In Daphnia And A Chironomid, Alexandra R. Job

Honors Thesis

Current pest control methods impose risks including pest resistance to insecticides, bioaccumulation of the insecticide, and ecosystem impact. There is a need for a better and more sustainable method of pest control in order to protect the environment and the populations reliant on it. Currently, an alternative method of pest control uses RNA interference (RNAi), that exploits heterologous protein expression to disable the insect pest, delivered by the use of nanoparticles. Nanocarriers show great promise in this method of use, but concerns of cytotoxicity, biodegradability, and transfer to off target organisms require careful consideration. This study focuses on optimizing a …

Biomedical Porcine Models For The Study Of Surgical Hemostasis, Hindlimb Ischemia, And Pancreatic Cancer, Shruthishree Aravind

Theses & Dissertations

Murine models have dominated the world of biomedical research and comparative medicine since their development in the early 1900s. [1] While they may be suitable models to study proteomics and genomics, they may not serve as effective translational models. [2-4] Murine models do not accurately model the pathophysiology of human disease and are limited by their size, application of medical imaging and intervention, which reduces their overall preclinical predictive value. [2-4]

Porcine models on the other hand, are slowly and steadily bridging the gap between murine models and human patients. [5] Pigs …