Molecular and Cellular Neuroscience Commons^™

Oxidative Stress Mediated Glutamate Release And Nmda Receptor-Dependent Synaptic Remodeling In Radiation-Induced Cognitive Dysfunction, Thanh Lam

Dissertations and Theses (Open Access)

In children younger than 14 years old, the brain and other parts of the central nervous system are the most common sites for solid tumors. Radiotherapy is an effective treatment for central nervous system (CNS) tumors. However, it often causes a progressive decline in cognitive functions, which is especially devastating for pediatric patients. Although post-mitotic neurons are generally considered resistant to radiation-induced immediate cell death, ionizing radiation causes complex neurochemical and structural changes that damage synaptic integrity. In this study, we examined the molecular cascades following a 10 Gy radiation dose applied to mouse cortical neurons. We found that radiation-induced …

Capsinoids, Non-Pungent Trpv1 Agonists, Induce A Mild Hypothermia That Provides Short- And Long-Term Neuroprotection After Ischemic Stroke, Alexander Andersohn, Alexander Andersohn

Dissertations and Theses (Open Access)

Therapeutic hypothermia (TH) has demonstrated neuroprotection in instances of cardiac arrest and neonatal hypoxia/ischemia but faces different challenges in application to stroke due to the activation of cold defense mechanisms in conscious patients. This dissertation examines the efficacy and specificity of capsinoids (a purified mixture of capsiate and dihydrocapsiate) to induce a sustained mild hypothermia in conscious mice that is neuroprotective after stroke. Capsinoids function as TRPV1 agonists. However, unlike capsaicin, capsinoids are vulnerable to esterase-mediated breakdown, thus significantly restricting their action to the site of delivery. We showed that capsinoids delivered intraperitoneally (IP) to mice induced a TRPV1-dependent drop …

Structural Functional Investigation Of Hap40, Amanda M. Solbach

Dissertations and Theses (Open Access)

STRUCTURAL FUNCTIONAL INVESTIGATION OF HAP40

Amanda Marie Solbach

Dissertation Advisor: Sheng Zhang, Ph.D.

Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the Huntingtin (HTT) gene, resulting in a mutant huntingtin (mHTT) protein with an elongated polyglutamine tract. While the genetic basis of HD is well established, the mechanisms underlying mHTT toxicity and its impact on cellular function remain incompletely understood. Recent discoveries implicate Huntingtin-associated protein 40 (HAP40) as a critical regulator of HTT stability and intracellular function. However, the physiological and pathological significance of this interaction has not been fully explored.

This …

Rod Photoreceptor Regeneration In A Zebrafish Model With Retinitis Pigmentosa, Eyad Shihabeddin

Dissertations and Theses (Open Access)

A cellular hallmark of inherited retinal degenerative diseases is progressive loss of photoreceptors until one is completely blind. Unlike mammalian models, Zebrafish have the ability to naturally regenerate their neurons after injury or disease is detected. We have generated a zebrafish model with the most common autosomal dominant form of the inherited retinal degenerative disease known as Retinitis Pigmentosa. We utilize immunohistochemistry, single-cell RNA sequencing, several analysis tools, behavioral assays and oligonucleotides to characterize our zebrafish model and identify the transcription factors necessary for rod photoreceptor regeneration. We show that our zebrafish model has continuous degeneration and regeneration of rod …

The Role Of The Circadian Clock In The Paraventricular Nucleus Of The Hypothalamus In Diurnal Energy Balance, Rachel Van Drunen

Dissertations and Theses (Open Access)

Circadian rhythms are internal biological rhythms that drive oscillations in physiology and metabolism. Maintained at the level of individual cells throughout the body, the circadian clock is necessary for driving tissue-specific temporal programs of energy balance. Though loss of the circadian transcription factor, BMAL1, in the paraventricular nucleus (PVN) of the hypothalamus has revealed its importance in driving rhythms in energy intake and metabolism, its transcriptional functions across time and in individual cell types in the PVN are not well understood. In this study, we show that loss of BMAL1 in the PVN not only results in arrhythmicity in processes …

Early Onset Alzheimer’S Disease Markers In Mouse Hippocampus Unveiled By Single-Cell Transcriptomic Analysis Following Cranial Radiotherapy, Tuba Aksoy

Dissertations and Theses (Open Access)

Cranial radiation therapy plays an integral role in the treatment of brain tumors but can lead to progressive cognitive deficits in survivors by mechanisms that are poorly understood. To develop preventive or mitigative strategies, it is crucial to better understand the underlying pathogenesis of radiation-induced cognitive impairments. The study investigated single-cell transcriptomics and DNA methylation changes as potential drivers of persistent cellular dysfunction after radiation exposure, specifically concentrating on the CA1-3 regions of the hippocampus and the prefrontal cortex due to their role in cognitive functions. Thirteen-week-old mice underwent whole-brain radiation at clinically relevant doses. Following whole-brain radiation, an assessment …

The Role Of Micrornas On Systemic And Central Nervous System- Inflammation In Aged Mice, Anik Banerjee

Dissertations and Theses (Open Access)

MicroRNAs play a crucial role in multiple biological processes, including development, cell differentiation, proliferation, metabolism, and cell death. Aberrant regulation of microRNAs is seen in many diseases, such as sepsis, cardiovascular disease, neurological diseases such as stroke, and metabolic disorders. Because of their involvement in disease processes, microRNAs have been investigated as both potential biomarkers, and as therapeutic targets. Age-related inflammatory diseases including diabetes, obesity, and atherosclerosis are important risk factors for infection and sepsis. Intestinal barrier impairment occurs with aging and after brain injuries, including stroke. Both aging and stroke increase the risk of infection and sepsis and are …

Molecular Mechanisms Of Opioid Use Disorder In Human Brain Models, Emily Mendez

Dissertations and Theses (Open Access)

Opioid use disorder (OUD) is a national and global public health crisis with no end in sight. While studies from animal models hint at widespread epigenetic and transcriptomic alterations of opioid drugs, the molecular consequences of long-term exposure to opioid drugs in human brain is still unclear, and human-centered translational models are necessary to discern the human cell type-specific effects of OUD.

Using postmortem brain Brodmann area 9 (BA9) from the UTHealth Brain Collection for Research on Psychiatric Disorders, I identified angiogenic gene networks perturbed in the RNA and protein of OUD subjects, as well as downregulation of many neuron-correlated …

Novel Roles Of Microtubule-Associated Tau In Radiation-Induced Brain Injury, Riya Thomas, Riya Thomas

Dissertations and Theses (Open Access)

Injury responses in cells lacking proliferation capacity such as terminally differentiated neurons consists of complex mechanisms to ensure cellular homeostasis. Brain tumor patients undergoing radiation therapy experience cognitive impairments similar to those seen in patients suffering from neurodegenerative diseases. Despite the plethora of research into radiation effects on proliferating brain cells, the impact of radiation on differentiated, post-mitotic neurons, including their structural and functional alterations, remain largely elusive. However, microtubule-associated tau, an important partner of cytoskeletal structural stability emerges as a pivotal player in the radiation-induced neuronal injury response, demonstrating compartmentalized functions such as repair-centric mechanisms and synaptic homeostasis. This …

Biophysical Model Of Retraction Motor Neurons And Their Modification By Operant Conditioning, Maria Rasheed

Dissertations and Theses (Open Access)

Operant conditioning (OC) is a form of associative learning in which an animal modifies its behavior based on the consequences that follow that behavior. Despite its ubiquity, the underlying mechanisms of OC are poorly understood. Insights into the mechanisms of OC can be obtained by studying Aplysia feeding behavior as it can be modified by OC. This behavior is mediated by a central pattern generator (CPG) network in the buccal ganglia that contains a relatively small number of neurons. This CPG generates rhythmic motor patterns (BMPs) that move food into the gut by closing a tongue-like structure (i.e., radula) during …

Identification And Delineation Of Neuronal Pathways Underlying Hypophagia, Jing Cai

Dissertations and Theses (Open Access)

In terms of metabolism, eating disorders manifest in two extreme directions: overnutrition, which can lead to obesity, and malnutrition, which can result in underweight or even starvation. Both extremes compromise the quality of life. According to the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) standard, eating disorders affect up to 17.9% of young women and 2.4% of young men. Although eating disorders are primarily defined as mental disorders rather than metabolic disorders, they are intertwined with complex emotions and sensory perceptions. However, in contemporary animal research related to eating disorders and feeding behaviors, the majority of neuroscientists still examine …

Med12 Is A Critical Regulator Of Neural Crest Lineage And Nervous System Myelination, Fatma Betul Aksoy Yasar

Dissertations and Theses (Open Access)

The Mediator complex (MED) is a multi-subunit protein complex integral to the eukaryotic transcription machinery. MED12 is a Cdk8- regulatory kinase module subunit directly implicated in human disease and is genetically altered in neurological disease and cancer. Numerous attempts at generating an in vivo system to study the role of Med12 failed due to embryonic lethality associated with germline or developmental disruption of Med12 gene. To understand the cellular and molecular processes associated with its role in disease, we generated multiple mouse models with targeted depletion of MED12 in distinct cellular lineages. Our genetically engineered models with induced and conditional …

Analysis Of The Distributed Representation Of Operant Memory In Aplysia, Renan Murillo Costa

Dissertations and Theses (Open Access)

Operant conditioning, a ubiquitous form of learning in which animals learn from the consequences of behavior, engages a high-dimensional neuronal population space spanning multiple brain regions. A complete characterization of an operant memory remains elusive. Some sites of plasticity participating in the engram underlying an example of operant memory in Aplysia have been previously uncovered. Three studies are described here that sought to draw closer to a thorough characterization of this memory. The first study used a computational model to examine the ways in which sites of plasticity (individually and in combination) contribute to memory expression. Each site of plasticity …

Innate Lymphoid Cell Characterization And Ilc2s In Neuroinflammation In Aging And Sex Differences, Alexis Mobley, Alexis S. Mobley

Dissertations and Theses (Open Access)

Aging affects immunologic responses by a global immune system suppression, including dysregulation of cytokine mediators, leading to increased inflammation throughout all systems, termed inflammaging. However, understanding healthy aging mechanisms can bypass this effect. Inflammaging also leads to poor outcomes during brain injury, making immune-targeting therapeutics tantamount to overall brain health and longevity. Moreover, sex affects disease etiology and severity through hormonal and chromosomal sex, as the X chromosome contains most immunology-based genes. Androgens have a generally suppressive effect on the immune system. Additionally, when immune responses are mounted, males are better at CD4+ T cell type (Th1) responses, while females …

Deciphering The Role Of Hsp110 Chaperones In Diseases Of Protein Misfolding, Unekwu M. Yakubu

Dissertations and Theses (Open Access)

Molecular chaperones maintain protein homeostasis (proteostasis) by ensuring the proper folding of polypeptides. Loss of proteostasis has been linked to the onset of numerous neurodegenerative disorders including Alzheimer’s, Parkinson’s, and Huntington’s disease. Hsp110 is a member of the Hsp70 class of molecular chaperones and acts as a nucleotide exchange factor (NEF) for Hsp70, the preeminent Hsp70-family protein folding chaperone. Hsp110 promotes rapid cycling of ADP for ATP, allowing Hsp70 to properly fold nascent or unfolded polypeptides in iterative cycles. In addition to its NEF activity, Hsp110 possesses an Hsp70-like substrate binding domain (SBD) whose biological roles are undefined. Previous work …

Investigating Mechanisms In Nociceptors Driving Ongoing Activity And Ongoing Pain, Elia Lopez

Dissertations and Theses (Open Access)

Ongoing (apparently spontaneous) pain at rest is a major complaint of patients suffering from many forms of acute and chronic pain, including acute and persistent postsurgical pain. Accumulating evidence suggests ongoing activity in nociceptors is a major driver of ongoing pain. Ongoing activity can be generated in sensory neurons in the absence of sensory generator potentials if one or more of three neurophysiological alterations occur – prolonged depolarization of resting membrane potential (RMP), hyperpolarization of action potential (AP) threshold, and/or increased amplitude of depolarizing spontaneous fluctuations of membrane potential (DSFs) to bridge the gap between RMP and AP threshold. Cellular …

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 …

Astrocytes Rescue Neuronal Health After Cisplatin Treatment Through Mitochondrial Transfer., Krystal English, Krystal English

Dissertations and Theses (Open Access)

Abstract

Astrocytes rescue neuronal health after cisplatin treatment through mitochondrial transfer.

Author: Krystal English

Advisory Professor: Dr. Cobi J. Heijnen, Ph.D.

Chemotherapy-induced cognitive impairments are associated with neuronal mitochondrial dysfunction. Cisplatin, a commonly used chemotherapeutic, induces neuronal mitochondrial dysfunction in vivo and in vitro. Astrocytes are key players in supporting neuronal development, synaptogenesis, axonal growth, metabolism and, potentially, mitochondrial health. We tested the hypothesis that astrocytes transfer healthy mitochondria to neurons after cisplatin treatment to restore neuronal health.

We used an in vitro system in which astrocytes with Mito-mCherry-labeled mitochondria were co-cultured with primary cortical neurons or neuronal stem …

Aging Lowers Pex5 Levels In Cortical Neurons In Male And Female Mouse Brains, Ndidi-Ese Uzor

Dissertations and Theses (Open Access)

Peroxisomes are small organelles with critical functions: lipid synthesis, breakdown of reactive oxygen species by antioxidant enzymes, and amino acid degradation. In the brain, peroxisomal lipids make up the myelin sheath. Brain peroxisomal dysfunction leads to lipid disruption or neurological consequences if key peroxisomal proteins are absent. Still, it is unclear how peroxisomes are affected in neurodegenerative diseases and in normal brain aging. This work examines peroxisomal markers in three settings: 1) in a neuronal and 2) animal model of Huntington disease (HD), where mutant huntingtin (mHtt), the causative protein in Huntington disease pathogenesis is expressed, and 3) in the …

Cellular And Circuit Properties Of Slow Oscillations In The Thalamic Reticular Nucleus, John O'Malley

Dissertations and Theses (Open Access)

During sleep, neurons in the thalamic reticular nucleus (TRN) generate distinct types of oscillatory activity. While the reciprocal synaptic circuits between TRN and sensory thalamic nuclei underlie the generation of sleep spindles, the mechanisms regulating slow (<1 >Hz) forms of thalamic oscillations are poorly understood. Under in vitro conditions, in the absence of synaptic inputs, TRN neurons can generate slow oscillations in a cell-intrinsic manner. Activation of postsynaptic Group 1 metabotropic glutamate receptors (mGluR) leads to long-lasting plateau potentials thought to be mediated by both T-type calcium currents and calcium-activated nonselective cation currents (I_CAN). However, the identity of …

Elevated Cochlear Adenosine Causes Hearing Loss Via Adora2b Signaling, Jeanne Manalo

Dissertations and Theses (Open Access)

Over 538 million people in the world have been diagnosed with hearing loss (HL). Current treatments for the most common type of HL, sensorineural HL, are limited to hearing aids and cochlear implants with no FDA-drugs available. The hearing process demands an abundance of ATP and HL is often attributed to a disruption in this metabolic energy currency. Patients who lack adenosine deaminase (ADA), the enzyme that irreversibly metabolizes adenosine, have high levels of adenosine that yield severe health problems, including HL; however, the pathogenic mechanisms behind HL and adenosine remain elusive. Our lab has found a HL phenotype in …

A Novel Switch-Like Function Of Delta-Catenin In Dendrite Development, Ryan Baumert

Dissertations and Theses (Open Access)

The formation of neuronal networks in the brain is tightly regulated, and dependent on the morphology of dendrites, the branch-like signal-receiving structures extending from neurons. Disruptions in dendrite development, or dendritogenesis, can lead to the atypical neuronal connectivity associated with multiple neurodevelopmental diseases. My research addresses molecular processes that underlie dendritogenesis via analysis of a pair of novel interactions involving the protein delta-catenin.

In neurons, delta-catenin localizes to dendrites and synapses, where it functions in their development and maintenance. Structurally, delta-catenin possesses a central Armadillo domain and a C-terminal PDZ-binding motif. This motif associates with PDZ domain-containing proteins, and is …

Development Of A High-Throughput System For Screening Of Anti-Prion Molecules, Katherine Do

Dissertations and Theses (Open Access)

The misfolded prion protein causes and transmits disease in both humans and animals. As other infectious agents, prions display strain variation, which can generate different pathological outcomes in affected individuals. Unfortunately, there are no known therapies for these diseases, which at present are invariably fatal. In this work, the Protein Misfolding Cyclic Amplification technology (PMCA, an in vitro test that replicates minimum quantities of infectious prions) has been modified to screen for small molecules inhibiting prion protein misfolding in a strain-specific manner. In order to approach a high-throughput PMCA system, technical aspects in PMCA has been optimized for application of …

Rejuvenation Of The Epigenetic Landscape Of The Aged Brain Through Manipulation Of Circulating Factors, Edward Koellhoffer

Dissertations and Theses (Open Access)

The aging population of the United States is expanding at an alarming rate. The Center for Disease Control and Prevention estimates that the population of those age 65 years and older will reach over 50 million by 2020 and will double to 100 million by 2060. This will not only put a massive strain on national healthcare resources, but will also increase the number of those who are not able to live and function independently. It is becoming increasingly vital to understand how the brain changes with age and mechanisms to possibly protect and rejuvenate the aged brain to a …

Data Collection Curated With An Application Ontology Describes The Methods And Results Upon Performing An Ex-Vivo Voltage-Clamp Assay On Outer Hair Cells Of The Mammalian Cochlea, Brenda Farrell, Jason Bengtson

Research Data

This data collection describes the electrical properties of outer hair cells isolated from the mammalian cochlea of the domestic guinea pig. This data was obtained by performing whole-cell patch clamp voltage clamp assay on cells and monitoring the electrical admittance during a DC voltage ramp. The membrane capacitance was then calculated at each membrane potential from this admittance, and the voltage-independent and voltage-dependent membrane capacitance was determined upon further analysis. In some case the DC conductance was also measured by interrogation of the cell with voltage-step function which was calculated from the change in the mean steady-state current with respect …

Hypothalamic Circuits In The Control Of Feeding And Emotional Behaviors, Leandra Mangieri

Dissertations and Theses (Open Access)

Feeding results from the integration of both nutritional and affective states, and is guided by complex neural circuitry in the brain. The hypothalamus is a critical center controlling feeding and motivated behaviors. We found that targeted photostimulation of projections from the lateral hypothalamus (LH) to the paraventricular hypothalamus (PVH) in mice elicited voracious feeding and repetitive self-grooming behavior. GABA neurotransmission in the LH->PVH circuit mediated the evoked feeding behavior, and elicited behavioral approach, whereas glutamate release promoted repetitive self-grooming, which was stress-related in nature. Optogenetic inhibition of LH^GABA ->PVH circuit reduced feeding after fasting, whereas photostimulation abruptly …

Cholinergic Control Of Cortical Circuit Activity, Rajan Dasgupta

Dissertations and Theses (Open Access)

Cholinergic neurons of the basal forebrain send extensive projections to all regions of the neocortex and are critically involved in a diverse array of cognitive functions, including sensation, attention and learning. Cholinergic signaling also plays a crucial role in the moment-to-moment control of ongoing cortical state transitions that occur during periods of wakefulness. Yet, the underlying circuit mechanisms of synaptic cholinergic function in the neocortex remain unclear. Moreover, acetylcholine continues to be widely viewed as a slow and diffuse neuromodulator, despite the preponderance of in vivo evidence demonstrating rapid cholinergic function. In this study, we used a combination of optogenetics …