Master of Science, The Ohio State University, 2007, Graduate School

Committee: Not Provided (Other) Subjects:

Doctor of Philosophy, The Ohio State University, 2024, Molecular, Cellular and Developmental Biology

Heart failure (HF) is one of the leading causes of morbidity and mortality globally. A growing body of evidence has indicated the 5-year mortality rates are about ~50% after initial HF diagnosis. Electrolyte imbalances have been implicated in predicting the outcome of HF patients, where lower serum sodium levels (hyponatremia; serum sodium <135mEq) have been strongly associated with increased mortality in HF. Hence, serum sodium levels have been a well-established adverse prognostic marker for patients with chronic HF. Recent evidence has suggested that lower serum chloride (hypochloremia, <97mEq) is associated with increased mortality risk in patients with chronic HF independent of serum sodium levels. Even though hypochloremia is associated with increased mortality in HF patients, the exact role of chloride (Cl ) homeostasis in cardiac function and how hypochloremia contributes to cardiac injury is unknown. Hence, our study focuses on understanding the mechanism of hyperchloremia-mediated ischemia-reperfusion (IR) injury and the role of Cl- channel in mediating hypochloremia effects. In the first part of this dissertation, we showed that hypochloremia increases mortality in left ventricular assist device (LVAD) placement and acute decompensated HF (ADHF) patients. This increase in mortality was associated with aggravated myocardial infarction post IR injury from our ex vivo studies with isolated rat hearts. In cardiac physiology, hypochloremia increases the beating of hiPSC-CM, which is attributed to increased intracellular calcium (Ca2+) cycling. Since hypochloremia affects the Cl- homeostasis, the mitochondrial functions: membrane potential, and reactive oxygen species production are affected post IR injury. In the second part of this thesis, we have explored the involvement of Cl- channel downstream of hypochloremia on intracellular Ca2+ cycling. Two Cl- channel inhibitors, 4,4'-Diisothiocyanato-2,2'-stilbenedisulfonic acid disodium salt (DIDS), non-specific pl (open full item for complete abstract)

Committee: Harpreet Singh (Advisor); Sandor Gyorke (Committee Chair); Mahmood Khan (Committee Member); Nuo Sun (Committee Member) Subjects: Biochemistry; Biology; Biophysics; Cellular Biology; Molecular Biology

Master of Science, The Ohio State University, 2024, Environmental Science

Blood-seeking mosquitoes primarily rely on thermal and chemical cues as they navigate towards hosts. Mosquitoes display specific preferences for target host temperature while avoiding harmful ambient temperature. This behavior known as thermotaxis is in part regulated by the nociceptor transient receptor potential ankyrin 1 (TRPA1), which is expressed in thermosensitive sensilla of mosquitoes. TRPA1 of female mosquitoes is known to detect both noxious temperatures and chemicals; when activated by these stimuli, TRPA1 triggers avoidance behaviors. Therefore, TRPA1 is considered a potential biochemical target for mosquito repellents and antifeedants. One aspect of TRPA1 channels from mosquitoes and other insects that has not been fully studied is the potential interactions between temperature and chemical agonists. In this study, I examined whether high ambient temperatures that activate Aedes aegypti TRPA1 (AaTRPA1) influence the sensitivity of the channel and behavior of mosquitoes to repellent TRPA1 chemical agonists. First, I expressed AaTRPA1 heterologously in Xenopus laevis oocytes and used whole-cell two-electrode voltage clamping to measure TRPA1 activity. I found that the electrophysiological response of AaTRPA1 to two chemical agonists (catnip oil, citronellal) was significantly reduced while the channel was activated by a thermal stimulus ( ~38°C). Moreover, in behavioral bioassays, I found that adult female Ae. aegypti were less repelled by catnip oil when exposed to a noxious temperature (~50°C). Collectively, my results suggest that TRPA1-agonizing repellents, such as catnip oil, may be less efficacious during extreme heat events, which are becoming more common as global climate change progresses.

Committee: Peter Piermarini (Advisor); Megan Meuti (Committee Member); Larry Phelan (Committee Member) Subjects: Cellular Biology; Entomology; Physiology

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

Doctor of Philosophy, Case Western Reserve University, 2024, Biomedical Engineering

Intracortical microelectrodes (IMEs) are a type of brain-computer interface that allows for the recording of neural signals to communicate between the brain and computers. IMEs can be used to restore motor function in people with spinal cord injury, treatment of neurological disorders, and are a strong basic science tool for understanding the brain. Unfortunately, implanted IMEs consistently see a steady decline in recording ability over time, leading to failure of the device. Damage to the blood-brain barrier (BBB) from IME implantation is a key contributor to device failure. After BBB breach, neurotoxic molecules invade the brain and cause a downstream cascade of neuroinflammation and oxidative stress that further damages the BBB, brain tissue, and the IME itself. Attempts to minimize BBB damage to improve neuroinflammation and IME longevity have shown limited success. Given the lack of solutions to the chronic stability of neural recordings, further investigation into understanding and minimizing the effects of BBB damage is warranted. In my dissertation, I investigate multiple strategies to mitigate and expand our understanding of how BBB damage can impact IME performance. Thermal damage to underlying vasculature because of cranial drilling has been shown to impact BBB permeability. To combat this, I developed a standardized surgical approach to limit surgeon variability and reduce thermal damage on the BBB. Next, I utilized the antioxidant dimethyl fumarate to promote BBB healing and reduce oxidative stress, resulting in acute improvements to IME function without long-term stability. Lastly, I investigated what unknown molecules enter the brain through the permeable BBB and contribute to neuroinflammation. I was the first to discover that gut-derived bacteria invade the site of implantation through the damaged BBB, which can be modulated with antibiotics to alter neuroinflammation and IME performance. New therapeutics can be developed utilizing this connecti (open full item for complete abstract)

Committee: Jeffrey Capadona (Advisor); Anirban Sen Gupta (Committee Chair); A. Bolu Ajiboye (Committee Member); Andrew Shoffstall (Committee Member); Gary Wnek (Committee Member) Subjects: Biomedical Engineering; Engineering

Doctor of Philosophy, University of Akron, 2023, Biology

Vision is a crucial sense. Sight enables us to navigate and interact with our surroundings. Our environments contain an almost infinite variety of shapes, contours, and colors. Yet we only have a finite number of cells, and those cells consume a finite amount of energy. Vision enables us to effectively interact with these complex environments despite these limitations. In order for retinal development to be completed, light-evoked activity is required. Various synapses in the inner retina also must be established in order for these signals to propagate further. Only after these things occur can the visual system function at full capacity. Because of this much of the aims center around timing of electrophysiological activity in the retina. The first aim of this dissertation will be to establish a timeline for which photoreceptors (rods and cones), and bipolar cells are capable of generating and transmitting light evoked activity. Disruption of this light evoked activity can result in residual immature and can result in visual deficits. The second aim of this dissertation will be to analyze a model of X-linked retinoschisis at timepoints before eye-opening and determine how cells physiological output is reduced by this disease. The transition and increasing influence of GABA occurs around the same time we have determined bipolar cells become capable of light-evoked activity. The final aim of this dissertation is to describe a computational model of the generation and propagation of retinal waves from the SAC. Together each aim is directed at synaptogenesis at and around eye-opening. How does the presence of light evoked activity alter the physiological output of electrochemical signals at the first synapse and beyond, and how do these signals influence early synaptic refinement due to retinal waves?

Committee: Jordan Renna (Advisor); Richard Londraville (Committee Member); Qin Liu (Committee Member); Neal Peachey (Committee Member); Dimitria Gatzia (Committee Member); Merri Rosen (Committee Member); Kevin Kaut (Committee Member) Subjects: Biochemistry; Biology; Cellular Biology; Neurobiology; Neurosciences; Ophthalmology

Doctor of Philosophy, Miami University, 2023, Biology

Neuronal networks that produce oscillations underlie rhythmic motor behaviors (e.g., walking, chewing, and breathing), and complex behaviors (e.g., memory formation, decision making, and sensory processing). Oscillatory networks are subject to neuromodulation, promoting network flexibility, and ultimately enabling individuals to adapt to changes in their environment. Network flexibility includes reconfiguration, such as neuronal switching, in which neurons can change participation from one network into another, or into two distinct networks simultaneously, in response to neuromodulation. While modulation of synapses is an identified mechanism for both recruitment and coordination of a switching neuron in a second network, it is unknown whether alternative mechanisms can be used. In this dissertation, I asked whether modulation of intrinsic membrane properties can serve as a mechanism for recruitment, while modulation of synapses enables coordination of switching neuron activity in a second network. To test this, I used the small, well-characterized feeding-related networks (pyloric [food filtering], ~1 Hz; gastric mill [food chewing], ~0.1 Hz) and identified modulatory inputs of the isolated stomatogastric nervous system of the crab, Cancer borealis. The modulatory projection neuron MCN5 releases the neuropeptide Gly1-SIFamide, which increases pyloric frequency, activates the gastric mill rhythm, and switches the pyloric-only LPG neuron into dual pyloric plus gastric mill-timed bursting. Using bath application of the Gly1-SIFamide peptide, plus photoinactivation to eliminate activity of select neurons, I mimicked MCN5-elicited pyloric and gastric mill network activity. Then, using current clamp electrophysiology techniques, I examined whether the LPG neuron switch into the gastric mill network occurs due to Gly1-SIFamide modulation of LPG intrinsic membrane properties, and whether LPG gastric mill-timed bursting is regulated by pyloric and gastric mill network n (open full item for complete abstract)

Committee: Dawn Blitz (Advisor); Kathleen Killian (Committee Member); Anna Radke (Committee Member); Joseph Ransdell (Committee Member); Paul James (Committee Member) Subjects: Biology; Neurosciences

Doctor of Philosophy (Ph.D.), Bowling Green State University, 2023, Photochemical Sciences

The lipid bilayer's integrity is essential for cell function as it acts as the primary barrier against external molecules like drugs and peptides, which can alter the bilayer's physical properties. This dissertation investigates how amphetamine (AMPH) and methamphetamine (METH), and the charged HIV1-TAT peptide impact the stability of lipid bilayers, using a home-built lipid bilayer apparatus that enables real-time monitoring through electrical and fluorescence measurements. Our findings indicate that AMPH and METH increase the lipid bilayer's ion permeability, with METH having a greater destabilizing effect. High concentrations of these stimulants, akin to levels in blood plasma of individuals with stimulant-related brain injuries, lead to pore formation in the bilayer. The extent of destabilization correlated with the drug concentration. We also studied the translocation dynamics of the charged HIV1-TAT peptide across the lipid bilayer. The analysis of current fluctuations showed that successful translocation of the TAT peptide is concentration-dependent, highlighting the significance of charge in inducing membrane deformation or pore formation. Additionally, molecular dynamic simulations were used to explore AMPH interactions with the lipid bilayer in greater detail. The results revealed AMPH's preferred orientation during interaction and its hydrophobic nature, as evidenced by the larger energy barrier encountered in the hydrophilic head group regions of the lipid bilayer. To complement these findings, we utilized surface-enhanced Raman spectroscopy (SERS) to estimate the concentrations of AMPH within lipid bilayers. The data showed a positive correlation between characteristic peak heights and AMPH concentrations. Moreover, whole-cell patch clamp measurements on neuronal cells were employed to examine AMPH's effects in a more intricate lipid environment. This research contributes to the understanding of how stimulants and charged peptides interact with lipid bi (open full item for complete abstract)

Committee: Hong Lu Ph.D. (Committee Chair); Dryw Dworsky Ph.D. (Other); Joseph Furgal Ph.D. (Committee Member); John Cable Ph.D. (Committee Member) Subjects: Chemistry

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

Master of Science (MS), Wright State University, 2023, Physics

Excitation of skeletal muscle cells triggers a large voltage spike known as an action potential (AP), leading to muscle contraction. Modeling of an AP is typically done using the method developed by scientists Hodgkin and Huxley (HH). In the HH method, voltage and time gated Na+ and K+ ionic currents are simulated, along with a positive “Leak” ionic current and capacitive current. Due to the complexity and the computational time required for simulation, direct fitting of HH parameters to experimental APs has rarely been attempted. A previous thesis at Wright State performed direct fitting for the case of a single compartment muscle cell. This study will introduce propagation to the existing model by adding small longitudinal segments simulating the currents flowing and triggering APs in later portions of the cell. If no adjustments to the single compartment HH parameters are made, adding increasing longitudinal segments leads to a very poor simulation of the AP shape. The simulated AP is too wide, and the peak voltage is too low. However, very few clear links between the number of segments and changes in specific HH parameter values were identified. Each parameter was found to vary by at least a factor of 2 between similar data sets. It is clear that multiple parameter sets are allowable, obscuring direct links between segments and parameter values. In order to further understand the robustness of the found parameter sets and to identify what regions of parameter space is allowable in order to achieve a well fit AP a confidence interval test was completed. Scanning through each parameter and fitting the rest revealed that each of α_h_bar, β_h_bar, kβh, V_n_bar, kαn, α_n _bar, β_n_bar, and Na permeability hold a well-defined interval in which near perfect fits can be found. While for kαh, kβn, and kβm no upper-bound was identified, and for K permeability, V_h_bar, kαm, β_m_bar, α_m_bar, V_m_bar the patterns where unclear.

Committee: Brent Foy Ph.D. (Advisor); Mark M. Rich M.D., Ph.D. (Committee Member); Amit Sharma Ph.D. (Committee Member) Subjects: Biophysics; Physics

Master of Science, Miami University, 2022, Biology

Oscillatory networks drive simple and complex behaviors. Neuronal switching, when a neuron changes participation between networks, contributes to flexibility and coordination between networks. Investigating cellular-level mechanisms of switching is challenging due to the inaccessibility of many switching neurons. The stomatogastric nervous system (STNS) in the crab, Cancer borealis, contains switching neurons in smaller, accessible networks, well-suited for studying switching. The established mechanism of recruiting a switching neuron is modulation of synapses. However recent work identified intrinsic property modulation as a mechanism for switching. In the STNS, the switching neuron LPG is constitutively active in a fast network. Neuropeptide (Gly1-SIFamide) modulation of intrinsic properties enables LPG to periodically escape the fast network and generate slower intrinsic bursts, simultaneously participating in both networks. The intrinsic properties and ion channels underlying this switch were unknown. I isolated LPG from both networks and used intracellular current injections to identify intrinsic properties modulated by Gly1-SIFamide. Through pharmacology and computational modeling, I identified ion channels contributing to the initiation and active phases of intrinsic bursts. The importance of these channels for intrinsic LPG bursting depended on the presence of fast network input. This study provides insight into how complementary intrinsic properties enable switching into dual-network participation.

Committee: Dawn Blitz (Advisor); Kathleen Killian (Committee Member); Paul James (Committee Member) Subjects: Biology; Neurobiology; Neurosciences

Doctor of Philosophy (PhD), Wright State University, 2021, Biomedical Sciences PhD

Huntington's disease (HD) has classically been categorized as a neurodegenerative disorder. However, the expression of the disease-causing mutated huntingtin gene in skeletal muscle may contribute to the symptoms of HD, namely those that involve involuntary muscle contraction. In the R6/2 transgenic mouse model of HD, we previously observed ion channel defects that could contribute to involuntary muscle contraction. Here, in R6/2 muscle we investigated the consequence of these ion channel defects on action potentials (APs), the first step in excitation-contraction (EC) coupling. We found that the ion channel defects were associated with depolarizing the baseline membrane potential during AP trains. We also observed changes in the AP waveform in R6/2 muscle, including a prolonged falling phase, which was associated with reduced K + channel expression (another ion channel defect). Next, we investigated the consequence of prolonged APs on intracellular Ca 2+ release flux, the second step in EC coupling. We observed an increase in Ca 2+ release flux duration, which compensated for a reduction in peak Ca 2+ release flux, resulting in normal levels of Ca 2+ available for contraction in R6/2 muscle. Finally, we investigated the consequence of prolonged APs and normal levels of Ca 2+ available for contraction on muscle force generation, the final step in EC coupling. We found that, when accounting for muscle atrophy, the force generated by one AP (twitch) was normal in R6/2 mice. This could be explained by the reduced parvalbumin and normal levels of Ca 2+ available for contraction we observed in R6/2 muscle. We conclude that downregulation of K + channels to prolong APs is a compensatory mechanism for muscle weakness that leads to increased Ca 2+ release duration and force production in R6/2 muscle. This is the first study to examine the entire EC coupling sequence in HD muscle, revealing the importance of the AP waveform in contributing to muscle force generation.

Committee: Andrew A. Voss Ph.D. (Advisor); Mark M. Rich M.D., Ph.D. (Committee Member); David R. Ladle Ph.D. (Committee Member); Michael Leffak Ph.D. (Committee Member); Dan R. Halm Ph.D. (Committee Member) Subjects: Biology; Biomedical Research; Physiology

Doctor of Philosophy, The Ohio State University, 2021, Chemical Physics

Mechanical stimuli from sound and head movements are converted to electrical signal sent to the brain by specialized cells called hair cells inside the inner ear. Hair cells are characterized by actin-filled hair-like stereocilia that sit on their apical surface. These stereocilia are arranged in increasing height and the top of the shorter stereocilium is connected to the side of the taller neighbor by a proteinaceous ‘tip link' composed of two members of the cadherin superfamily of adhesive proteins. The lower half of the tip link is made of protocadherin-15 (PCDH15), a single pass transmembrane cadherin that is embedded in the membrane of the shorter stereocilium where it interacts with the transduction channel complex. In response to the disturbances caused by mechanical stimuli, the tip link pulls on the transduction channel complex thereby opening the ion channels and thus depolarizing the hair cell by allowing an influx of cations. This releases neurotransmitters and sends an electrical signal to the brain. In addition to PCDH15, three more proteins are essential components of the transduction channel complex. Including, the transmembrane channel-like proteins 1 and 2 (TMCs), the tetraspan membrane protein of the hair cell stereocilia (TMHS), and the transmembrane inner-ear expressed protein (TMIE). The structure and function of TMIE are unknown, while TMCs are believed to be the pore-forming subunits of the transduction channel complex but their structures remain elusive. On the other hand, TMHS has been shown to form a complex with PCDH15 but its exact function and mechanism of action remains elusive. With the help of my colleagues, I utilized molecular dynamics simulations to explore molecular mechanism of ion conduction through TMC1 homology models. Our results show that TMC1 can conduct ions at rates comparable to the ion conduction rates of transduction channel complex in vivo. We found that its conductance is highly dependent on conformational changes (open full item for complete abstract)

Committee: Marcos Sotomayor (Advisor); Dongping Zhong (Committee Member); Ralf Bundschuh (Committee Member); Sherwin Singer (Committee Member) Subjects: Biochemistry; Biophysics; Molecular Physics

Doctor of Philosophy, The Ohio State University, 2021, Biomedical Engineering

Cardiac action potentials are initiated by sodium ion (Na+) influx through voltage-gated Na+ channels. Na+ channel gain-of-function (GOF) enhances Na+ influx, generating a late Na+ current that prolongs action potential duration (APD) and ultimately triggers pro-arrhythmic early afterdepolarizations (EADs). This GOF can arise in both inherited conditions associated with mutations in the gene encoding the cardiac Na+ channel, such as Long QT Syndrome Type 3 (LQT3), and acquired conditions. LQT3 can be a “concealed” disease, as patients with LQT3-associated mutations often remain asymptomatic until later in life; however, arrhythmias can also arise early in life, demonstrating a complex age-associated manifestation. In this thesis, I use multiple in silico models to study the role of Na+ channel localization in the presence of a GOF mutation and during development. I show altering the intercellular cleft can regulate EAD formation in the presence of a Na+ channel GOF. I also find that simulations with neonatal and early age-associated parameters predict normal APD, while EADs form in adult-associated tissue. Finally, simulations predict that conduction velocity (CV) depends on both cell size and gap junctional coupling during development in healthy tissue.

Committee: Seth Weinberg (Advisor); Thomas Hund (Committee Member); Rengasayee Veeraraghavan (Committee Member) Subjects: Biomedical Engineering

PhD, University of Cincinnati, 2020, Allied Health Sciences: Communication Sciences and Disorders

The Atlantic bottlenose dolphin (Tursiops truncates Montagu) rely heavily on acoustic sensory input to survive and is a frequent study species in audiology research. The event-related evoked response Mismatch Negativity (MMN) is an electrophysiological exam that records synchronized firing of neurons from the auditory cortices and frontal lobe, allowing for assessment of echoic memory and sound differentiation capability. Currently, there are no published studies on MMN testing with Odontocetes. Three male Atlantic Bottlenose dolphins were tested with in water electrophysiological testing at the Indianapolis Zoo. Oddball paradigms included a frequency difference between two pure-tone stimuli (standard 2000Hz, deviant 500Hz) and two different biological stimuli (T. truncatus whistles). The results provide the first published evidence that an MMN waveform can be elicited in dolphins with typical morphology and high repeatability but variability in latencies and MMN area. P1, N1, P2 latencies were determined for standard and deviant waveforms of each dolphin as well as the area (µVolts RMS) and onset of the MMN peak. Within individual variation was evaluated with descriptive statistics and cluster analyses with grouping of data for each individual dolphin. The use of complex acoustic stimuli with biological origin (dolphin whistle components) further evaluated auditory cognitive capabilities and resulted in similar MMN waveform parameters. Continuing AEP research with playback stimuli (biological or anthropogenic in origin) is necessary to assess cognitive abilities in marine mammals. Such research will allow for application of AEP testing as veterinary assessments to marine mammals to evaluate hearing or assess exposure to high levels of noise.

Committee: Peter Scheifele Ph.D. (Committee Chair); Jeffrey DiGiovanni Ph.D. (Committee Member); Brian Earl Ph.D. (Committee Member); James Miller Ph.D. (Committee Member); Noah Silbert Ph.D. (Committee Member) Subjects: Acoustics

Doctor of Philosophy, University of Akron, 2020, Integrated Bioscience

Visual processing begins with phototransduction when rod and cone photoreceptors in the outer retina transform incident photons into electrochemical potentials. The unique spectral sensitives of the expressed light-sensitive opsin (s) as well as several other factors shape an individual photoreceptors response properties. Subsequently, photoreceptor outputs distribute amongst distinct postsynaptic partners establishing parallel intraretinal channels for information flow. Furthermore, light-evoked responses in the mouse retina are known to increase significantly after eye-opening between postnatal days 12-14 (P12-14). This correlates with activities of the inner retina, confirming that outer retinal function increases after eye-opening and stabilizes around P30 (maturity). Previous in-vivo electroretinogram (ERG) studies have demonstrated light-evoked photoreceptor activity at P10. Such responses coincide with initial synaptogenesis between photoreceptors and second-order bipolar cells. However, this is a full 2-3 days after synaptogenesis of bipolar cells and third-order ganglion cells that relay retinal outputs to higher-order visual system regions. Moreover, various developmental factors determine the onset of photoreceptor responsivity, one being the gradual increase in phototransduction-specific genes and proteins. In partial disagreement with previous electrophysiological findings, molecular analyses indicate that much of the machinery for cone phototransduction is present before P10 and just before eye-opening in rods. Therefore, it was hypothesized that photoreceptors are responsive and second-order bipolar cells can respond to photoreceptor output days before eye-opening in mice. It was found that photoreceptor-evoked a-waves were detected in response to both green and UV flashes of light at P8 and bipolar cell-evoked b-waves were responsive within the 24 hours to follow using ex-vivo electroretinograms (ERGs). Furthermore, seminal studies have demonstrated (open full item for complete abstract)

Committee: Jordan Renna (Advisor); Qin Liu (Committee Member); Adam Smith (Committee Member); Merri Rosen (Committee Member); Yong Lu (Committee Member) Subjects: Biology; Biophysics; Cellular Biology; Evolution and Development; Molecular Biology; Neurobiology; Neurosciences; Optics; Physiology

Master of Science (MS), Wright State University, 2020, Physiology and Neuroscience

Humans are exposed daily to a variety of metals that can be harmful to our immune system. Although certain divalent metal cations are essential for numerous cellular functions and are critical trace elements in humans, the uptake mechanisms of these ions remain mostly unknown. Transient receptor potential melastatin 7 (TRPM7), which is expressed in a variety of human cell types, including lymphocytes and macrophages, conducts many divalent metal cations. TRPM7 channels are largely inactive under normal physiological conditions due to cytoplasmic magnesium acting as a channel inhibitor. Magnesium is a cofactor for many biochemical reactions. Low serum levels of magnesium, hypomagnesemia, can occur from increased magnesium loss from renal or gastrointestinal systems, redistribution of magnesium across the cell membranes, and decreased magnesium intake. Magnesium depletion allows both physiological and non-physiological divalent metal cations to enter through TRPM7, which is highly expressed in T-lymphocytes. Alterations to TRPM7 channel activity by channel blockers were found to affect the cell viability sequence. Through the use of Jurkat, a leukemic T-lymphocyte cell line which expresses high levels of TRPM7, HAP1 cells, and a TRPM7 kinase-dead mouse model, the entry of both physiological and non-physiological cations can be quantitated by measuring cell toxicity. A cell toxicity/viability assessment in Jurkat T-lymphocytes provided the sequence of Cd2+ > Zn2+ > Co2+ > Ni2+ > Mn2+ >> Sr2+ ≈ Ba2+ ≈ Ca2+ ≈ Mg2. Homeostatic mechanisms alter the effects of divalent metal cation entry and viability of T-lymphocytes, suggesting that TRPM7 in part contributes to metal ion entry.

Committee: Juliusz Ashot Kozak Ph.D. (Advisor); Christopher N. Wyatt Ph.D. (Committee Member); David R. Ladle Ph.D. (Committee Member) Subjects: Cellular Biology; Immunology; Pharmacology; Physiology

Doctor of Philosophy, The Ohio State University, 2020, Anatomy

With a prevalence surpassing 80 million, stroke is a prominent cause of patient mortality and disability world-wide. The majority of strokes are ischemic in etiology, caused by cerebrovascular occlusion that deprives the brain of oxygen and glucose. The consequential continuous activation of excitatory neurotransmitter receptors, intracellular calcium accumulation, inflammation, and reactive oxygen species proliferation ultimately result in neuronal death. Beyond the ischemic brain insult, a growing body of evidence points to far-reaching pathophysiological consequences of acute ischemic stroke. Shortly after stroke onset, impairments to immune, autonomic, and motor pathways lead to dysfunction across organ systems. These end organ abnormalities play a major role in the morbidity and mortality of acute ischemic stroke and argue for the classification of stroke as a systemic disease. As the leading global contributor to disability, stroke necessitates rehabilitation to facilitate functional recovery. Yet despite the need for evidence-based therapies, little attention has been given to the neuromuscular response following ischemic stroke. Motor units are comprised of a single lower motor neuron axon and all myofibers it innervates. Though not directly injured by the central stroke lesion, lower motor neurons rely on cortical input for motor communication at the neuromuscular junction. To that end, we aimed to (a) characterize the impact of ischemic stroke on the neuromuscular system and (b) explore potential therapeutic modulation of stroke-induced alterations at the neuromuscular interface. Through in vivo longitudinal study, we investigated muscle contractility and identified a reduction in plantarflexion tetanic torque of the stroke-affected hindlimb. We also tested motor unit functionality and discovered that stroke significantly reduced motor unit number estimation. Rather than an actual loss of motor units from denervation, our subsequent investigation of neu (open full item for complete abstract)

Committee: Eileen Kalmar PhD (Advisor); Shahid Nimjee MD, PhD (Advisor); W. David Arnold MD (Committee Member); Cameron Rink PhD (Committee Member) Subjects: Anatomy and Physiology; Medicine; Neurobiology; Neurology; Neurosciences; Pathology; Physical Therapy; Physiology; Rehabilitation; Therapy

Doctor of Philosophy, The Ohio State University, 2020, Mechanical Engineering

Neurotechnology has experienced significant growth in recent years and has already led to multiple transformative neuromodulation clinical trials. Notwithstanding these advances, a major limitation of prior techniques is that invasive electrodes, a necessary component when interfacing with neuronal tissue, result in injury and inflammation which alters the neuronal tissue microenvironment. This dissertation presents a novel active device, a polypyrrole based synaptic transistor, engineered to detect synaptic signals in real-time across a nerve membrane at its native functional state. The transistor forms an ad hoc synaptic junction with the nerve at the synaptic cleft, containing electrolyte in between, by utilizing ionic coupling to relay information between the two membranes. The ad hoc synaptic transistor is observed to have a high bandwidth in a partially reduced state such that it can measure dynamic cation concentration changes in the cleft occurring in timescales of milliseconds both in-vivo and in-vitro. This dissertation establishes a novel synaptic transistor architecture which is conceptually analogous to a neuron. The synthetic synaptic transistor developed in this work emulates synaptic signals and synaptic functions observed in neurons. Characterization studies and mathematical modeling of the transistor, based on the Fitzhugh-Nagumo neuron circuit model, help explain the ionic coupling observed between the two membranes (pre-synaptic and post-synaptic) and the spatio-temporal dependence of the recorded response on input stimuli magnitude, rate and frequency. Parametric analysis of the transistor's electrical properties helped elucidate the effect of pre-synaptic membrane capacitance on synaptic performance of the device. This dissertation demonstrates that an ad hoc synaptic junction, formed between neurons and a synaptic transistor, allows continuous monitoring of nerve action potentials, nerve health and the onset and progression of polyneuropat (open full item for complete abstract)

Committee: Vishnu Sundaresan Prof. (Committee Chair); Chandan Sen Prof. (Committee Member); Jose Otero Dr. (Committee Member); Noriko Katsube Prof. (Committee Member); Daniel Gallego-Perez Dr. (Committee Member) Subjects: Biomedical Engineering; Engineering; Materials Science; Mechanical Engineering; Neurosciences; Statistics

Master of Science (MS), Wright State University, 2020, Anatomy

The nervous system is responsible for interpreting information and coordinating that organism's physiological response. Action potentials conduct along neuron axons to carry information within the nervous system. Saltatory conduction allows the action potential to travel rapidly along the axon from one Node of Ranvier to the next. Nodes of Ranvier are densely packed with different proteins, notably voltage-gated sodium channels (Nav). Methylglyoxal, a toxic metabolite of glycolysis that is elevated in diabetes mellitus, alters nerve excitability by eliciting changes in protein function and structure within the Nodes of Ranvier. This study investigated the effects of methylglyoxal exposure on nerve conduction in optic nerves of mice, to test the hypothesis that methylglyoxal exposure would decrease conduction velocity. The conduction velocity, peak amplitude, and latency of optic nerve compound action potentials were recorded from saline- and methylglyoxal-treated mice. While results did not reach statistical significance, trends were evident in the analyzed parameters.

Committee: David R. Ladle Ph.D. (Advisor); Patrick M. Sonner Ph.D. (Committee Member); Keiichiro Susuki M.D., Ph.D. (Committee Member) Subjects: Neurobiology; Neurology; Neurosciences