Molecular and Cellular Neuroscience Commons^™

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 …

Targeting The Cerebrovasculature In Sepsis: A Focus On The Brain Microvascular Endothelium, Divine C. Nwafor

Graduate Theses, Dissertations, and Problem Reports (ETD)

The blood-brain barrier (BBB) is a critical interface between the systemic circulation and the brain. It is a specialized multicellular unit composed of brain microvascular endothelial cells (BMECs), pericytes, a basement membrane, and astrocytic end foot processes. BMECs are a principal component of the BBB that provide the structural framework needed for the stringent transport of molecules into the brain. BMEC dysfunction permits the trafficking of neurotoxins from systemic circulation into the brain, which ultimately exacerbates BBB dysfunction and neuroinflammation. Studies have shown that BBB dysfunction is a key determinant of cognitive decline in sepsis. However, there are critical knowledge …

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 …

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 …

Photoreceptor Phosphodiesterase (Pde6): Activation And Inactivation Mechanisms During Visual Transduction In Rods And Cones, Rick H. Cote

Faculty Publications

Rod and cone photoreceptors of the vertebrate retina utilize cGMP as the primary

intracellular messenger for the visual signaling pathway that converts a light stimulus into an electrical response. cGMP metabolism in the signal-transducing photoreceptor outer segment reflects the balance of cGMP synthesis (catalyzed by guanylyl cyclase) and degradation (catalyzed by the photoreceptor phosphodiesterase, PDE6). Upon light stimulation, rapid activation of PDE6 by the heterotrimeric G-protein (transducin) triggers a dramatic drop in cGMP levels that lead to cell hyperpolarization. Following cessation of the light stimulus, the lifetime of activated PDE6 is also precisely regulated by additional processes. This review summarizes …

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 …

Neutrophil-To-Lymphocyte Ratio: A Biomarker To Monitor The Immune Status Of Astronauts, Amber M. Paul, Siddhita D. Mhatre, Egle Cekanaviciute, Ann-Sofie Schreurs, Candice G.T. Tahimic, Ruth K. Globus, Sulekha Anand, Brian E. Crucian, Sharmila Bhattacharya

Publications

A comprehensive understanding of spaceflight factors involved in immune dysfunction and the evaluation of biomarkers to assess in-flight astronaut health are essential goals for NASA. An elevated neutrophil-to-lymphocyte ratio (NLR) is a potential biomarker candidate, as leukocyte differentials are altered during spaceflight. In the reduced gravity environment of space, rodents and astronauts displayed elevated NLR and granulocyte-to-lymphocyte ratios (GLR), respectively. To simulate microgravity using two well-established ground-based models, we cultured human whole blood-leukocytes in high-aspect rotating wall vessels (HARV-RWV) and used hindlimb unloaded (HU) mice. Both HARV-RWV simulation of leukocytes and HU-exposed mice showed elevated NLR profiles comparable to spaceflight …

Aci-35 And Aadvac1 Active Immunotherapy As Preventative Treatment Options For Chronic Traumatic Encephalopathy, Emily C. Boehlein

Selected Honors Theses

One of the most common, as well as one of the most dangerous injuries amongst athletes today is mild traumatic brain injury (mTBI), commonly known as concussion. Aside from physical symptoms such as nausea, dizziness, and headaches; concussions have can have longterm effects on brain physiology. A common neurological disease that can result from multiple concussions is Chronic Traumatic Encephalopathy (CTE), characterized by symptoms such as severe depression, anxiety, confusion, and aggression; amongst others.1 On the cellular level, CTE is classified by a unique pathway that leads to the hyperphosphorylation of tau protein and subsequent clumping of tau-containing neurofibrillary tangles …

Degradation Of Transcriptional Repressor Atf4 During Late-Phase Long-Term Potentiation, Spencer Smith

Biology Theses

Maintenance of long-term synaptic plasticity requires gene expression mediated by cAMP-responsive element binding protein (CREB). Gene expression driven by CREB can commence only if the inhibition by a transcriptional repressor ATF4 (activating transcription factor 4; aka CREB2) is relieved. Previous research showed that the removal of ATF4 occurs through ubiquitin-proteasome-mediated proteolysis. Using chemically induced hippocampal long-term potentiation (cLTP) as a model system, we investigated the mechanisms that control ATF4 degradation. We observed that ATF4 phosphorylated at Serine-219 increases upon induction of cLTP and decreases by about 30 min thereafter. Proteasome inhibitor β-lactone prevents the decrease in ATF4. We found that …

Ubc-9 Acts In Gaba Neurons To Control Neuromuscular Signaling In C. Elegans, Victoria A. Kreyden, Elly B. Mawi, Jennifer Kowalski

Scholarship and Professional Work - LAS

Regulation of excitatory to inhibitory signaling balance is essential to nervous system health and is maintained by numerous enzyme systems that modulate the activity, localization, and abundance of synaptic proteins. SUMOylation is a key post-translational regulator of protein function in diverse cells, including neurons. There, its role in regulating synaptic transmission through pre- and postsynaptic effects has been shown primarily at glutamatergic central nervous system synapses, where the sole SUMO-conjugating enzyme Ubc9 is a critical player. However, whether Ubc9 functions globally at other synapses, including inhibitory synapses, has not been explored. Here, we investigated the role of UBC-9 and the …

Functions Of Fibroblast Growth Factor Homologous Factor 2 In Excitable Tissues, Christopher Marra

Dissertations, Theses, and Capstone Projects

Purpose: Fibroblast Growth Factor Homologous Factors (FHFs) are a group of proteins known to associate with and modulate voltage-gated sodium channels (Na_v) in excitable cells. The four FHF genes are differentially expressed in specific cell-types, with FHF2 expressed prominently in the hippocampus, cerebral cortex, heart and dorsal root ganglia. Due to previous unavailability of an Fhf2 knockout mouse, this gene’s functions have been understudied in comparison to other those encoding other FHFs. The purpose of this research has been to better understand the normal physiological functions of FHF2 at the cellular and system levels in the heart, sensory …