Master of Science, Miami University, 2024, Biology

Coordination between central pattern generators (CPG) is important in proper functioning of related rhythmic behaviors such as vocalization, breathing and locomotion. Despite their importance, the cellular mechanisms of inter-network coordination and how it impacts muscles remain largely unidentified. Using the small, well-characterized networks in the stomatogastric nervous system of the crab, Cancer borealis, I identify the role of a dual-network neuron in coordinating the feeding-related pyloric (“fast”: 1 Hz: filtering food) and gastric mill (“slow”: 0.1 Hz: chewing) CPG networks, during a unique modulatory state elicited by the neuropeptide Gly1-SIFamide. The dual-network neuron, LPG, rhythmically increases and decreases the frequency of the pyloric rhythm in time with different phases of the slower gastric mill rhythm. Using these findings, I show that this complex coordination pattern is distinctly translated into electrical responses of two behaviorally different muscles, innervated by LPG. Where the LPG innervated pyloric muscle follows LPG's dual-network activity, while the gastric mill muscle prioritizes gastric mill over pyloric activity. This study provides insight into a unique coordination mechanism that is funneled through a dual-network neuron, and how the muscles innervated by this neuron respond to and participate in the overall coordination of related but distinct behaviors.

Committee: Dawn Blitz Dr (Advisor); Joseph Ransdell Dr (Committee Member); Kathleen Killian Dr (Committee Member) Subjects: Neurobiology; Neurosciences; Physiology

Doctor of Philosophy (PhD), University of Toledo, 2019, Biomedical Sciences (Molecular Medicine)

Insulin-like growth factor 1 (IGF-1) and insulin exert biological effects through highly homologous tyrosine kinase receptors, which are ubiquitously expressed in rodents. During the last two decades, substantial progress has been made in understanding the role of IGF-1 and insulin signaling in the brain. Major progress has been made in identifying differences of IGF-1 and insulin signaling in the brain and understanding the phenotypic discrepancies of disruptions of the IGF-1 receptors (IGF1Rs) and insulin receptors (IRs) in the brain. Metabolic diseases such as obesity and diabetes are global public health crises. Moreover, perturbations of metabolism cause various reproductive diseases such as abnormal puberty onset, irregular estrus cycle, altered ovarian function, infertility and reproductive system cancers. Thus, understanding and deciphering brain IGF1R and IR signaling are crucial to current research and crucial for potential therapeutic interventions for metabolic and reproductive diseases. Neurons are the fundamental units of the brain and carry out distinct functions, which raises another challenge -- understanding the role of a given subset of neurons. Two subsets of neurons-leptin receptor (LepRb) neuron and kisspeptin (Kiss1) neuron have drawn my attention due to their distinct activities in metabolism and reproduction respectively. Current technique Cre/loxP system enables conditional suppression of gene expression in distinct subsets of neurons of interest. We used this technique to generate transgenic mice to study the role of IGF1R and IR signaling in LepRb neurons and Kiss1 neurons. Chapter 1 gives a review of metabolic and reproductive function of IGF1R and IR, and a central control of metabolism and reproduction by LepRb neurons and Kiss1 neurons. By characterizing reproductive and metabolic phenotype of mice lacking IGF1Rs and/or IRs exclusively in LepRb neurons (IGF1RLepRb mice and IGF1R/IRLepRb mice), we found that IGF1RLepRb and IGF1R/IR (open full item for complete abstract)

Committee: Jennifer Hill (Committee Chair); Beata Lecka-Czernik (Committee Member); Edwin Sanchez (Committee Member); David Giovannucci (Committee Member); Joshua Park (Committee Member) Subjects: Biomedical Research

MS, University of Cincinnati, 2024, Engineering and Applied Science: Biomedical Engineering

Peripheral neuropathy is a diverse affliction caused by numerous forms of traumatic injuries and genetic diseases. Damage or mutation in the peripheral nervous system (PNS) can result in unpleasant alterations to normal sensation, such as chronic itch or chronic pain. There is no cure for peripheral neuropathy and research models of the PNS are limited due to its vital nature in an organism and its grand scale. Only in-vitro and in-utero models allow for observing interactions between the distal and proximal ends of sensory neurons (SNs) in tandem. Current three-dimensional (3D) in-vitro models enable simulating the PNS in different tissue environments, such as the skin. However, current innervated models are limited in options for measuring action potentials of SNs in the 3D environment. Such models use non-repeatable measurements or costly experimental measuring apparatuses, making processes that change over time, such as healing or degradation, a significant challenge to observe. In this article we describe the creation of an innervated dermis optimized to provide surface access to SNs so individual neuron action potentials can be clearly distinguished from each other while still achieving transdermic sensation for use with calcium imaging. Next, we develop our own method for repeatably measuring action potentials using our model that provides continuous measurement of action potentials in a non-destructive manner, without the need for a customized imaging apparatus. Our new model can simultaneously measure multiple action potentials from dozens of neurons numerically and continuously across multiple days.

Committee: Stacey Schutte Ph.D. (Committee Chair); Eric Nauman Ph.D. (Committee Member); Greg Harris Ph.D. (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, The Ohio State University, 2024, Biochemistry Program, Ohio State

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by survival motor neuron (SMN) protein deficiency that results in motor neuron loss and muscle atrophy. SMN is encoded by two nearly identical genes in humans, SMN1 and SMN2 which functionally differ by a C to T change in exon 7. This change greatly reduces exon 7 inclusion from the majority transcripts from SMN2. The truncated SMN protein is unstable and rapidly degrades, resulting in reduced SMN levels. SMA patients have a mutation or loss of SMN1 and therefore, rely completely on the SMN2 gene for SMN production. It has been demonstrated in both animal models and humans that increasing SMN levels prior to onset of symptoms provides the greatest therapeutic benefit. Currently, there are three FDA approved SMN inducing therapies for treatment of SMA: antisense oligonucleotide, Spinraza™, gene replacement therapy Zolgensma™, and small molecule drug, Evrysdi™. While the current therapies are efficacious, many patients are symptomatic at diagnosis with varying levels of motor function and consequently, response to treatment is variable. Treatment after motor neuron loss has occurred is effective, although to a lesser degree. We treated three groups of severe SMA mice starting before, during, and after symptom onset to determine if combining the two mechanistically distinct SMN inducing therapies, the antisense oligonucleotide (ASO) and small molecule compound, could improve the therapeutic outcome both before and after motor neuron loss. We found, compared with individual therapies, dual treatment significantly increased FL-SMN transcript and protein production resulting in improved survival and weight of SMA mice. Additionally, when administered late symptomatically, motor unit function was completely rescued with no loss in function at 100 days of age in the dual treatment group. Therefore, we have shown this dual therapeutic approach successfully increases SMN protein and rescues motor (open full item for complete abstract)

Committee: Arthur Burghes PhD (Advisor); Kathrin Meyer PhD (Committee Member); Michael Kearse PhD (Committee Member); Michael Freitas PhD (Committee Member) Subjects: Biochemistry; Biomedical Research; Genetics; Molecular Biology; Neurobiology

Master of Science, University of Akron, 2023, Biology

There are six different types of retinal ganglion cells that express the photopigment melanopsin. Of those six types, M1s have the highest expression of melanopsin with dendrites stratifying across the OFF section of the inner plexiform layer. Previous studies have established that intrinsically photosensitive retinal ganglion cells distribute asymmetrically across the retina and are affected by glaucoma. I hypothesize that since M1s localize asymmetrically across the retina their location and the effect of early glaucoma will influence M1s cellular morphology. Analysis was conducted based on M1 ganglion cell morphological differences between an early glaucoma mouse model DBA/2J and a control mouse model Gpnmb+/SjJ. Early glaucoma had a significant influence on M1 cellular morphology such as cell counts, soma size, dendritic length, dendritic field size and dendritic field diameter due to genotype and M1 regional location. The results from this experiment suggest early glaucoma affects M1 ganglion cells morphology.

Committee: Jordan Renna (Advisor); Samuel Crish (Committee Member); Qin Liu (Committee Member) Subjects: Biology; Neurobiology

Master of Science in Biomedical Engineering (MSBME), Wright State University, 2023, Biomedical Engineering

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease which targets motoneurons (MNs), yet underlying disease mechanisms are not well understood. Evaluating the intrinsic excitability of MNs in ALS could lead to a better understanding of mechanisms causing neurodegeneration. The SOD1-G93A (SOD) model is the most commonly studied animal model of ALS. However, past studies have shown highly conflicting results on SOD MN excitability. Interestingly, I show that depending on the level of membrane depolarization, SOD MNs show opposite results of both hyper- and hypo-excitability. This reveals that differences in the methodology of measuring excitability can heavily impact the study results. Finally, I have investigated the firing abnormalities leading to hypoexcitability in SOD MNs at high levels of membrane depolarization. Results indicate that these firing abnormalities are due to decreased Kv2.1 channel conductance. Furthermore, these firing abnormalities could be the basis for developing a biomarker which could be used to diagnose ALS earlier.

Committee: Sherif Elbasiouny Ph.D. (Advisor); Keiichiro Susuki M.D., Ph.D. (Committee Member); Jaime Ramirez-Vick Ph.D. (Committee Member) Subjects: Engineering; Neurobiology; Neurosciences; Physiology

PHD, Kent State University, 2022, College of Arts and Sciences / School of Biomedical Sciences

Having transitioned from a terrestrial lifestyle to an aquatic one over roughly 50 million years, cetaceans (whales, dolphins, and porpoises) make for prime subjects of study of respiratory and olfactory anatomy. As obligately aquatic mammals, they are often considered to have reduced olfactory anatomy. Here, I provide evidence that baleen whales have retained this anatomy, and toothed whales lack olfactory anatomy. In reconstructing the upper respiratory tracts of prenatal dolphins from computed tomography, I document the anatomy of the air sacs, pterygoid sinus systems, and asymmetries thereof. Olfactory anatomy was absent. However, in bowhead whales (Balaena mysticetus), a species of baleen whale, nasal chambers and turbinates were visible in prenatal development. I describe and clarify the anatomy within their nasal chambers. Olfactory epithelium, identified histologically, covers the dorsalmost and caudalmost corner of the nasal chamber, including some of the ethmoturbinates. I identify olfactory epithelium using explicit criteria of mammalian olfactory epithelium. Immunohistochemistry revealed the presence of olfactory marker protein, which is only found in mature olfactory sensory neurons. Although it seems that these neurons are scarce in bowhead compared to typical terrestrial mammals, our results suggest that bowheads have a functional sense of smell, which they may use to find prey. The closest living relatives of cetaceans are artiodactyls, even-toed ungulates, such as sheep, camels, and giraffes. I used Cetartiodactyla, the clade that comprises artiodactyls and cetaceans, as the taxon to test the relationships found in Bird et al. (2018). They found that once body mass and phylogeny are accounted for, it is possible to use the surface area of the cribriform plate to predict the number of olfactory receptor genes that fossil mammals have. I confirmed their results and predicted gene counts in fossil whales, thereby documenting a decrease in (open full item for complete abstract)

Committee: J. G. M. Thewissen (Advisor); Samuel Crish (Committee Member); Mary Ann Raghanti (Committee Member); Edgar Kooijman (Committee Member); Tobin Hieronymus (Committee Member) Subjects: Anatomy and Physiology; Animals; Biology; Evolution and Development; Histology; Morphology; Paleontology

Doctor of Philosophy, Northeast Ohio Medical University, 2019, Integrated Pharmaceutical Medicine

Glaucoma, the leading cause of irreversible blindness worldwide, is a group of neurodegenerative disorders characterized by progressive and irreversible retinal ganglion cell (RGC) loss beginning with an optic neuropathy. Due to our lack of knowledge of the complicated etiology and mechanisms of glaucoma progression, no cure is available to prevent blindness. My purpose in this dissertation was to explore early contributors to glaucoma pathology in an effort to develop targeted therapy. Glaucoma is a multifactorial neurodegenerative disease in which various factors have been identified to play a significant part in its pathogenesis. For example, increased intraocular pressure can disrupt ocular blood flow to the eye, resulting in hypoxia. Although hypoxia was identified as a contributing factor for glaucoma, no one has yet identified the hypoxic cell types, hypoxia timeline and extent during glaucoma. In this dissertation, I contributed to glaucoma research by filling this gap in our knowledge to deepen our understanding of early changes after ocular hypertension. First, I determined the timeline of hypoxia in different cell types in the visual pathway using two hypoxia detection methods, an antibody against hypoxia-associated protein adducts, and a reporter protein expressed as a result of HIF1 stabilization. In addition, during hypoxia, autophagy, degradation of damaged organelles, and mitophagy, selective degradation of mitochondria, are induced. Second, I characterized hypoxia, autophagy, and oxidative stress using two models of glaucoma, the DBA/2J mouse model and a model of ocular hypertension. Finally, I used mass spectrometry to explore the half-life of mitochondrial electron transport chain complexes to better understand mitochondrial turnover, and possibly mitophagy, during glaucoma. Through these investigations, I have utilized multiple techniques, such as: Intraocular injection; intraperitoneal injection; tail vein injection; tissue sectioning using mic (open full item for complete abstract)

Committee: Denise Inman Dr. (Advisor); Brett Schofield Dr. (Committee Member); Vahagn Ohanyan Dr. (Committee Member); John Johnson Dr. (Committee Member); Samuel Crish Dr. (Committee Member) Subjects: Neurobiology; Neurosciences

MA, Kent State University, 2021, College of Arts and Sciences / Department of Anthropology

Neurodevelopment and brain aging varies between species and across the lifespan of all mammals. The brain undergoes significant changes through fetal development, early life development, and through aging and senescence even in the absence of pathology. Animal models are commonly used to learn more about the development and aging of the human brain however little is known about the development and aging of one of humans' closest evolutionary relatives, chimpanzees. The objective of this study was to determine age and/or species related effects on neuron density (Nv), glia density (Gv), and glia to neuron ratio (G:N) in Brodmann's area 9 (BA9) of the prefrontal cortex (PFC) using direct comparative methods in stereology to compare Nv, Gv, and G:N between age cohorts within-species and between-species in humans and chimpanzees. We found that there were no age-related effects on Nv, Gv, or G:N ratio within species across the lifespan but there were differences between species in Nv and Gv with chimpanzees having increased cell densities of both types. Additionally, there were significant differences between the developmental and young adult human cohorts in Gv with the young adult cohort having decreased Gv as compared to the developmental group. Additional analysis revealed differences in the way that cell densities changed across the lifespan between species indicating that aging has different effects on the PFC of the human brain in comparison to the chimpanzee brain. However, this research sample was limited with few young individuals in the chimpanzee sample restricting our ability to detect early age-related patterns in chimpanzees or between species in the younger cohorts.

Committee: Mary Ann Raghanti (Advisor); Richard Meindl (Committee Member); Anthony Tosi (Committee Member) Subjects: Aging; Neurobiology; Neurosciences; Physical Anthropology

Master of Science (MS), Wright State University, 2021, Computer Science

Homeostatic synaptic plasticity is the process by which neurons alter their activity in response to changes in network activity. Neuroscientists attempting to understand homeostatic synaptic plasticity have developed three different mathematical methods to analyze collections of event recordings from neurons acting as a proxy for neuronal activity. These collections of events are from control data and treatment data, referring to the treatment of neuron cultures with pharmacological agents that augment or inhibit network activity. If the distribution of control events can be functionally mapped to the distribution of treatment events, a better understanding of the biological processes underlying homeostatic synaptic plasticity can be achieved. The aim of this project was to create a tool that allows researchers to quickly process, visualize, and then analyze the homeostatic synaptic plasticity data using the three analysis methods, as well as evaluate the viability of a fourth method.

Committee: Michael Raymer Ph.D. (Committee Chair); Kathy Engisch Ph.D. (Committee Co-Chair); T.K. Prasad Ph.D. (Committee Member); Thomas Wischgoll Ph.D. (Committee Member) Subjects: Biology; Computer Science; Mathematics; Neurobiology; Neurosciences; Statistics

Master of Science (MS), Wright State University, 2021, Anatomy

Multiple studies have shown that gene expression changes occur in sensory neurons after peripheral nerve injury (PNI). These expression changes include many genes that are turned on specifically in response to injury, but much less is know about expression changes in stable genetic markers of particular sensory neuron populations. This study characterized the expression of three markers of proprioceptive neurons Inhbb, Heatr5a, Cyp2s1 in lumbar dorsal root ganglion (DRG) neurons in intact animals and after PNI. To perform these experiments, we subcloned segments of the coding sequences of these genes and generated DIG-labeled riboprobes. Control experiments demonstrated the validity of these probes for these genes on brain tissue from adult mice. Then we examined expression in the lumbar L4-L6 DRGs from adult mice that had undergone sciatic nerve transection or sham surgeries. Our results are preliminary but suggest that overall expression patterns did not change with each of the genes when comparing control and injured tissue. Nevertheless, further investigation is needed to make any conclusive results.

Committee: David R. Ladle Ph.D. (Advisor); Patrick M. Sonner Ph.D. (Committee Member); Mark M. Rich M.D., Ph.D. (Committee Member) Subjects: Anatomy and Physiology; Animal Sciences; Biology; Biomedical Research; Neurobiology

Doctor of Philosophy, The Ohio State University, 2021, Neuroscience Graduate Studies Program

Chronic stress is a major factor in anxiogenesis that has been attributed to the activation and prolonged elevation of maladaptive immune signaling in the CNS and the periphery. A primary response to stress in the murine model for psychosocial stress, social defeat, consists of the activation of brain microglia and their subsequent recruitment of peripheral monocytes to the cerebral vasculature. Both microglia and monocytes are active producers for inflammatory cytokine IL-1b and other inflammatory mediators. Although there have been myriad studies that showed the importance for IL-1 signaling in the CNS for psychosocial stress and its deleterious behavioral responses, only recently have we developed more powerful tools that allow for discovery of the specific cell-type responses to this cytokine that drive anxiety-like behavior. As such, we first sought to examine the role for the primary IL-1b receptor, IL-1R1, and to determine which cell type in the brain is the primary responder to microglial and macrophage IL-1b (Chapter 2). Social defeat induced generalized social withdrawal, as demonstrated by reductions in social interactivity with juvenile mice, and cognitive deficits as measured by a working memory task. Global knockout of IL-1R1 (IL-1R1-/- mice) prevented these stress-induced behavioral deficits, as well as stress-associated monocyte trafficking to the brain, microglia activation, and elevated cytokine levels. We subsequently discovered that the neuronal IL-1 receptor (nIL-1R1) was the primary driver for these behavioral deficits, and that the IL-1R1+ neurons localized in the hippocampus were able to have direct effects on behavior after stress. Since microglia are both direct and indirect sources for IL-1b in the CNS, we examined the effects of microglial depletion via CSF1R antagonist PLX5622 on the other major cell types of the hippocampus after social defeat (Chapter 3). We employed single-cell RNA-sequencing to determine per-cell alterations in the t (open full item for complete abstract)

Committee: Jonathan Godbout PhD (Advisor); Ning Quan PhD (Advisor); John Sheridan PhD (Committee Member); Tamar Gur MD, PhD (Committee Member) Subjects: Immunology; Neurosciences

PhD, University of Cincinnati, 2020, Engineering and Applied Science: Computer Science and Engineering

The work shown in this dissertation demonstrates the implementation of a specialized neural network for associative memory within novel neuromorphic hardware. The architecture is implemented using CMOS-based circuitry for information processing and memristive devices for the network's memory. The architecture is based on a non-Von Neumann version of computer architecture called in-memory computing where information storage and processing reside within a single location. The CMOS circuitry within the architecture has both digital and analog components to perform processing. The memristive devices used in the architecture are a newer form of memristive device that possesses a gate that is used to potentiate/depress the device. These gated-memristive devices allow for simpler hardware architectures for tasks such as reading/writing to a device simultaneously. The architecture demonstrated here uses a property that is often seen within various memristive devices where the state is semi-volatile. This semi-volatile state can be used in tandem with a spiking neuromorphic architecture to perform unique tasks during learning depending on the degree of volatility in the device. Once memories are programmed into the network, it can then later recall previously seen memories by observing partial information from them and performing pattern completion. The final portion of this dissertation focuses on studying how the network behaves when exposed to a larger dataset of information over time and analyzing how the network performs recall on that data. An array of metrics will be used to evaluate the network's performance during these tests, and potential expansions of network functionality are explored and studied in order to enhance its capabilities in certain applications.

Committee: Rashmi Jha Ph.D. (Committee Chair); Marc Cahay Ph.D. (Committee Member); Manish Kumar Ph.D. (Committee Member); Cory Merkel Ph.D. (Committee Member); Ali Minai Ph.D. (Committee Member) Subjects: Computer Engineering

Doctor of Philosophy, The Ohio State University, 2020, Biochemistry Program, Ohio State

Spinal muscular atrophy is caused by mutation or deletion of SMN1 and retention of SMN2 leading to SMN protein deficiency. We developed an immortalized mouse embryonic fibroblast (iMEF) line in which full-length wild-type Smn (flwt-Smn) can be conditionally deleted using Cre recombinase. iMEFs lacking flwt-Smn are not viable. We tested the SMA patient SMN1 missense mutation alleles A2G, D44V, A111G, E134K, and T274I in these cells to determine which huSMN mutant alleles can function in the absence of flwt-Smn. All missense mutant alleles failed to rescue survival in the conditionally deleted iMEFs. Thus, the function lost by these mutations is essential to cell survival. However, co-expression of two different huSMN missense mutants can rescue iMEF survival and snRNP assembly, demonstrating intragenic complementation of SMN alleles. In addition, we show that an Smn protein lacking exon 2B can rescue iMEF survival and snRNP assembly in the absence of flwt-Smn, indicating exon 2B is not required for the essential function of Smn. Furthermore we used this cell line in a random mutagenesis screen to identify a suppressor of SMNE134K loss of function. We obtained 5 mutant suppressor lines that survive entirely on the nonfunctional SMNE134K mutant and an unidentified suppressor mutation. Through whole genome sequencing methods, we identified candidate suppressor mutations in SMN complex associates Gemin2, Gemin3, Gemin5, and SmF. We confirmed the SmF mutation as a mutant suppressor of SMNE134K and demonstrate snRNP assembly is more efficient in mutant SMNE134K and SmF suppressor complexes than wild-type conditions. For the first time, using this novel cell line, the function of SMN alleles was assayed in the complete absence of flwt-Smn and the mechanism of lost function for an SMA causing mutation has been identified.

Committee: Arthur Burghes PhD (Advisor); Brian Kaspar PhD (Committee Member); Mark Parthun PhD (Committee Member); Jill Rafael-Fortney PhD (Committee Member) Subjects: Biochemistry; Genetics; Molecular Biology

Master of Science in Biomedical Engineering (MSBME), Wright State University, 2020, Biomedical Engineering

Kv2.1 channels mediate slow-activating K+ rectifier current within the membrane of spinal motoneurons (MNs), and they are known to co-localize with other synapses and ion channels. Although Kv2.1 channels are suggested to regulate MN excitability, little research has gone into investigating its potential contribution to MN-altered excitability in Amyotrophic Lateral Sclerosis (ALS). Using the male SOD1-G93A mouse model of ALS, we examined Kv2.1 cluster area and density in lumbar MNs at four key stages of disease progression. In our experiments, MNs were separated by type via SK3 immunoreactivity in order to isolate and compare the responses of disease-resistant (slow; SK3+) vs. disease-vulnerable (fast; SK3-) MNs at postnatal (P) days P10, P30, P90, and end-stage (ES; P120-140). Our results show that in disease-resistant MNs cluster area does not change relative to wild-type until ES when it significantly decreases. In disease-vulnerable MNs cluster area is increased at P90 before also significantly decreasing at ES. Additionally, no changes were found in cluster density throughout disease progression. Electrophysiological recordings using the whole-cord in-vitro spinal cord preparation supported an increase in cluster area at P90 by demonstrating lower net excitability in SOD MNs relative to wild-type, further suggesting pathologically decreased MN activity. These results provide critical, novel information on how disease-resistant vs. disease-vulnerable MNs regulate their excitability throughout ALS.

Committee: Sherif M. Elbasiouny Ph.D., P.E. (Advisor); Mary Fendley Ph.D. (Committee Member); Matt Sherwood Ph.D. (Committee Member) Subjects: Biomedical Engineering; Neurosciences

Doctor of Philosophy, University of Toledo, 2020, Exercise Science

Neuromuscular dysfunction in shoulder girdle and upper extremity muscles is commonly observed in individuals with glenohumeral labral repair as an under-appreciated consequence of joint injury. Postoperative neural impairments from muscular, spinal and supraspinal pathways are hypothesized to contribute to the persistent muscle weakness, which may negatively affect shoulder-specific function and perceived quality of life in this population. Although identifying the specific origin of impairment has been theorized to help inform targeted treatment approaches to facilitate muscular recovery, there is limited evidence regarding origin of these neural impairments in individuals with glenohumeral labral repair. In order for the assessment and interventions to be effective, understanding comprehensive profile of neuromuscular function is an important step to allow clinicians to make evidence-based clinical decision in the course of rehabilitation. The focus of manuscript 1 was to compare peripheral, spinal and supraspinal measures of neuromuscular function in the upper extremity musculature between individuals with glenohumeral labrum repair and uninjured matched controls. We found unilateral weakness in shoulder abduction strength, unilateral impairment in corticospinal excitability for the upper trapezius, and bilateral impairment in spinal-level motoneuron pool excitability for the flexor carpi radialis in individuals with glenohumeral labral repair compared to uninjured controls. The focus of manuscript 2 was to determine the relationships between objective upper extremity muscle function and patient-reported outcomes in individuals with glenohumeral labral repair. We found lesser wrist flexor strength and lower corticospinal excitability explained worse perceived regional function. Lesser activity level explained better physical health, and elder age explained better mental health. The focus of manuscript 3 was to determine whether commonly described measures of neur (open full item for complete abstract)

Committee: Grant Norte (Committee Chair); Christopher Ingersoll (Committee Member); Sadik Khuder (Committee Member); Neal Glaviano (Committee Member) Subjects: Health Sciences; Kinesiology; Neurosciences; Sports Medicine

PHD, Kent State University, 2020, College of Arts and Sciences / Department of Biological Sciences

Mammalian reproductive success depends on gonadotropin-releasing hormone (GnRH) neurons to stimulate gonadotropin secretion from the anterior pituitary and activate gonadal steroidogenesis and gametogenesis. Genetic screening studies in patients diagnosed with Kallmann syndrome (KS), a congenital form of hypogonadotropic hypogonadism (CHH) discovered several causal mutations, including those in the fibroblast growth factor (FGF) system. This signaling pathway regulate neuroendocrine progenitor cell proliferation, fate-specification, and cell survival. Indeed, the GnRH neuron system was absent or abrogated in transgenic mice with reduced (i.e., hypomorphic) Fgf8 and/or Fgf receptor (Fgfr) 1 expression, respectively. Moreover, we found that GnRH neurons could not be detected in the embryonic olfactory placode (OP) of Fgf8 hypomorphic mice, the putative birthplace of GnRH neurons. These observations and together with those in human KS/CHH patients indicate that FGF8/FGFR1 signaling system is a requirement for the ontogenesis of the GnRH neuronal system and function. In this manuscript, we will focus on both transcription and epigenetic factors which control the expression of genes, such as Fgf8 that are known to be critical for GnRH neuron ontogenesis, fate-specification, and the pathogenesis of KS/CHH.

Committee: Wilson Chung PHD (Advisor); Kristy Welshhans PHD (Committee Member); Jennifer McDonough PHD (Committee Member); Bansidhar Datta PHD (Committee Member); Mary Ann Raghanti PHD (Committee Member) Subjects: Biology; Biomedical Research; Chemistry; Developmental Biology; Endocrinology; Molecular Biology; Molecular Chemistry; Neurobiology; Neurosciences

Doctor of Philosophy, The Ohio State University, 2020, Biomedical Sciences

There are trillions of cells, which make up hundreds of different cell types, found in the human body. These cells make up not only tissues but dictate the functions of those tissues. In diseased tissues, cell types can have a profound impact on the outcome of a patient. For these reasons, having a comprehensive understanding of cell types is important. In the past 10 years, single cell RNA sequencing has profoundly impacted our understanding of known and previously unknown cell types. Along with the numerous single cell datasets, a multitude of bulk expression datasets, multi-omic datasets, and curated information also exist. All of these data sources must be leveraged together to most improve our understanding of human tissues and diseases at the single cell level. We developed methodologies, frameworks, and algorithms that leverage multiple diverse datasets simultaneously to better understand single cell RNA sequencing data and as a result tissue heterogeneity as a whole.

Committee: Yan Zhang (Advisor); Kun Huang (Advisor); Jeffrey Parvin (Committee Member); Christopher Bartlett (Committee Member) Subjects: Bioinformatics; Biomedical Research

Doctor of Philosophy, Case Western Reserve University, 2020, Biology

The nervous system is part of a closed loop of sensory information and motor commands which responds to the environment and generates adaptive behavior. To understand these processes, neuroethologists study this unbroken loop in the context of natural behavior using experimentally tractable animal models. The most powerful of these models relate the activity of individual neurons to behavior. Feeding in the marine mollusc Aplysia californica is one such model: animals vary their responses to food depending on its mechanical properties, a small number of identified neurons control this behavior, and these neurons can be monitored in intact animals. Because the motor control and biomechanics of the behavior have been studied extensively, the functional role of individual neurons can be understood. I characterized adaptive responses to different food stimuli and their motor control. After implanting electrodes in intact animals, I fed them uniform food that was either easy to swallow (unloaded seaweed strips) or required greater force (loaded strips anchored to a force transducer). To assist with analysis, I designed a new software tool for synchronizing the playback of video of behavior with neural and force signals, which should be of general interest to behavioral neuroscientists. The rate of swallowing was reduced when animals fed on loaded strips and retraction duration was increased. I observed a previously undescribed pattern of force generation that is consistent with the use of a multifunctional muscle group and the action of a specialized motor neuron. I found that the presence of load triggers the recruitment of identified motor neurons following Henneman's size principle, first described in vertebrates. I also present preliminary results from experiments with other varieties of food, including natural seaweed that elicits more variable responses; perturbative experiments, in which extra force is applied to food during swallowing; and initial effort (open full item for complete abstract)

Committee: Hillel Chiel Ph.D. (Advisor); Karen Abbott Ph.D. (Committee Chair); Jessica Fox Ph.D. (Committee Member); Peter Thomas Ph.D. (Committee Member); Mark Willis Ph.D. (Committee Member) Subjects: Animal Sciences; Behavioral Sciences; Biology; Computer Science; Experiments; Neurobiology; Neurosciences; Organismal Biology

Master of Mathematical Sciences, The Ohio State University, 2019, Mathematical Sciences

In this paper, we examine the dynamics of neuronal systems with astrocytes. We use standard conventions for modeling such systems and, use XPP to observe and classify their behaviour according to model parameters. We begin with a short introduction to the biological foundations of neuroscience and to the field of mathematical neuroscience in particular. Then, we move to studying specific models, beginning with a simple system composed of two inhibitory neurons and a population of astrocytes. We use so-called fast/slow analysis and a one-dimensional map to do study the impact of gap-junctional coupling among astrocytes in modulating neuronal firing patterns. Next, we consider a model composed of two excitatory and two inhibitory neurons along with a population of astrocytes. We classify the overall model behaviour and additionally the behaviour of post-inhibitroy rebound, in particular. Next, we consider a model of ten excitatory neurons, ten inhibitory neurons, and a population of astrocytes. Finally, we briefly discuss potential future work.

Committee: David Terman (Advisor); Eben Kenah (Committee Member) Subjects: Biology; Mathematics; Neurobiology; Neurosciences