Master of Science, The Ohio State University, 2008, Graduate School

Committee: Not Provided (Other) Subjects:

Doctor of Philosophy, Northeast Ohio Medical University, 2024, Integrated Pharmaceutical Medicine

Alzheimer's disease (AD), the leading cause of dementia, is a worldwide public health issue that is getting progressively worse as the population ages. AD is a neurodegenerative disorder characterized by its progressive and ultimately fatal nature. Surprisingly, the biological onset of the disease can occur decades before the emergence of observable symptoms. Despite ongoing research and clinical trials, effective disease-modifying treatments for AD remain elusive, with most of the investigative focus being on one of the two key pathological proteins of this disease, amyloid beta (Aβ). The other protein, pathological tau, has been comparatively understudied even though it has been observed to precede Aβ deposition in the early stages of dementia and exhibits a stronger correlation with cognitive decline as the disease progresses. Several key factors are associated with increased AD risk with the most influential including female sex and midlife onset of cardiometabolic stressors such as type II diabetes, obesity, hypertension and hyperlipidemia. Irisin and VGF are two endogenous hormones known to mitigate the impact of these key midlife AD risk factors and their levels in blood and brain potentially serve as biomarkers for the disease. Both irisin and VGF have been examined as neuroprotective therapeutics against AD pathology such as Aβ and neuroinflammation but have not been investigated in the context of tauopathy. The work presented in this dissertation addressed a central hypothesis that VGF and irisin can mitigate tau pathogenesis and disease progression. Overall, the data collected from these studies support this hypothesis but also introduce many unexpected nuances and additional variables that qualify the conclusions on the neuroprotective potential of these agents in tauopathy. Here, I found that exogenous irisin treatment administered to tauopathy model htau mice at presymptomatic disease stages mitigated emerging neuropathology in only female mice. Wh (open full item for complete abstract)

Committee: Christine Dengler-Crish (Advisor); Erin Reed (Committee Member); Mohammad Yunus Ansari (Committee Member); Jessica Ferrell (Committee Member); Matthew Smith (Committee Member) Subjects: Neurosciences

Master of Engineering, Case Western Reserve University, 2024, Biomedical Engineering

Sleep waves have been studied for their effects and implications on humans. Studies have focused on different aspects to study the effects of wake and sleep periods, however, have shown conflicting results. We focus our study on the effect of slow sleep waves (< 1 Hz) characteristic of non-REM sleep on synaptic weights in vitro. We induced long-term potentiation using high-frequency stimulation in the CA3 region of the hippocampus and recorded from CA1. Low-frequency spikes were induced in vitro using halved concentrations of magnesium and calcium compared with regular artificial cerebrospinal fluid. With respect to previously induced long-term potentiation, we found a reduction of 23.67 ± 62.97 % in evoked potentials' slope, however, the decrease wasn't statistically significant. We conclude that slow sleep waves are unable to produce a significant effect on synaptic weight, and the effect produced by the solution used could be dependent on the amplitude and frequency of induced spikes.

Committee: Dominique Durand (Advisor); Chia-Chu Chiang (Committee Member); Kenneth Gustafson (Committee Member) Subjects: Biomedical Engineering; Experiments; Neurobiology; Neurosciences

PhD, University of Cincinnati, 2022, Engineering and Applied Science: Electrical Engineering

A major goal in robotics is to endow robots with the ability of autonomous goal-directed navigation. To achieve this, robots must be able to learn new environments and the areas of interest within them. This problem is traditionally considered under the robotics field of simultaneous localization and mapping (SLAM). It can also be directly mapped to a reinforcement learning problem, especially in cases where the robot is allowed to actively explore its environment. Unfortunately, despite decades of research, robots are still unable to autonomously learn new environments and perform goal-driven navigation with the level of adeptness seen in animals. Thus, it is worthwhile to investigate the computational processes behind spatial cognition in mammals to see whether they can be adapted for artificial agents. The exact mechanisms for the rapid spatial learning and efficient navigation observed in mammals remains poorly understood, and is of great interest to researchers in neuroscience, reinforcement learning and robotics. Of particular interest is the quick learning of rewarded (goal) locations through reinforcement learning because the majority of today's reinforcement learning techniques are slow and data intensive. Over the past few decades, numerous experimental and theoretical studies in neuroscience have led to the consensus that the hippocampus and its surrounding brain regions play a crucial role in memory formation in mammals -- especially rodents. Many neurons of the rodent hippocampus and surrounding regions are spatially modulated. They are able to learn context-dependent spatial representations and rapidly associate reward values with them for use in subsequent goal-directed navigation. This dissertation proposes computational models for robot navigation based on the processes and computations in the rodent hippocampus that are relevant to spatial cognition. These models allow the formation of actionable spatial representations in an (open full item for complete abstract)

Committee: Ali Minai Ph.D. (Committee Chair); Rashmi Jha Ph.D. (Committee Member); Dieter Vanderelst Ph.D. (Committee Member); Tamara Lorenz Ph.D. (Committee Member); Manish Kumar Ph.D. (Committee Member) Subjects: Artificial Intelligence

PhD, University of Cincinnati, 2023, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary

MicroRNAs (miRNAs) are small, noncoding RNA molecules that post-transcriptionally modify gene expression, providing rapid, precise gene regulation. This is essential at dynamic sites like the synapse. The majority of excitatory synapses in the brain occur on small protrusions along the dendrite called dendritic spines, which vary in size, shape, and density. Each dendritic spine is a discrete biochemical compartment with dynamic properties that sculpt the way a neuron receives excitatory input. MiR-324-5p is emerging as an important regulator of dendritic spines. In this study, we employ techniques to reduce miR-324-5p expression and function, examining its role in dendritic spine regulation, and investigating alterations in dendritic spine density, morphology, and plasticity in the mouse hippocampus during adulthood, development, and in the context of neurological disease. Utilizing a novel Mir324 knockout (KO) mouse model, in which the gene precursor to miR-324-5p is lost, we uncover that miR-324-5p loss leads to reduced dendritic spine density, altered dendritic spine morphology including a decreased proportion of thin spines, and impaired maintenance of long-term potentiation (LTP), an essential process for learning and memory. Altered dendritic spine characteristics were also shown in the hippocampus of mice treated with a miR-324-5p antagomir, which binds to and blocks the function of miRNA. Previous work has implicated miR-324-5p in seizure. Seizure, LTP, and development are three essential plastic processes in the brain. Thus, we next investigated the effect of Mir324 KO in development, noting that hippocampal miR-324-5p expression varies across development in mice, with peak expression around postnatal day (PD) 28-45, coinciding with dendritic spine density stabilization. We show that Mir324 KO results in differential effects at different developmental timepoints, ultimately delaying dendritic spine density reduction in the hippocampus. To assess the mechan (open full item for complete abstract)

Committee: Steve Danzer Ph.D. (Committee Chair); Kenneth Campbell Ph.D. (Committee Member); Charles Vorhees Ph.D. (Committee Member); Renu Sah Ph.D. (Committee Member); Christina Gross Ph.D. (Committee Member) Subjects: Neurology

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

Structural alterations to the hippocampus have been widely observed among clinical populations, including posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). However, it is not yet clear how these changes promote and maintain psychopathology. Pattern separation, or the process by which similar stimuli are made more distinct at encoding, has been posited as a possible mechanism underlying fear overgeneralization, which characterizes many commonly occurring symptoms of fear and internalizing disorders. Furthermore, pattern separation has been functionally linked to the hippocampus. This study explored relationships between symptoms of psychopathology (i.e. anxiety, depression, PTSD), hippocampal subfield morphometry, and pattern separation performance. Specifically, these analyses sought to examine whether hippocampal subfield morphometry is an indirect pathway linking psychological symptoms to pattern separation performance. Data were obtained from the Fitness, Aging, Stress, Traumatic Brain Injury Exposure Repository (FASTER; N = 38). Linear regression models examined associations between measures of psychological symptoms (i.e. anxiety, depression, PTSD) and performance on a behavioral task of pattern separation. Correlation tests were conducted to examine associations between measures of psychological symptoms and hippocampal subfield volumes. Mediation analyses were then conducted to investigate whether hippocampal subfield morphometry links psychological symptoms to pattern separation performance. All analyses were statistically adjusted for age, sex, and years of education. Results revealed that symptoms of anxiety and PTSD were associated with improved performance on more difficult trials of a pattern separation task. By contrast, depression and PTSD symptomatology were 3 associated with impaired performance on less difficult trials of a behavioral pattern separation task. Depression symptoms were also negatively associated with subicul (open full item for complete abstract)

Committee: Jasmeet Hayes (Advisor); Scott Hayes (Committee Member); Baldwin Way (Committee Member) Subjects: Clinical Psychology

Doctor of Philosophy, Case Western Reserve University, 2023, Biomedical Engineering

Neural signals are primarily transmitted from one neuron to another through chemical and electrical synapses. We have studied another mechanism through which groups of orderly arranged neurons can communicate with other groups by endogenous electric fields independent of synaptic transmission. Large electric fields have been well documented particularly in epilepsy characterized by highly synchronized activity. We hypothesized that this electric field associated with the epileptic event can be used to control the generation and propagation of the spikes and seizures. In this study, induced epileptic activity was induced by 4-Aminopyridine in hippocampal and cortical slices as well as in the hippocampus in in-vivo experiments. Two recording electrodes were used to record the activity in the slices. Four recording electrodes along the longitudinal axis was used for these acute in-vivo experiments. Two recording electrodes and two stimulating electrodes were used for controlling the electric field using an extracellular voltage clamp. Induced activity propagated by electric field coupling across a physical cut in hippocampal and cortical slices. Theta waves, epileptic interictal spikes, and seizure like events also propagated across a physical cut or transection in the hippocampus in in-vivo experiments at a speed about 0.1 m/s characteristic of electric field coupling mediated propagation. The interictal spikes when analyzed for parameters differentiating spikes that make through the cut to the electrodes on the other side of the transection showed that sharp high amplitude spikes have a higher probability of propagating than smaller wider spikes. The feedback system using the extracellular voltage clamp suppressed 100% of the spikes and seizures induced. Electric fields play an important role in the generation and propagation of epileptic events even through a transection in the tissue. We have successfully used the endogenous field to control the induction (open full item for complete abstract)

Committee: Dominique Durand (Advisor) Subjects: Biomedical Engineering; Biomedical Research; Engineering; Neurosciences

Doctor of Philosophy, The Ohio State University, 2023, Neuroscience Graduate Studies Program

Traumatic brain injury (TBI) is the leading cause of injury-induced disabilities that decrease quality of life. Neuroinflammation propagated by immune cells like microglia causes or worsens post-TBI maladies and is impacted by environmental factors after injury. Stress is a significant post-TBI factor that profoundly influences inflammation and provides a gateway to dysfunctional neuroimmune responses and behavioral decline following TBI. Mounting preclinical and clinical evidence finds TBI suppresses hypothalamic-pituitary-adrenal (HPA)-axis activity in response to stressors. Even though the HPA-axis is a key mediator of stress-immune bidirectional communication, little is known about the consequences of aberrant stress responses after injury. Sleep disturbances are a clinically relevant post-TBI stressor that could better elucidate the relationship between HPA-axis dysfunction and maladaptive inflammation after TBI. Indeed, acute sleep disruption engages the dysfunctional HPA-axis after lateral fluid percussion (lFPI) with suppressed production of stress hormone, corticosterone (CORT) (Chapter 2). Sleep disruption further exacerbates TBI-induced glial-mediated inflammation and causes lasting anxiety-like behavior. Prevalence of HPA-axis dysfunction in preclinical and clinical TBI populations is better reported, however mechanisms of how TBI alters HPA-axis regulation remain unknown. To determine how TBI influences stress-responsive circuitry and long-term inflammatory and behavioral consequences of sleep disturbances, transient sleep fragmentation (SF) was used as a transient, daily stressor chronically after lFPI (Chapter 3). SF engages the intact HPA-axis of uninjured sham mice, eliciting robust neuronal activity of the first step in the HPA-axis, the paraventricular nucleus (PVN). TBI enhances glucocorticoid receptor (GR) sensitivity in the hippocampus, a major regulator of HPA-axis reactivity that could confer TBI-induced suppression, associated with suppresse (open full item for complete abstract)

Committee: Olga Kokiko-Cochran (Advisor); Leah Pyter (Committee Member); John Sheridan (Committee Member); Jonathan Godbout (Advisor) Subjects: Neurosciences

Doctor of Philosophy, The Ohio State University, 2023, Psychology

In the dentate gyrus (DG) of the hippocampus, neural stem cells (NSCs) give rise to adult-born neurons that integrate into the local circuitry and support hippocampal function, a process known as neurogenesis. In addition to their ability to produce new cells, NSCs express and secrete a variety of factors, known collectively as the NSC secretome. While the ability of niche cells to regulate NSCs and neurogenesis has been a primary focus of ongoing research, there have been considerably fewer studies examining how NSCs regulate their microenvironment with their secretome. We have previously identified adult DG NSCs as a significant source of vascular endothelial growth factor (VEGF), which is necessary to maintain NSC quiescence in adulthood. However, the molecular mechanisms underlying VEGF signaling in NSC quiescence, and NSC-VEGFs role in signaling to other niche cells has yet to be fully elucidated. Here we investigate the reliability of a widely used transgenic mouse model in studies of adult NSCs (Chapter 2) and found that use of stop-floxed reporters to investigate cell autonomous gene function in NSPCs may lead to false conclusions. We used these findings to inform model choices while investigating a cell autonomous signaling pathway of VEGF in adult DG NSCs and discovered that VEGF signals through VEGFR2 in a cell internal autocrine loop to maintain quiescence in DG NSCs (Chapter 3). Finally, we explored the ability of NSCs to maintain the neurovascular niche of the adult mouse DG though VEGF expression and found that loss of NSC-specific VEGF led to complete vascular niche disruption, not thought changes to the vasculature, but by inhibiting NSC migration (Chapter 4). Together, these studies reveal a previously unrecognized role of NSC-VEGF in maintaining the neurogenic niche of the adult mouse DG. Our findings encourage future investigation into NSC-expressed factors that mediate their niche, which is imperative before developing effective NSC-based thera (open full item for complete abstract)

Committee: Elizabeth Kirby (Advisor); Jonathan Godbout (Committee Member); Benedetta Leuner (Committee Member); Kathryn Lenz (Committee Member) Subjects: Neurosciences

PhD, University of Cincinnati, 2022, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary

Patients in status epilepticus (SE) present with continuous seizures that are life-threatening without successful and emergent seizure termination. Despite the fact that current therapies fail to stop seizures in 20% of patients, physicians have relied on essentially the same treatment strategy for SE for almost 50 years: anti-seizure medications, such as benzodiazepines and other anti-convulsive agents. When treatment fails, patients enter refractory SE for which the mortality rate can reach 60%. Not only is SE a medical emergency with a high mortality rate, but survivors are also often left with irreversible and lasting brain damage. After a single episode of SE, almost half of patients will develop spontaneous recurrent seizures and temporal lobe epilepsy. Further, psychiatric comorbidities, such as anxiety and depression, are highly associated with the chronic epileptic state. Therefore, to reduce both mortality and morbidity, this proposal aimed to elucidate the underlying mechanisms that drive the severity and consequences of SE. As a life-threatening stressor, SE results in robust activation of the hypothalamic-pituitary-adrenal axis and stress hormone (i.e., glucocorticoid) release. Multiple lines of evidence suggest that glucocorticoids exposure can enhance neuronal excitability and exacerbate neurotoxic injury. However, it remains unclear which brain regions and cell types might directly mediate these effects. This dissertation examines the role of GR among ventral hippocampal excitatory neurons during status epilepticus, hypothesizing that the seizure-induced stress response acts through hippocampal GR to worsen SE outcomes. Through viral-mediated GR deletion in the preclinical setting, I have shown that GR among hippocampal glutamatergic neurons plays a critical role in governing seizure progression during pilocarpine-induced seizures. Furthermore, this proposal went on to characterize GR expression among inhibitory interneurons of the hippocampus, revea (open full item for complete abstract)

Committee: Christina Gross Ph.D. (Committee Member); Steve Danzer Ph.D. (Committee Member); Jeffrey Tenney M.D. Ph.D. (Committee Member); Katrina Peariso M.D. Ph.D. (Committee Member); James Herman Ph.D. (Committee Member) Subjects: Neurology

PhD, University of Cincinnati, 2022, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary

Epilepsy is defined by the occurrence of recurrent and unprovoked seizures. Currently, little is known about the pathological changes that occur during epileptogenesis, the process by which a healthy brain becomes epileptic. As a result, research that adds to our understanding of the mechanistic changes in epilepsy is crucial to developing novel therapeutic options. The accumulation of improperly integrated adult hippocampal dentate granule cells (DGCs) is thought to have a role in temporal lobe epilepsy (TLE). DGCs regulate excitatory signaling in the hippocampus and undergo neuroplastic alterations during epileptogenesis. However, the mechanism that causes these abnormal alterations is unclear. Recently, the mechanistic target of rapamycin (mTOR) signaling pathway has emerged as a promising new target to combat epileptogenesis. The mTOR pathway regulates neuronal growth and synaptic strength by integrating a wide range of cellular processes through mTORC1 and mTORC2. Raptor (regulatory-associated protein of mTOR) and Rictor (rapamycin-insensitive companion of mTOR) are critical proteins that activate mTORC1 and mTORC2, respectively. Studies indicate pharmacological inhibition of mTOR with the mTOR antagonist rapamycin is anti-epileptogenic in rodent TLE models and reduces seizure incidence in patients with genetic hyperactivation of mTOR. These data support the concept that mTOR has a role in the development of acquired epilepsy, especially since mTOR hyperactivation is widespread in animal models and human TLE patients, and rapamycin can inhibit several TLE-related pathological alterations in DGCs. However, because rapamycin is administered systemically, it is unknown where the drug acts to produce its positive effects. Rapamycin could act directly on hyperexcitable neurons in the epileptic focus, it could work on other targets in the brain or even operate in the periphery. Our guiding hypothesis is that rapamycin has disease-modifying effects by blocking (open full item for complete abstract)

Committee: Christina Gross Ph.D. (Committee Member); Mark Baccei Ph.D. (Committee Member); Jeffrey Tenney M.D. Ph.D. (Committee Member); Kim Seroogy Ph.D. (Committee Member); Steve Danzer Ph.D. (Committee Member) Subjects: Neurosciences

Master of Science in Biomedical Sciences (MSBS), University of Toledo, 2022, Biomedical Sciences (Bioinformatics and Proteomics/Genomics)

Temporal Lobe Epilepsy (TLE) is one of the most common neurological disorders and is characterized by recurrent and spontaneous seizures. Although TLE genetic and electrophysiological markers such as gamma oscillations are well characterized, alterations in the interactions between neurons predisposing a cortical region to seizures are not fully understood. To study these non-linear interactions, we incorporated RNA expression changes into a microcircuit computer model of the hippocampus, an area strongly implicated in TLE. Cellular deconvolution of bulk RNAseq data with single-cell transcriptomic data from the hippocampi of pilocarpine-induced temporal lobe epilepsy mice revealed three distinct cell clusters characterized as pyramidal (PYR) cells, oriens-lacunosum moleculare (OLM) interneurons, and parvalbumin-positive (PV) interneurons. We used the differential expression (log fold change) of genes coding for the Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid (AMPA), N-methyl-D-aspartate (NMDA), and Gamma-aminobutyric acid type A (GABAA) receptor subunits in the control and epileptic conditions for each cell cluster to guide scaling of receptor density iv in the model. The model was composed of 800 PYR, 200 PV and 200 OLM neurons. PYR cells of the model activate PV, OLM, and other pyramidal cells via NMDA and AMPA receptors; in return, the PV and OLM interneurons inhibit PYR cells by acting on their GABAA receptors. Guided by the RNA expression data, we ran simulations where we increased the density of PYR AMPAR, OLM NMDAR, PV AMPAR, and PV GABAAR scaling. PYR GABAAR subunits were both upregulated and downregulated and thus, both changes were implemented when running simulations. Our simulations showed two dynamical changes with the RNA sequence changes. The first is the expected increased seizure susceptibility, reflected as increased gamma power. That pattern took place with pyramidal AMPAR/GABAAR upscaling. The second pattern was a surprising reduc (open full item for complete abstract)

Committee: Robert Mccullumsmith (Advisor); Rammohan Shukla (Committee Co-Chair); Mohamed Sherif (Committee Member); Bruce Bamber (Committee Member); Imran Ali (Committee Member) Subjects: Bioinformatics; Biophysics; Neurosciences

Doctor of Philosophy, Case Western Reserve University, 2022, Neurosciences

Neurotrophic factors are released in the brain in response to neural activity. In so doing, they can modulate neuronal circuits. Yet how exactly neurotrophic factors impact networks of the brain and by what underlying mechanisms are just becoming understood. Neuregulin 1 (NRG1) is one such trophic factor that is released in the brain upon neuronal activity. NRG1 binds to and stimulates the receptor tyrosine kinase (RTK) ErbB4 that is expressed in inhibitory interneurons. Stimulation of ErbB4 kinase then increases Gamma-Aminobutyric Acid (GABA) neurotransmission in the cortex and HPC. Yet how ErbB4 kinase dynamically impacts the cortex, HPC, and relevant behaviors remains unknown. By developing a novel chemo-genetic animal model to specifically manipulate ErbB4 kinase, we identify two distinct network functions of the brain that ErbB4 kinase regulates, along with relevant behaviors involved in these network functions. First, we identify a novel behavioral function for the ventral HPC (vHPC) to prefrontal cortex (PFC) circuit. We find that the vHPC-PFC is highly synchronous during top-down attention. We next identify how ErbB4 plays a role in top-down attention, by regulating vHPC-PFC synchronicity. We further validate that ErbB4 kinase dynamically regulates GABAergic transmission via presynaptic xviii modulation. Lastly, we identify how ErbB4, via regulation of GABAergic transmission, controls vHPC-PFC synchrony through vHPC inputs to the PFC that lead PFC neurons to fire in phase. Together, we identify how ErbB4 kinase dynamically regulates the synchrony between two regions for top-down attention. Next, we examine how NRG1-ErbB4 kinase regulates a memory consolidation network event in the HPC called the sharp wave ripple (SW-R). Specifically, we find that NRG1-ErbB4 kinase dynamically regulate the occurrence of SW-Rs, especially during awake periods. Furthermore, we uncover that ErbB4 kinase regulates levels of neuronal firing, specifically pyramidal neurons (Py (open full item for complete abstract)

Committee: Lin Mei Dr. (Advisor); Ben Strowbridge Dr. (Committee Chair); Qian Sun Dr. (Committee Member); Dominique Durand Dr. (Committee Member); Heather Broihier Dr. (Committee Member) Subjects: Neurobiology; Neurosciences

Doctor of Philosophy, Miami University, 2022, Biology

Sex differences exist in neuroendocrine regulation of energy homeostasis. Estrogens are one of important central contributing factors to these sex differences. This research is warranted since obesity and metabolic disturbances, and chronic stress continue to be top health concerns, and sex differences are witnessed in these aspects. For example, chronic stress disrupts energy homeostasis, leading to negative consequences in both the regulation of mood/emotion and metabolism. Females are known to be more vulnerable to the psychological consequences of stress, such as depression and anxiety, while males are more vulnerable to the metabolic consequences of stress. Sex differences that exist in the susceptibility to stress-induced affective disorders led scientists to hypothesize that gonadal hormones are regulating factors that should be considered during stress studies. Further, estrogens are heavily recognized for their protective effects on metabolic dysregulation, such as antiobesogenic and glucose and insulin-sensing effects in males and females. Perturbations to energy homeostasis offer hints to the underlying mechanisms that regulate it. Here I perturb energy homeostasis of rats by both physiological restraint stress, or high-fat diet (HFD) or fasting dietary regimen, all of which are factors prevalent in society today. Both Metabolic and stress-protective effects of estrogens primarily work through estrogen receptor α (ERα), which is differentially expressed between the sexes in hypothalamic and extrahypothalamic nuclei. In chapter 2, ERα immunoreactivity was quantified in specific hypothalamic nuclei after exposure to HFD or fasting in adult female rats. Specifically, we hypothesized that ERα would be upregulated after short-term HFD in regions in which ERα has a primarily anorectic influence and upregulated after fasting in regions in which ERα has a primarily orexigenic influence. Furthermore, limbic regions that are not typically ass (open full item for complete abstract)

Committee: Haifei (Claire) Shi (Advisor); Matthew McMurray (Committee Member); Paul James (Committee Member); Paul Harding (Committee Member); Kathleen Killian (Committee Member) Subjects: Molecular Biology

Doctor of Philosophy, The Ohio State University, 2022, Neuroscience Graduate Studies Program

Continuous neurogenesis in the adult hippocampus is a remarkable example of mammalian brain plasticity and is an important process for certain forms of learning and memory. Neural stem cells (NSCs) are the source of adult-born neurons, and the maintenance of this cell population throughout the lifespan is highly regulated by integrating cell-internal and -external signaling. Neurotransmitter signaling regulates adult hippocampal neurogenesis under basal conditions and may be an important mechanism coupling stimulated physiological states or disease conditions to changes in neurogenic output. Glutamate, the main excitatory neurotransmitter in the brain, may regulate neurogenesis by recruiting quiescent NSCs to re-enter the cell cycle, proliferate, and produce neuronal progeny. However, the molecular mediators by which NSCs sense and respond to glutamate signaling are unclear. The prevailing model in the literature is that glutamate stimulates receptors expressed at the plasma membrane of NSCs, triggering pro-proliferative intracellular cascades. However, few studies directly test this idea. Here, we present data that do not support a role for glutamate receptors in regulating the response of NSCs to glutamate, but rather implicate excitatory amino acid transporter 1 (EAAT1). We report that while cultured NSCs derived from adult rodent hippocampus express EAATs, ionotropic receptors, and metabotropic receptors, of these molecules only EAAT1 is necessary for NSCs to increase cell cycle entry in response to glutamate (Chapter 2). Using RNA sequencing, we demonstrate that cultured NSCs treated with glutamate upregulate gene expression related to lipid, amino acid, and protein synthesis in an EAAT-dependent manner, while NSCs experiencing EAAT inhibition upregulate quiescence-related and downregulate mitotic-related gene expression (Chapter 3). We also investigated potential downstream effectors of EAAT signaling, and find evidence supporting stored calcium release, gluta (open full item for complete abstract)

Committee: Elizabeth Kirby (Advisor); Benedetta Leuner (Committee Member); C.L. Glenn Lin (Committee Member); Min Zhou (Committee Member) Subjects: Cellular Biology; Neurobiology; Neurosciences

Doctor of Philosophy (Ph.D.), Bowling Green State University, 2021, Psychology/Experimental

The current study examined reward probability associative learning to either spatial or feature information in homing pigeons in an open-field, laboratory setting. Additionally, the role of the avian hippocampal formation (HF) was examined in the current study by using both control sham-lesioned and hippocampal-lesioned animals in spatial or feature contexts in which rewarded goals varied in differential risk-reward properties. Homing pigeons were divided into two main experimental conditions, space or feature, and were then divided again into two brain manipulation groups, control sham-lesioned or hippocampal-lesioned. Animals were trained to locate three specific risk-reward (High-Variable 75%, Low-Variable 25%, and Constant 100%) dependent food sites (based on locations or colors) in an open-field environment. It was hypothesized that control sham-lesioned homing pigeons would develop a stronger risk-reward association with spatial information than with feature information. Additionally, it was hypothesized that control sham-lesioned and hippocampal-lesioned homing pigeons trained to feature information would perform similarly on a risk-reward based discrimination. Furthermore, it was hypothesized that control sham-lesioned homing pigeons trained to spatial information would perform differently from hippocampal-lesioned homing pigeons on a risk-reward discrimination based on space. Results indicated that homing pigeons that were provided with feature information were more likely to choose the riskier outcome during High-Variable trials, the constant outcome during Low-Variable trials, and made fewer incorrect choices in comparison to homing pigeons that were only provided spatial information. Control sham-lesioned and hippocampal-lesioned homing pigeons trained to feature both learned to seek out risk-reward outcomes and there were no significant differences in performance. By contrast, performances of control sham-lesioned and hippocampal-lesioned homing pigeo (open full item for complete abstract)

Committee: Verner Bingman Ph.D. (Advisor); HeeSoon Lee Ph.D. (Other); Richard Anderson Ph.D. (Committee Member); Howard Casey Cromwell Ph.D. (Committee Member); Sherona Garrett-Ruffin Ph.D. (Committee Member) Subjects: Behavioral Psychology; Cognitive Psychology; Experimental Psychology; Neurosciences; Psychology

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, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary

Creatine (Cr) is a nitrogenous acid that acts as an energy buffer in cells. It is concentrated in tissues with high energy demand like the heart, brain, and muscle. It plays an essential role in bioenergetic homeostasis by providing phosphate pools for the rapid production of ATP. The loss of Cr is devastating, causing intellectual disability, delays in language development, and epilepsy. These Cr deficiency syndromes (CDS) are due to either the lack of a functioning Cr transporter (CrT) or one of the two Cr synthesis enzymes. Creatine transporter deficiency (CTD) is the most prevalent cause of CDS, affecting 1-2% of males with X-linked intellectual disability. Unlike inborn errors of Cr synthesis that can be treated with Cr supplementation, there is no treatment for CTD. It is unclear if the decline in cognition is directly caused by Cr loss or a loss of ATP associated with Cr loss. CrT knockout mice (Crt -/y) have reduced brain ATP levels that could play a role in cognitive decline. The ketogenic diet (KD) has been suggested to increase cellular ATP levels. The KD is a low carbohydrate, high fat diet that generates ketone bodies which can be used as the primary metabolite for ATP production. Mice were placed on the KD starting on P21 to mimic the early-life treatment that is likely required for CTD. Mice placed on the KD had reduced weight gain and lean mass, with increased body fat compared with control diet (CD) fed mice. There was increased mortality in KD fed mice, with Crt-/y mice having higher mortality on the KD than Crt+/y mice. The KD did not improve the learning and memory deficits in Crt-/y mice. However, KD fed Crt+/y mice had spatial learning deficits while also showing increased fear memory. This suggests that early life exposure to a KD does not rescue Cr-mediated cognitive deficits but can impair learning in otherwise healthy mice. Regardless of genotype, the KD did not affect hippocampal electron transport chain proteins or activity. Further, the (open full item for complete abstract)

Committee: Christina Gross Ph.D. (Committee Chair); Stephen Benoit Ph.D. (Committee Member); Steve Danzer Ph.D. (Committee Member); Matthew Skelton Ph.D. (Committee Member); Yvonne Ulrich-Lai Ph.D. (Committee Member) Subjects: Neurology

MA, Kent State University, 2020, College of Arts and Sciences / Department of Anthropology

In order for any type of social relationship to form, social recognition and social memory must be maintained as they provide the foundation on which social relationships are built. Oxytocin (OT) has been correlated to a variety of other prosocial behaviors such as pair bonding, social recognition memory, and trust in a wide variety of species. Serotonin plays a role in regulating OT levels and expression, acting on OT by way of 5HT receptors that are located in the PVN and SON. Together, OT and serotonin work in concert to affect social behavior in primates and rodents, which relies on intact social recognition ability. The hippocampus plays a vital role in social recognition and OT and 5HT act within this region to influence memory and social behaviors. Previous research discovered that OT manipulation to male prairie voles on the first day of life altered serotonin expression in adult brain regions involved in social behaviors, especially aggression. The current project will build on these findings by evaluating whether early exposure to OT or its antagonist alters serotonin within the hippocampus of prairie voles. We expect that there will be differences in the amount of serotonin based on the treatment of either high OT, low OT, OTA, or the saline control in regions of the hippocampus. However, our results indicated that OT manipulation does not have an effect on serotonin expression in the adult hippocampus.

Committee: Mary Ann Raghanti (Advisor); Linda Spurlock (Committee Member); Richard Meindl (Committee Member) Subjects: Biology; Physical Anthropology

Doctor of Philosophy, The Ohio State University, 2020, Neuroscience Graduate Studies Program

Cancer patients and survivors commonly report fatigue and cognitive impairments that can last months to years into remission. This cancer-associated cognitive impairment is commonly referred to as “chemobrain,” and these symptoms lead to decreased quality of life and poorer long-term survival outcomes. Inflammation has been posited as a key contributor to cancer-induced cognitive impairment, given that these symptoms persist following cessation of chemotherapy. Notably, increased fatigue and poorer cognition have been correlated with flattened cortisol slopes in cancer patients. As circulating cortisol, rest-activity cycles, and memory are all modulated by circadian, 24-hour rhythms, it stands to reason that cancer and cancer treatments may elicit chemobrain symptoms, in part, by disrupting the circadian clock. Here, I examine the extent to which paclitaxel chemotherapy, a microtubule-binding taxane agent, and non-metastatic mammary tumors disrupt circadian rhythmicity in a mouse model. First, in Chapter 2 I demonstrate that paclitaxel inhibits memory recall through a contextual fear conditioning task. This disrupted memory recall is accompanied by increased hippocampal and hypothalamic inflammation as measured by glial reactivity. Next, in Chapter 3 I demonstrate that individual CA1 pyramidal neurons exhibit 24-hour rhythms using a Per1-Venus clock gene reporter mouse. Other hippocampal cell types (astrocytes and GAD65/67-positive interneurons) exhibit clock gene expression and in vivo clock gene rhythms were observed at single-cell resolution in the posterior parietal cortex. In chapter 4, I demonstrate that paclitaxel chemotherapy ablates rhythms in circulating corticosterone, alters the free-running period of voluntary wheel running, and attenuates the amplitude of clock genes in multiple brain regions and the adrenal glands. Finally, in Chapter 5 I show that non-metastatic mammary tumors dysregulate time-of-day differences in hypothalamic clock gene expression (open full item for complete abstract)

Committee: Leah Pyter (Advisor); Karl Obrietan (Advisor); Fischer Andrew (Committee Member); Tedeschi Andrea (Committee Member) Subjects: Biology; Biomedical Research; Immunology; Neurobiology; Neurosciences