Molecular and Cellular Neuroscience Commons^™

Developmental Influences On The Initial Subjective Rewarding Effects Of Etoh, Madison Waldron

Master’s Theses

The present studies were aimed to better understand developmental contributions to the risk for disordered drinking, and facilitate the long-term goal of developing effective interventions for individuals at high risk for alcohol use disorders. Experiment 1 assessed the effect of adolescent pre-exposure to ethanol on adult place preference, as well as, sex- and beta-endorphin(bE)-related contributions. Adolescent C57BL/6J and bE deficient mice were injected with 1.5g/kg of ethanol or saline and put back into their home cages. At the time of adulthood, we employed a single-exposure conditioned place preference paradigm (SE-CPP) to investigate the impact of preexposure on the initial subjective …

Identifying Molecular Pathways Underlying Noise-Induced Tinnitus, Mckenzie Rice

Williams Honors College, Honors Research Projects

Tinnitus is a serious neurological condition effecting 10-15% of adults, and can lead to other symptoms such as difficulty concentrating and sleeping, anxiety, and depression. Currently there are no FDA approved drugs to prevent or treat tinnitus, mainly due to a lack of understanding of its cellular and molecular pathways. T- and L- type calcium channels have been implicated in the modulation of tinnitus, as well as the dysfunction of gamma-aminobutyric acid (GABA) neurons. This study used the sound-based avoidance detection (SBAD) method in order to detect tinnitus and determine whether pharmacological treatments had an effect in mediating tinnitus. T-type …

Characterizing Galectin And Lysosomal Rupture's Role In Spreading Parkinson Disease Pathology, Kevin Burbidge

Dissertations

The misfolding and subsequent accumulation of alpha-synuclein (α-syn) is central to the pathogenesis of Parkinson's disease (PD). Several lines of evidence suggest pathological α-syn spread cell-to-cell via a "prion-like" mechanism. Furthermore, this pathological α-syn is capable of "seeding" further misfolding of non-pathological α-syn, converting them to the pathological form. While a vast body of both genetic and experimental evidence indicates that α-syn is critical to PD development, how α-syn induces progressive neuronal dysfunction and cell death remains unclear.Autophagy, conventional for macroautophagy, is the primary degradation pathway for α-syn aggregates. Autophagy also influences the unconventional secretion of both pathological and non-pathological …

Myelin, Cpla2, And Azithromycin: Modulation Of Macrophage Activation In Spinal Cord Injury Inflammation, Timothy J. Kopper

Theses and Dissertations--Physiology

Spinal cord injury (SCI) produces a chronic inflammatory state primarily mediated by macrophages consisting of resident microglia and infiltrating monocytes. These chronically activated SCI macrophages adopt a pro-inflammatory, pathological state that continues to cause additional damage after the initial injury and inhibits recovery. While the roles of macrophages in SCI pathophysiology are well documented, the factors contributing to this maladaptive response are poorly understood. Here, we identify the detrimental effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-dependent role for cytosolic phospholipase-A2 (cPLA₂) in myelin- mediated potentiation of pro-inflammatory macrophage activation. Macrophage- mediated inflammatory …

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

Graduate Theses, Dissertations, and Problem Reports (ETD)

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 consistent …

Cloning And Functional Characterizations Of Circular Rnas From The Human Mapt Locus, Justin R. Welden

Theses and Dissertations--Molecular and Cellular Biochemistry

Under pathophysiological conditions, the microtubule protein tau (MAPT) forms neurofibrillary tangles that are the hallmark of sporadic Alzheimer’s disease as well as familial frontotemporal dementias linked to chromosome 17 (FTDP-17). In this work, I report that MAPT forms circular RNAs through backsplicing of exon 12 to either exon 10 or exon 7 (12→10; 12→7), and that these circular RNAs are translated into proteins.

Using stable cell lines overexpressing the circular tau RNAs 12→7 and 12→10, we have discovered that the tau circular RNA 12→7 is translated in a rolling circle, giving rise to multiple proteins. This circular RNA …

Cloning And Characterization Of The Vasopressin-Oxytocin Neuropeptide Signaling System In The Vocal Control System Of The Zebra Finch (Taeniopygia Guttata), Emily R. Tortora

Dissertations and Theses

Vasopressin (VP) and Oxytocin (OT) are neuropeptides produced in the hypothalamus and expressed in the cerebrum and pituitary gland of the brain. Studies of VP and OT have long demonstrated their influence on social behaviors in mammals. Comparative analyses of these neuropeptides and in-depth analyses in non-mammalian species may reveal the specific mechanistic roles these hormones play in social behavioral functioning. The acquisition of complex behavioral patterns involves sensory-motor functions. How social interactions modulate sensory-motor mechanisms that promote complex behavior acquisition and maintenance can be well study in vocal learning birds. Here, in addition to reviewing the pertinent literature, I …

Interclass Gpcr Heteromerization Affects Localization And Trafficking, Rudy Toneatti

Theses and Dissertations

Class A serotonin (5-hydroxytryptamine) 2A (5-HT_2AR) and class C metabotropic glutamate 2 receptors (mGluR2) are seven transmembrane receptors (7TMRs or G protein-coupled receptors – GPCRs) involved in multiple neuropsychiatric disorders including schizophrenia. Previous findings from our laboratory reported that 5-HT_2AR and mGluR2 are dysregulated in the prefrontal cortex of patients suffering from this psychiatric condition, although 5-HT_2AR’s expression was recovered in antipsychotic-medicated patients. Genome-wide association studies on schizophrenia reported that endosomal trafficking that regulates cell surface abundance of another 7TMR implicated in this disease (dopamine D2 receptor) can be altered. Ligand-activated receptors, including the …

The Role Of Glt-1 Signaling In Oligodendrocytes During Development And Myelin Repair, Elizabeth Thomason

Theses and Dissertations

The differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating oligodendrocytes (OLGs) requires an increase in the complexity of process morphology, alterations in membrane trafficking, and the production of myelin proteins. Branching and process extension have already been shown to follow glutamate signaling through OLG-expressed excitatory amino acid transporters (EAATs), mostly via GLT-1. It is of note that glutamate homeostasis often goes awry in multiple sclerosis (MS), the main demyelinating disease in humans. Thus, we have sought to gain an understanding of the role that GLT-1 plays under the myelination and remyelination conditions that arise during natural development of OLGs and …

The Receptor Basis Of Serotonergic Modulation In An Olfactory Network, Tyler Ryan Sizemore

Graduate Theses, Dissertations, and Problem Reports (ETD)

Neuromodulation is a nearly ubiquitous process that endows the nervous system with the capacity to alter neural function at every level (synaptic, circuit, network, etc.) without necessarily adding new neurons. Through the actions of neuromodulators, the existing neural circuitry can be adaptively tuned to achieve flexible network output and similarly dynamic behavioral output. However, despite their near ubiquity in all sensory modalities, the mechanisms underlying neuromodulation of sensory processing remain poorly understood. In this dissertation, I address three main questions regarding the mechanisms of one modulator (serotonin) within one sensory modality (olfaction). I begin by establishing a "functional atlas" of …

Using Zebrafish To Elucidate The Expression And Gene Regulatory Network Of The Genomic Screen Homeobox Transcription Factors And Bring Innovative Science Learning Experiences To West Virginia, Rebecca Ann Coltogirone

Graduate Theses, Dissertations, and Problem Reports (ETD)

Central nervous system (CNS) development requires a code of regionally expressed transcription factors that impart initial neuronal cell identity, connectivity, and function. The absence of a transcription factor code would eliminate the neurodevelopmental logic producing diverse cell types in the CNS. Furthermore, early disruptions in transcription factor expression can affect later connectivity and function of neuronal circuits mediating sensory processing, defects in which are often observed as comorbid with various neurodevelopmental disorders (NDDs). Characterizing transcription factor expression and function is therefore an essential step in discerning the molecular mechanisms underlying human NDDs. genomic screen homeobox 1 and 2 (gsx1 …

Beyond Low-Earth Orbit: Characterizing Immune And Microrna Differentials Following Simulated Deep Spaceflight Conditions In Mice, Amber M. Paul, Margareth Cheng-Campbell, Elizabeth A. Blaber, Sulekha Anand, Sharmila Bhattacharya

Publications

Spaceflight missions can cause immune system dysfunction in astronauts with little understanding of immune outcomes in deep space. This study assessed immune responses in mice following ground-based, simulated deep spaceflight conditions, compared with data from astronauts on International Space Station missions. For ground studies, we simulated microgravity using the hindlimb unloaded mouse model alone or in combination with acute simulated galactic cosmic rays or solar particle events irradiation. Immune profiling results revealed unique immune diversity following each experimental condition, suggesting each stressor results in distinct circulating immune responses, with clear consequences for deep spaceflight. Circulating plasma microRNA sequence analysis revealed …

Prenatal Alcohol Exposure Alters Transcriptional Expression Of Stress And Tlr4-Related Immune Signaling Factors In The Brain Following Early Life Stress, Chaselyn D. Ruffaner-Hanson

Biomedical Sciences ETDs

Background: Depression and anxiety disorders, believed to be caused by stress-related neuropeptides and pro-inflammatory molecules in the brain, are prevalent comorbidities of fetal alcohol spectrum disorders (FASD).

Methods: Brain tissue was collected following a 4-hour maternal separation stress during the early postnatal period, postnatal days 10 and 12, from mice subjected to 1^st and 2^nd trimester prenatal alcohol exposure (PAE).

Hypothesis: We hypothesized that PAE leads to glucocorticoid receptor insensitivity, stress molecule overexpression, and potentiated toll-like receptor 4 (TLR4) pathway inflammatory responses in the brain following early life stress.

Results: PAE and stress increased mRNA expression of TLR4 …

The Role Of Anti-Inflammatory Cytokine Interleukin-10 (Il-10) In Tauopathies, Lea L. Weston

Biomedical Sciences ETDs

Tauopathies are neurodegenerative diseases, including Alzheimer’s disease, that are associated with pathological accumulation of the microtubule associated protein tau (MAPT, or tau) (Lee et al., 2001). Abnormal hyperphosphorylated tau (pTau) strongly correlate with cognitive impairment (Nelson et al., 2012). Neuroinflammation is also associated with tauopathies (Gerhard et al., 2006b; Edison et al., 2008) and is implicated in driving tau pathology (Yoshiyama et al., 2007, Maphis et al., 2015b). Therefore, it is compelling to understand the role of anti-inflammatory cytokines in limiting neuroinflammation and tau pathology. Interleukin-10 (IL-10) is a well-established anti-inflammatory cytokine with roles in limiting inflammation in the central …

Calcium Dyshomeostasis In Neurodegeneration, Nicholas Emanuel Karagas

Dissertations and Theses (Open Access)

Neurodegenerative diseases, despite constituting a major and growing cause of mortality globally, have few effective treatments. In order to develop novel therapeutics to combat neurodegeneration, a better understanding of the molecular mechanisms underlying these diseases is needed. Neurons rely on Ca²⁺ to mediate many of their unique functions, and aberrant Ca²⁺ signaling has been broadly implicated in neurodegeneration. The goal of this dissertation is to delineate specific examples of Ca²⁺ dyshomeostasis that I have uncovered in Drosophila models of neurodegeneration.

I first define the role a neurodegeneration-associated mutation plays in perturbing presynaptic [Ca²⁺], which is …

Reversal Of Neurodegeneration By Engineered Monocytes In Alzheimer’S Disease, Chao-Hsien Chen

Dissertations and Theses (Open Access)

The health challenges posed by Alzheimer’s disease (AD) continue to grow as societies age worldwide. Accumulation of Tau-associated pathology correlates with clinical cognitive deterioration in AD. Resident myeloid cells within the central nervous system (CNS) have a limited capacity to uptake and degrade Tau; however, the resulting secretion of proinflammatory cytokines only acts to accelerate neurodegeneration. Therapeutic antibodies can reduce the neurotoxic oligomeric form of Tau (o-Tau), but in doing so they also aggravate inflammation. Attenuating mutation of the antibody Fc region can silence inflammation but also eliminates its capacity to mediate o-Tau clearance by CNS myeloid cells. Thus, there …

Qki-Mediated Cholesterol Biosynthesis In Eye Lens And Myelin Of The Central Nervous System, Seula Shin, Seula Shin

Dissertations and Theses (Open Access)

Cells obtain cholesterol in two ways, de novo biosynthesis and uptake from circulation. While most tissues utilize both sources, eye lens and brain depend extensively on cholesterol biosynthesis due to the limited supply from circulation. Lens cell membrane consists of highest portion of cholesterol. Brain is the most cholesterol-rich organ, which accounts for 23% of total cholesterol. Genetic mutations of cholesterol biosynthesis enzymes in humans and animal models present cataracts and hypomyelinating disorders linked to neurological impairment. Yet, it remains unclear how gene expression of cholesterol biosynthesis is regulated in lens and brain. Therefore, studying cholesterol biosynthesis in both tissues …

Qki-Mediated Cholesterol Biosynthesis In Eye Lens And Myelin Of The Central Nervous System, Seula Shin, Seula Shin

Dissertations and Theses (Open Access)

Cells obtain cholesterol in two ways, de novo biosynthesis and uptake from circulation. While most tissues utilize both sources, eye lens and brain depend extensively on cholesterol biosynthesis due to the limited supply from circulation. Lens cell membrane consists of highest portion of cholesterol. Brain is the most cholesterol-rich organ, which accounts for 23% of total cholesterol. Genetic mutations of cholesterol biosynthesis enzymes in humans and animal models present cataracts and hypomyelinating disorders linked to neurological impairment. Yet, it remains unclear how gene expression of cholesterol biosynthesis is regulated in lens and brain. Therefore, studying cholesterol biosynthesis in both tissues …

Sexually Dimorphic Oxytocin Receptor-Expressing Neurons In The Anteroventral Periventricular Nucleus Regulates Maternal Behavior, Kaustubh Sharma

LSU Doctoral Dissertations

The neurohypophysial hormone oxytocin is involved in the regulation of social behaviors, including social recognition, pair bonding, and sex-specific parental behaviors in a variety of species. Oxytocin triggers these social behaviors by binding to oxytocin receptors (OXTR) in various parts of the brain. Oxytocin-induced sex-typical behavior, therefore, suggests a sexual dimorphic distribution of OXTR in the brain. In recent years, the oxytocin system in the brain received tremendous attention as a potential pharmacological target for treatment of many psychiatric disorders, such as anxiety, autism spectrum disorders, and even sex-specific psychiatric disorder like postpartum depression (PPD). An important problem and a …

White Matter Plasticity In Anxiety: Disruption Of Neural Network Synchronization During Threat-Safety Discrimination, Jia Liu, Ekaterina Likhti, A. Duke Shereen, Tracy A. Dennis-Tiwary, Patricia Casaccia

Advanced Science Research Center

Recent evidence highlighted the importance of white matter tracts in typical and atypical behaviors. White matter dynamically changes in response to learning, stress, and social experiences. Several lines of evidence have reported white matter dysfunction in psychiatric conditions, including depression, stress- and anxiety-related disorders. The mechanistic underpinnings of these associations, however, remain poorly understood. Here, we outline an integrative perspective positing a link between aberrant myelin plasticity and anxiety. Drawing on extant literature and emerging new findings, we suggest that in anxiety, unique changes may occur in response to threat and to safety learning and the ability to discriminate between …