Doctor of Philosophy, Case Western Reserve University, 0, Physiology and Biophysics

Neurodegenerative diseases are nervous system disorders characterized by selective types of neuronal cell death. The causal factors for the different diseases vary, and clear molecular and cellular pathways underlying the pathogeneses remain elusive. However, accumulating evidence has suggested that mitochondrial dysfunction plays a critical role in disease-associated cell death due to the enormous energy demands of neurons. To improve the efficiency of oxidative respiration and generate more ATP, proteins on mitochondrial inner membrane form a complex adjacent to cristae junction. This complex, called the mitochondrial contact site and cristae organizing system (MICOS), maintains proper cristae morphology and stabilizes the intracristal environment for important mitochondrial functions, such as oxidative respiration. Previous studies have revealed that disruption of the MICOS leads to similar mitochondrial defects as in neurodegenerative diseases. This suggests MICOS loss as an upstream event of mitochondrial dysfunction and neuronal cell death in these disorders. In the present study, MICOS disruption was found in both Alzheimer's disease (AD) and Huntington's disease (HD) with different target components and molecular mechanisms. CHCHD6 was specifically connected to AD through a feedback loop that lowered CHCHD6 levels and increased APP processing. In cellular and animal AD models and human AD brains, the APP intracellular domain fragment inhibited CHCHD6 transcription by binding its promoter. CHCHD6 and APP bound to and stabilized each other. Reduced CHCHD6 enhanced APP accumulation on mitochondria-associated ER membranes and accelerated APP processing and induced mitochondrial dysfunction and neuronal cholesterol accumulation, promoting the amyloid pathology. Compensation for CHCHD6 loss in an AD mouse model ameliorated the AD-associated neuropathology and cognitive impairment. In contrast to AD, the specific MICOS component contributing to MICOS loss in HD wa (open full item for complete abstract)

Committee: George Dubyak (Committee Chair); Corey Smith (Committee Member); Xin Qi (Advisor); Wencheng Xiong (Committee Member); Sudha Chakrapani (Committee Member) Subjects: Biology; Biomedical Research; Cellular Biology; Molecular Biology; Neurosciences; Pathology; Physiology

PhD, University of Cincinnati, 2021, Arts and Sciences: Chemistry

Guanosine is a crucial molecule within the central nervous system known to play a role in neuromodulation and protection in the instance of chemical or physical damage to the brain. Neurochemical release is a dynamic process, necessitating an analytical method that can capture rapid and subsecond signaling events. Fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes is an electrochemical technique enabling detection of rapidly released electroactive compounds. In this dissertation, I have detailed an FSCV technique for the quantitation and characterization of dynamic guanosine events within living brain tissue. In the first chapter, I describe the chemistry and neurobiology of guanosine, covering its role within the central nervous system, the metabolic pathways of guanosine and its regulation, and its receptors and transporters. I also describe extant and popular detection techniques for guanosine and its sister compound adenosine. In Chapter 2, I describe the guanosine FSCV waveform I developed for my first graduate project. Here, I go into detail regarding the full characterization of this waveform and present a proof-of-concept for in-tissue detection of guanosine. In the following chapter, I present an additional FSCV waveform allowing for the codetection of both guanosine and adenosine. This waveform is a modified version of the adenosine waveform which enables simultaneous detection of the purine ribonucleosides. This waveform could prove useful in the future for codetection of the ribonucleosides, as earlier studies have suggested an intricate interaction between guanosine and adenosine with important downstream modulatory effects. In the fourth chapter, I use the guanosine waveform to detect endogenous, spontaneous guanosine transients ex vivo. Guanosine events were recorded during a control period and in response to a drug and neurochemical injury. This study marks the first ever recordings of subsecond, dynamic guanosine events in the brain (open full item for complete abstract)

Committee: Ashley Ross Ph.D. (Committee Chair); Ryan White (Committee Member); Mark Baccei Ph.D. (Committee Member); Noe Alvarez Ph.D. (Committee Member) Subjects: Chemistry

Master of Science, The Ohio State University, 2021, Psychology

Objective: This thesis aims to identify novel relationships between modifiable physical and health variables, Alzheimer's disease (AD) biomarkers, and cognitive function in a cohort of older adults with mild cognitive impairment (MCI). Methods: Metrics of cardiometabolic risk (e.g., body mass index), stress (e.g., cortisol), inflammation (e.g., c-reactive protein), neurotrophic/growth factors (e.g., brain-derived neurotrophic factor), and AD (e.g., plasma tau) were assessed in 154 MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) at baseline (mean age = 74.1; sd =7.5; mean education = 16.0; sd = 2.9). Of these 154 participants, 126 had 2-year follow-up data available for analyses (mean age = 74.0; sd = 7.6; mean education = 16.0; sd = 2.9). Participants also completed a comprehensive neuropsychological battery. Individual test scores and composite scores of memory and executive function published by ADNI were assessed. Partial least squares correlation (PLSC), an unbiased and flexible multivariate technique, was employed to examine cross-sectional associations among these physiological variables and cognition. Partial least squares regression (PLSR), a multivariate technique that defines optimal combinations of variables that best predict an outcome, was used to identify which, if any, of these physiological variables are important in predicting memory or executive function at 2-year follow-up. Results: The PLSC analysis revealed a latent variable describing a unique combination of AD biomarkers, neurotrophic/growth factors, education, and stress that were significantly associated with specific domains of cognitive function, including episodic memory, executive function, processing speed, and language, representing 45.2% of the covariance in the data. Age, BMI, and tests of basic attention and premorbid IQ were not significant. The PLSR analyses revealed that baseline metrics of cardiometabolic function, inflammation, and AD biomarkers (open full item for complete abstract)

Committee: Scott Hayes Ph.D. (Advisor); Jasmeet Hayes Ph.D. (Committee Member); Ruchika Prakash Ph.D. (Committee Member) Subjects: Aging; Clinical Psychology

PHD, Kent State University, 2020, College of Arts and Sciences / School of Biomedical Sciences

Parkinson's disease (PD) is a common neurodegenerative disease predominantly affecting the elderly. Classic hallmarks of PD pathology include the drastic loss of dopaminergic neurons in the substantia nigra and the formation of α-synuclein-containing Lewy bodies in the remaining neurons. Currently, no therapies have proven effective in slowing or stopping the progression of the disease. Therefore, the development of a novel disease modifying therapy is of great importance. Neuroinflammation plays an integral role in the pathogenesis of PD and strategies to combat neuroinflammation represent a promising treatment avenue. Glycoprotein nonmetastatic melanoma protein B (GPNMB) may represent a possible therapy for PD. GPNMB levels are increased in human PD brain samples suggesting it may play a role in the disease. Additionally, GPNMB has been shown to be neuroprotective in an ALS mouse model, a cerebral ischemia and reperfusion mouse model, and is anti-inflammatory in astrocytes. Another factor that may play a role in neurodegeneration and neuroinflammation is the actin bundling protein L-plastin (LPL). There aren't many studies examining LPL in neurodegeneration or neuroinflammation, but LPL KO mice have a less severe phenotype and reduced inflammation compared to wild-type mice in a mouse model of autoimmune encephalomyelitis. LPL is also involved with NLRP3 inflammasome activation and NADPH oxidase function, so inhibiting LPL may have an anti-inflammatory effect. In this dissertation, we showed that transgenic overexpression of GPNMB protected against MPTP-induced neurodegeneration. Furthermore, we showed that GPNMB overexpression prevented against MPTP-induced gliosis and microglial morphological changes. Additionally, in primary mouse microglia, we showed that recombinant GPNMB reduced LPS-induced increases in inflammatory gene expression and increased anti-inflammatory gene expression. This suggests that GPNMB may be stimulating microglia towards an M2 anti-inf (open full item for complete abstract)

Committee: Fayez Safadi Ph.D. (Advisor); Derek Damron Ph.D. (Committee Member); Edgar Kooijman Ph.D. (Committee Member); Eric Mintz Ph.D. (Committee Member); Jason Richardson Ph.D. (Committee Member) Subjects: Biology; Biomedical Research

PHD, Kent State University, 2019, College of Arts and Sciences / School of Biomedical Sciences

Neuroinflammation, a hallmark of many neurodegenerative diseases is mediated by microglia, the primary immune cells of the central nervous system (CNS). Activated microglial cells respond to neuronal injury and remove cellular debris, infectious agents via phagocytosis conferring neuroprotection. However, the chronic activation of these cells impairs neuronal function through the excessive release of NO and proinflammatory cytokines TNF-α and interleukins (IL-6, IL-1β and IL-12) which contributes to neuroinflammation and subsequent neurodegeneration in the brain. Thus, suppressing microglial activation is an effective therapeutic strategy to combat neuroinflammation associated with degenerative brain diseases. While anti-inflammatory agents are required to treat neurodegeneration, they may not be sufficient on their own as the disorder is multifaceted and complex but may be effective as part of a combination therapy. Therefore, improved treatment options focused on combinatory neuroprotective effects of simvastatin (Sim) and brain derived neurotrophic factor (BDNF), seem most beneficial in restoring CNS damage, as Sim is known to inhibit inflammation, promote cell survival and BDNF is a predominant neurotrophic factor that mediates survival and growth of a variety of neurons in the CNS. However, the delivery of combination therapeutics that hold promise for the treatment of neurological disorders lack clinical efficacy due to their inability in reaching high enough concentrations in the brain primarily due to the blood brain barrier (BBB), blood-cerebrospinal fluid (CSF) barrier, presence of efflux systems, enzymatic degradation, and several other factors such as rapid clearance from circulation and off-target effects. This calls for the need to develop an efficient drug delivery system (DDS) to overcome obstacles that impede CNS drug delivery and alternate approaches to bypass the BBB. Since microglia function as macrophages, the DDS must be also be effectively rem (open full item for complete abstract)

Committee: Moses Oyewumi Ph.D. (Committee Chair); Werner Geldenhuys Ph.D. (Committee Member); Fayez Safadi Ph.D. (Committee Member); Denise Inman Ph.D. (Committee Member); Douglas Delahanty Ph.D. (Committee Member) Subjects: Biomedical Research; Nanoscience; Nanotechnology; Pharmacology

Master of Sciences, Case Western Reserve University, 2017, Clinical Research

Anterior visual pathway disease affects >50% of multiple sclerosis (MS) patients. Optical coherence tomography (OCT) monitors MS-related retinal degeneration. Retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thinning in MS correlates with clinical and visual disability, and brain atrophy. Mesenchymal stem cells (MSC) are immunomodulatory in MS animal models, targeting inflammatory CNS injury. A recent Cleveland Clinic phase 1 trial demonstrated feasibility/tolerability of autologous MSC transplant in MS patients. My study analyzed GCL and RNFL relationships with clinical, visual, and MRI measures, before and after MSC transplant. MSC transplant affected no differences from baseline to 6 months in GCL or RNFL thickness. Linear mixed effects models predicted significant, but modest GCL thickness increases following MSC transplant. Thus, MSC neuroprotection was indirectly modeled, but not directly measured clinically or radiographically. Future MSC trials in MS should utilize OCT, a sensitive biomarker for neurodegeneration and response to experimental neuroprotective agents.

Committee: Robert Fox (Committee Chair); Jeffrey Cohen (Committee Member); Robert Bermel (Committee Member); Daniel Ontaneda (Committee Member) Subjects: Medicine

Doctor of Philosophy (PhD), Wright State University, 2016, Biomedical Sciences PhD

Plasmalogens are glycerophospholipids abundant in brain and heart tissues. Evidence suggests that they have antioxidant properties. Studies from our laboratory showed that rats treated with myo-inositol plus ethanolamine (ME) have elevated ethanolamine plasmalogens (PE-Pls) in brain and are protected against phosphine-induced oxidative stress. We hypothesized that ME elevates PE-Pls levels and protects against oxidative stress through oxidation of its vinyl ether bond. We tested this hypothesis in Neuro-2A cell culture and assessed the effects of treatments with myo-inositol (M), ethanolamine (Etn), or a combination (ME) on the: (1) effects on phospholipid (PL) classes, especially Etn PLs; (2) effects on cell viability in response to H2O2-induced oxidative stress; and (3) molecular species of Etn PLs preferentially affected by ME and H2O2 treatments, especially PE-Pls and their degradation byproducts – lyso-phosphatidylethanolamines (LPE). 31P NMR data show that treating the cells with equimolar amounts (500 uM) of M or Etn for 24 h did not influence PL levels, but ME yielded a 3-fold increase in both PE-Pls and PE (p<0.001). Cells exposed to 650 uM H2O2 for 24 h decreased cell viability to 53% ± 1.7. While pretreatment with M or ME significantly increased cell survival to 62% ± 1.2 or 80% ± 0.6, respectively (p<0.05), Etn alone had no effect. Mass spectrometry showed that ME preferentially elevated the levels of PE-Pls species containing saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) by 60%, while PE-Pls containing polyunsaturated fatty acids (PUFA) increased by only 10%. H2O2 caused a significant decrease in PE-Pls (27%), producing a 39% increase in LPE and a 4-fold increase in glycerophosphoethanolamine (GPE), but had no impact on PE levels, suggesting that LPE and GPE were primarily byproducts of PE-Pls degradation. Surprisingly, all these effects were blocked by pre-treating cells with ME prior to H2O2 exposure. Taken together, these data su (open full item for complete abstract)

Committee: Nicholas Reo Ph.D. (Advisor); Nicholas DelRaso Ph.D. (Committee Member); Michael Raymer Ph.D. (Committee Member); James Olson Ph.D. (Committee Member); Jeffery Gearhart Ph.D. (Committee Member) Subjects: Biochemistry; Neurosciences

Doctor of Philosophy, The Ohio State University, 2015, Molecular, Cellular and Developmental Biology

Sight-threatening diseases of the eye are prevalent across the world and result in a progressive loss of visual acuity that often culminates in blindness. These ocular diseases are caused by the degeneration and death of neurons in the retina, the neurosensory tissue of the eye. A promising possible treatment for retinal diseases is to stimulate neuronal regeneration from the Muller glia. Muller glia regenerate the retina in cold blooded vertebrates, but fail to do so mammalian retinas. To achieve retinal regeneration, Muller glia must de-differentiate into Muller glia-derived progenitor cells (MGPCs), proliferate, differentiate into neurons, and functionally integrate into neuronal circuits. Identification of the signaling pathways that influence the reprogramming of Muller glia into MGPCs is key to harnessing the potential of these cells to regenerate the retina. This dissertation focuses on understanding the role Glucocorticoid Receptor (GCR)- and Wnt-signaling pathways, in regulating proliferative, regenerative and neuroprotective properties of Muller glia in the avian retina in vivo. In the first part of this dissertation, we analyze the impact that the GCR- signaling pathway has on the MGPCs in the presence and absence of damage. The primary amino acid sequence of GCR and its expression by Muller glia is highly conserved across vertebrate species, including chickens, mice, guinea pigs, dogs and humans. We find that, in damaged retinas, activation of GCR-signaling suppresses the formation MGPCs via inhibition of MAPK-signaling, and inhibition of GCR-signaling stimulates the formation of proliferating MGPCs. In undamaged retina, FGF2/MAPK-signaling stimulates the formation of MGPCs, and activation of GCR-signaling reduces the number of proliferating MGPCs in FGF2 treated retinas. We also find that inhibition of the GCR-signaling enhances the neuronal differentiation of MGPC-derived cells in damaged retina. The second part of this dissertation describes th (open full item for complete abstract)

Committee: Andy Fischer (Advisor) Subjects: Biology; Cellular Biology; Developmental Biology; Molecular Biology; Neurosciences

PHD, Kent State University, 2015, College of Arts and Sciences / School of Biomedical Sciences

Many types of epilepsy, autoimmune or otherwise, are associated with the presence of autoantibodies against neuronal proteins. Paradoxically, antibodies (IVIg) have also been used to treat epilepsy. The goals of this research were twofold: 1) Determine the CNS location of antibodies in patients with non-autoimmune epilepsies and the targets of these antibodies; and 2) Examine the effects of endogenous and exogenous specific and non-specific antibodies in two status epilepticus (SE) models Immunohistochemistry and Western blotting were used to localize antibodies in patients with epilepsy, multiple sclerosis (MS) and arteriovenous malformation. Further analysis by ELISA, HEp-2 assay and immunoprecipitation revealed antibody targets. In mouse model experiments, lupus-prone or C57B6/J mice were injected with pilocarpine or kainic acid and monitored by EEG. Mice were treated with IV or IP injection of native or denatured IgGs, at time of or 12 hours before chemoconvulsant. Tissues were processed for immunohistochemistry and ELISA. Brain regions from patients with epilepsy contained extravasated IgGs. Intracellular antibodies were found in epilepsy but not in MS brain. In brain from patients with epilepsy, only neurons displayed nuclear IgGs. All subcellular fractions from brain resections of patients with epilepsy contained extravasated IgGs. In the nuclear IgG pool, anti-histone autoantibodies were identified by two independent methods. Serum analysis revealed anti-histone and anti-chromatin antibodies only in patients with epilepsy. In lupus-prone mice elevated serum IgGs favored post-SE survival. C57B6/J mice injected with native rat IgGs displayed a 40% reduction in pilocarpine-SE compared to control. IgGs extravasated in brains of untreated SE mice, but IgG-treated mice, with no pilocarpine-SE, experienced no parenchymal accumulation of IgGs. IgG leakage was observed in brain samples from KA treated mice and IgG treatment was largely ineffective. These r (open full item for complete abstract)

Committee: Derek Damron Ph.D (Committee Chair); Trine Jorgensen Ph.D (Committee Member); Gary Koski Ph.D (Committee Member); Ernest Freeman Ph.D (Committee Member) Subjects: Biology; Biomedical Research; Cellular Biology; Immunology; Medicine; Neurobiology; Neurosciences

Doctor of Philosophy, The Ohio State University, 2014, Integrated Biomedical Science Graduate Program

Neuroinflammation and demyelination in multiple sclerosis (MS) lead first to neuronal dysfunction, then to the potential for neurodegeneration. Voltage-gated potassium ion channels have key roles in maintaining the resting membrane potential of a neuron in readiness for neurotransmission. This includes repolarization of the membrane following an action potential, which involves a depolarization event mediated by voltage-gated sodium channels. Myelin, the many-layered lipid sheath surrounding axons, is known to participate in molecular interactions with the axonal membrane to target ion channels to important, specialized locations along the axon. The water channel aquaporin-4 (AQP4), expressed in astrocyte endfeet, also plays an important role in maintaining ionic and fluid homeostasis in the neuronal environment. Because progression of disease and permanent disability in MS appears related to the degree of neuronal loss, neuroprotective treatments are needed in MS. Although a nonspecific Kv channel blocker is currently approved for symptomatic treatment of MS, it is not known to provide any neuroprotective effect, it has significant side effects, and its mechanism of action is not clear. In my dissertation research, I used two animal models of MS, chronic or relapsing-remitting experimental autoimmune encephalomyelitis (chEAE or rrEAE) to mimic progressive or relapsing-remitting MS, respectively, and to characterize the effect of inflammatory, demyelinating lesions upon the expression and localization patterns of AQP4 and key Kv channels. I found that Kv 1.2, expressed in myelinated axons in spinal cord (SC) white matter (WM), was redistributed in lesioned areas from its normal location at the juxtaparanode (JXP). The JXP localization could be recovered in remitting rrEAE, but not late chEAE. Kv 2.1, normally clustered on the soma and proximal dendrites of alpha motor neurons located in SC ventral gray matter (GM), was declustered and reduced in expressi (open full item for complete abstract)

Committee: Chen Gu PhD (Advisor); Brian Kaspar PhD (Committee Member); Amy Lovett-Racke PhD (Committee Member); John Oberdick PhD (Committee Member) Subjects: Biology; Biomedical Research; Neurobiology; Neurosciences

PhD, University of Cincinnati, 2013, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary

Anesthesia is an evolving practice that enables painful or invasive procedures. The fundamental question of how anesthetics work remains; Science magazine listed "How do general anesthetics work" as one of the big remaining mysteries in science. This research focuses on four topics pertaining to anesthesia; surrogate endpoints for assessing safety, studying the continuum of anesthesia, neuroprotection from hypoxia/re-oxygenation, and postoperative cognitive dysfunction. The surrogate endpoint study consisted of the review of approximately 200 patient records by 13 anesthesiologists, with risk assigned using a Likert scale. Hypoxia was ranked as one of the most important physiological parameters when assessing sedation risk. A novel index, AUCDesat, was best correlated to the safety assessments, with the constituent components (incidence, depth, and duration) highly correlated, though not as well as AUCDesat. This index may prove to be a valuable measure in assessing risk and quantifying hypoxia when studying outcomes and injury. The study of the continuum of sedation and anesthesia defined by the ASA was a human clinical study of 20 volunteers sedated with increasing concentrations of propofol while maintaining a steady state concentration of fentanyl. The level of sedation was assessed with MOAA/S and BIS scores. The patient was stimulated on the tibial nerve with transcutaneous electrical stimulation. This study reinforced that the anesthetic state is a function of patient stimulus and anesthetic drug concentration, and that anesthesia is a continuum that does not stop at general anesthesia; it has increasingly deeper planes of anesthesia. The research investigated neuroprotection from hypoxia/re-oxygenation of rat hippocampus slices exposed to hypoxia/re-oxygenation episodes. Injury assessment used TTC. Computational modeling and gene expression evaluated potential mechanisms. The study showed hypoxia/re-oxygenation injury is greater when it has (open full item for complete abstract)

Committee: Steven Kleene Ph.D. (Committee Chair); Steven Lisco M.D. (Committee Member); Mark Baccei Ph.D. (Committee Member); Kenneth Strauss Ph.D. (Committee Member); Hongsheng Wang Ph.D. (Committee Member) Subjects: Neurology

Master of Science (MS), Wright State University, 2009, Pharmacology and Toxicology

Sarin, also known as Sarin (German agent B) is classified as a weapon of mass destruction. Sarin (O-isopropyl methyl phosphonofluoridate) is a highly toxic nerve agent originally produced for chemical warfare and has been used in terrorist activities. Sarin is an extremely potent acetylcholinesterase inhibitor with high specificity and affinity for the enzyme. High sarin doses causes death due to anoxia resulting from airway obstruction, weakness of the muscles of respiration, respiratory failure and convulsions. Current treatments are still not effective at protecting against long term effects following exposure. A current approach aims to counteract the increased glutamatergic and cholinergic neurotransmission occurring in sarin neurotoxicity. In vitro and in vivo, serotonin (5-HT) 1A agonist prevented toxicity from glutamate. We determined the neuroprotective capabilities of serotonin (5-HT) 1A agonists as novel pharmacological countermeasures to chemical warfare agents. Rodents have higher amount of carboxylesterase enzyme and requires higher doses of sarin than other species. To address this issue we administered 1.5 mg/kg of CBDP (2-/o-cresyl/-4 H-1: 3: 2-benzodioxa-phosphorin-2-oxide), which specifically blocks carboxyl esterase and makes mouse model comparable to that of human exposure. We determined 1mg/kg dose of serotonin (5-HT) 1A agonists 8-OH-DPAT from dose response curve based on neuroprotection, with toxic challenge of 1.5 mg/kg CBDP and dose of sarin yielding 25-50 % mortality. This mortality rate gave enough number of survivors with seizures and neurodegeneration for reliable baselines. Measurements were mortality, weight loss AChE activity in blood and CNS, functional observational battery (FOB) and histology compared to control and toxic challenge mice. In addition, a time response curve after toxic challenge was determined with 1mg/kg of 8-OH-DPAT at time points of 1, 15, 30, 45, 60 minutes and 2, 4, 6 hours. We observed neuroprotection by 8-OH- (open full item for complete abstract)

Committee: James Lucot PhD (Advisor); David Cool PhD (Committee Member); Khaled Elased PhD (Committee Member) Subjects: Behaviorial Sciences; Pharmacology; Toxicology

PhD, University of Cincinnati, 2011, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary

The studies in this dissertation are designed to examine the effects of subthalamic nucleus deep brain stimulation (STN DBS) in the 6-hydroxydopamine (6-OHDA) rodent model of Parkinson's disease (PD). The first study examines whether STN DBS can provide neuroprotection to the dopaminergic neurons of the substantia nigra (SN) in the face of previous large-scale dopamine neuron loss, similar to what patients have upon initial diagnosis. The second study examines the effects of STN DBS on trophic factors within the STN itself and its target structures in both unlesioned and 6-OHDA lesioned animals. Findings from these studies demonstrate that STN DBS can provide neuroprotection to remaining dopaminergic neurons in the SN. Furthermore, the results show that STN DBS can upregulate brain-derived neurotrophic factor (BDNF) within the SN, striatum, globus pallidus interna, and M1 motor cortex. Taken together, these results demonstrate that STN DBS has the potential to be a disease-modifying therapy for PD, with important effects on cell survival and plasticity within the basal ganglia and motor cortex. They also suggest the need for further study of the use of STN DBS as a treatment for early stage PD as well as its use in other disorders in which downregulation of BDNF has been implicated. Finally, the more through understanding of STN DBS gained by these types of studies may aid in the risk-benefit analysis when deciding upon STN DBS as a treatment option.

Committee: James Herman PhD (Committee Chair); Michael Behbehani PhD (Committee Member); Timothy Collier PhD (Committee Member); Jack Lipton PhD (Committee Member); Fredy Revilla MD (Committee Member); Kim Seroogy PhD (Committee Member); Caryl Sortwell PhD (Committee Member) Subjects: Neurology

PhD, University of Cincinnati, 2011, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary

The studies in this dissertation are designed to address whether antidepressant-mediated neuroplasticity can benefit Parkinson's disease (PD). The first aim investigates whether antidepressants are neuroprotective to dopamine (DA) neurons in the 6-OHDA rat model of PD. The second aim examines whether antidepressant therapy can increase neurotrophic factors relevant to DA neuron survival in the intact and degenerating nigrostriatal system. The final aim extends the scope of the previous two aims to determine whether antidepressants have disease-modifying effects in a population of early PD patients. Findings from these studies show the tricyclic antidepressant (TCA) amitripyline (AMI) partially protects DA neurons of the injured nigrostriatal system. Furthermore, results show divergent regulation of brain derived-neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) occurs within the nigrostriatal system in response to AMI treatment before and after 6-hydroxydopamine lesion. Taken together, these results suggest that AMI treatment elicits significant trophic changes important to DA neuron survival within both the intact and injured nigrostriatal system. Additionally, results from our patient-level meta-analysis indicate TCAs have disease-modifying effects in an early population of PD. Further, they suggest that untreated mild depression is associated with a higher probability to begin therapy compared to subjects taking antidepressants or non-depressed subjects. Interestingly, there was no impact on annualized UPDRS scores for antidepressant treatment or depression severity. These results suggest tricyclic therapy may provide additional therapeutic benefit for PD patients beyond the treatment of depressive symptoms. Additionally, they highlight the importance of treating depression in PD. Overall, the studies in this dissertation show that antidepressants mediate neuroplastic changes that extend beyond the mesolimbic system, which may have (open full item for complete abstract)

Committee: Timothy Collier PhD (Committee Chair); David Yurek PhD (Committee Member); James Herman PhD (Committee Member); Jo El Schultz PhD (Committee Member); Kim Seroogy PhD (Committee Member); Caryl Sortwell PhD (Committee Member) Subjects: Neurology

Doctor of Philosophy, The Ohio State University, 2012, Neuroscience Graduate Studies Program

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the Central Nervous System (CNS). About 80% of MS patients start the disease as a form of Relapsing Remitting MS (RRMS) that is characterized by frequent inflammatory attacks followed by spontaneous recovery. However, about 10 years after disease onsite, 50% of the patients enter into secondary progressive MS (SPMS). At this stage, inflammation is limited, however, neurological decline continues. Therefore, both dysregulated immune function and neurodegeneration seem to contribute to the pathogenesis of MS. Clinical trials showed that Dimethyl Fumarate (DMF), a novel oral treatment for MS, significantly reduced gadolinium enhancing lesions in Relapsing-Remitting MS (RRMS). The safety record, efficacy and oral availability of DMF makes it potentially more beneficial to MS patients than currently available therapies. Yet, neither the molecular mechanism nor the potential neuroprotective effect of DMF has been fully investigated. One interesting observation from the Phase II clinical trial was a reduction in IFN-γ producing CD4+ T cells (Th1) in fumarate treated patients. Because Th1 cells are considered to be the pathogenic cells in MS, this clinical observation may have identified one mechanism of action of DMF. The first part of my graduate work was dedicated to understanding the cellular and molecular mechanism behind this clinical observation. Using dendritic cell generated both in vitro and in vivo, we demonstrate that DMF inhibits dendritic cell (DC) maturation by significantly reducing proinflammatory cytokine production and the expression of MHC class II, CD80 and CD86. Importantly, this immature DC phenotype generated fewer activated T cells that were characterized by decreased IFN-γ and IL-17 production. Further molecular studies demonstrate that DMF exerts its effects on DCs via suppression of both Nuclear Factor ¿¿¿¿B (NF-¿¿¿¿B) and Extracellular signal-Regulated Kinase 1 and 2 (ERK1/2) (open full item for complete abstract)

Committee: Michael Racke (Advisor); Dana McTigue (Committee Member); Gary Wenk (Committee Member); Jonathan Godbout (Committee Member) Subjects: Neurobiology

Doctor of Philosophy, The Ohio State University, 2009, Integrated Biomedical Sciences

Since the neurons of the retina are unable to be replaced naturally by the body, cellular replacement therapies have been widely pursued as treatments for degenerative retinal diseases such as glaucoma and macular degeneration. However, given the complexity of developmental cues required to properly specify particular cells types and our limited understanding thereof, feasible replacement strategies are in their infancy. An example of tightly regulated fate specification is the type-II cholinergic amacrine cell. We found that during a brief time in development the fate of the type-II cholinergic amacrine cell is dependent upon appropriate levels of cholinergic signaling. There is a paucity of neuron replacement studies in models of glaucoma where the retinal ganglion cells are lost. The replacement of ganglion cells may prove to be very challenging given the complex phenotype of these neurons. Therefore, neuroprotective therapies may be more beneficial to treat diseases where ganglion cells die. In several photoreceptor replacement studies there is evidence that eyes containing transplants had preserved visual function. However, very few of these studies showed convincing evidence of neuronal replacement; transplanted cells migrated into the retina, but failed to express neuronal markers. It is theorized that the maintained visual function result from neuroprotective factors released by the transplanted cells. We therefore sought to determine if transplanted embryonic retinal cells can protect ganglion cells from cholcicine –mediated death. We also investigated whether the developmental stage of the transplant was a factor that affected the neuroprototective capacity of these cells. We found that transplanted embryonic retina from embryonic day ten elicited the greatest neuroprotective effects. Additionally, we determined that the transplanted embryonic retina cells failed to differentiate as retinal neurons within the mature retina.

Committee: Andrew Fischer J (Advisor); Christine Beattie PhD (Committee Member); Heithem El-Hodiri PhD (Committee Member); Dana McTigue PhD (Committee Member) Subjects: Biomedical Research

Doctor of Philosophy, The Ohio State University, 2007, Neuroscience

Spinal cord injury (SCI) is a long lasting, debilitating condition with no cure. Cervical SCI is the most common form of human SCI, often leaving patients paralyzed with a 15-20 year decrease in life expectancy. The majority of animal SCI contusion models are focused on thoracic injury. SCI at this level results in deficits almost entirely due to white matter damage that disconnects the rostral nervous system from the caudal spinal cord. Damage at the cervical level is different; in addition to the disconnection, gray matter damage affects the neurons controlling the upper extremities and diaphragm. To investigate injury at the cervical level, we characterized a unilateral C5 cervical contusion model in rats. By examining six-week behavioral recovery after SCI, we demonstrated that functional deficits are dependent upon the severity of injury. Analysis of the histopathology revealed that behavioral consequences are a result of damage to both the gray and white matter. Unilateral injury provides within-subject controls and preserves bladder and respiratory function. Many treatments for experimental rat SCI improve behavioral and histological outcomes but have yet to be implemented after human SCI. Treatments must be safe and tested in clinically relevant models to move from animals to humans. We examined the effects of three different clinically acceptable drugs. Methlyprednisolone and minocycline have anti-inflammatory effects if given after injury. Topiramate blocks glutamate receptors and hence excitotoxicity, an important component of secondary injury. Minocycline and methylprednisolone treatment yielded no significant behavioral or histological improvements when tested after moderate-severe unilateral cervical contusion injury. Topiramate was first tested in a model of excitotoxicity and then after cervical SCI and was compared to NBQX, a standard AMPA-receptor antagonists used in animal models of disease. Both drugs preserved neurons after excitotoxic injury, b (open full item for complete abstract)

Committee: Jacqueline Bresnahan (Advisor) Subjects: Biology, Neuroscience

Doctor of Philosophy, Case Western Reserve University, 2009, Neurosciences

The World Heath Organization estimates that 15 million people worldwide have a stroke annually with many of these individuals suffering from an ischemic attack that will lead to their permanent disability or death. One approach for developing targeted stroke therapies is to identify endogenous responses to cerebral ischemia and determine whether their addition promotes tissue survival. The studies in this thesis focus on the effects of activin A in cerebral ischemia. In this study, experimental cerebral ischemia and reperfusion resulted in the rise of activin βA mRNA in the ischemic hemisphere and increased phosphorylated smad2/3 signals in neurons adjacent to the site of injury. In a defined cell culture model that uses hydrogen peroxide (H2O2)-free radical stress, activin A addition protected cortical neurons against oxidative challenge. H2O2 treatment increased neuronal activin βA mRNA expression and inhibition with neutralizing antibodies to activin A resulted in robust neuronal death. These studies indicate that cells respond to cerebral ischemia with increased activin βA expression and activin A addition promotes the survival of cortical neurons. Studies investigating the effects of added activin A after cerebral ischemia and reperfusion in vivo revealed a robust tissue protective effect. Intraventricular administration of activin A prior to stroke onset protected against ischemia-induced tissue death and provides evidence that activin A promotes tissue survival in ischemic stroke. Analysis of activin A treatment 6 hours after ischemia and reperfusion revealed that despite delayed administration, activin A effectively reduced tissue death at 24 and 72 hours and improved neurobehavior. Moreover, activin A treatment spared neurons within the ischemic hemisphere and led to a concomitant reduction in microglial activation. Activin A resulted in reduced phosphorylation of the stress-responsive signals, p38 and c-jun N-terminal kinase (JNK), members of the mitogen (open full item for complete abstract)

Committee: Alison Hall PhD (Advisor); Jerry Silver PhD (Committee Chair); Gary Landreth PhD (Committee Member); Nicole Ward PhD (Committee Member); Warren Selman MD (Committee Member) Subjects: Biomedical Research; Neurology

Doctor of Philosophy, Case Western Reserve University, 2013, Biomedical Engineering

The brain normally uses glucose as its primary fuel, but is able to use ketone bodies as an alternative fuel during fasting, starvation, or feeding of high-fat, low-carb diets. Ketosis, as a physiological state, has been shown to be neuroprotective since the 1920s. The biochemical links between ketosis and neuroprotection has been of interest to clinicians and scientists. To investigate the metabolic mechanism, we hypothesized that 1) the total energy demand (glucose + ketone bodies) is constant during ketosis 2) in chronic ketosis, ketone bodies spare glucose from oxidative metabolism and shunts towards neurotransmitters. Using Positron Emission Tomography (PET) and 2-tissue compartment modeling, we show that the cerebral metabolic rate of glucose (CMRglc) decreases linearly (9% per 1mM blood ketone body increase) in rats with diet-induced ketosis. In another study, using Liquid Chromatography and Gas-Chromatography Mass Spectrometry (LC-MS, GC-MS), we applied carbon-13 (13C) isotopic flux analysis in ketotic rat brains with either [U13C]-glucose or [U13C]-acetoacetate intravenous infusions. The data show that ketosis reduced glucose carbon flux into the citric acid cycle and ¿-aminobutyric acid (GABA), whereas ketone body carbon flux increased in these pathways. In conclusion, ketone bodies partition and spare glucose oxidative metabolism in ketotic rat brain. This may lead to further understanding to neuroprotection from changes of metabolic energy balances.

Committee: Joseph LaManna Ph.D (Advisor); Xin Yu Sc.D (Committee Chair); Michelle Puchowicz Ph.D (Committee Member); Zhenghong Lee Ph.D (Committee Member); Gerald Saidel Ph.D (Committee Member); Kingman Strohl M.D (Committee Member) Subjects: Biochemistry; Biomedical Engineering; Biophysics; Medical Imaging; Medicine; Nutrition; Physiology