Department: Neuroscience ![[clear]](close-x.png "Remove this limiter")
34 matches in the database.
These are records: 1 - 30.
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1.
An, Min.
Positional cloning and functional analysis of the SF3B1gene in zebrafish.
Degree: PhD, Neuroscience, 2007, Ohio State University
► Zebrafish toast b460( tst) is a recessive embryonic lethal mutation, characterized by…
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▼ Zebrafish toast b460( tst) is a recessive embryonic lethal mutation, characterized by visible defects in both neural crest and blood development. tstis involved in the neural plate border development in zebrafish embryos, resulting in the complete lack neural crest derivatives and a decrease in the number of Rohon-Beard sensory neurons. In addition, lateral plate mesoderm development is also affected in tstmutants, as development of most of its derivatives are disrupted during hematopoiesis, vasculogenesis, and cardiogenesis. Other ectodermal and mesodermal derivatives develop normally in tstmutants. The tstlocus has been positionally cloned and encodes splicing factor 3b subunit 1 ( sf3b1). Sequence analysis between wild-type and homozygous mutant genomic DNA identified the nucleotide mutation at 5′ splicing site in the 4th intron of sf3b1genomic DNA where T is changed to G in the tstmutant gene. The nucleotide change causes abnormal splicing in tsthomozygotes with variant transcripts. The truncations are predicted to occur in the extreme N-terminal region of the protein, thus eliminating essential functional regions and are therefore predicted to be non-functional. The presence of normal transcripts and the more severe phenotype of sf3b1 morphants compared to tstmutants indicate that the tstmutation is hypomorphic. Zebrafish genome analysis shows that sf3b1is a single-copy gene. It is expressed ubiquitously during early embryonic development in zebrafish. Studies of interactions between sf3b1and key transcriptional regulators of neural crest development and hematopoiesis reveal that deficiency of sf3b1function not only causes disruption in the expression levels of genes required for sublineage fate specification, but also results in abnormal pre-mRNA splicing of some of these genes. As a result, the survival, migration, and differentiation of cells derived from both neural plate border and lateral plate mesoderm are severely disrupted. These results demonstrate that the ubiquitous and essential pre-mRNA processing gene sf3b1is required to different degrees by specific embryonic cell populations during development. Thus, while some genes are required by all cell types, the timing and degree of the requirement for such ”housekeeping” genes differs for specific embryonic cell population during embryogenesis.
Advisors/Committee Members: Henion, Paul D.
Subjects: Biology, Neuroscience
Keywords: Splicing factor 3b subunit 1 ( sf3b1),; Neural plate border,; Lateral plate mesoderm,; Early embryogenesis; Positional cloning; Zebrafish
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2.
Butcher, Gregory Quinn.
The mitogen-activated protein kinase (MAPK) pathway: a signaling conduit for photic entrainment of the central mammalian circadian clock.
Degree: PhD, Neuroscience, 2006, Ohio State University
► The central biological clock, located in suprachiasmatic nuclei (SCN) of the hypothalamus…
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▼ The central biological clock, located in suprachiasmatic nuclei (SCN) of the hypothalamus in mammals, coordinates physiological and behavioral processes to an approximate 24 hr (circadian) rhythm. The endogenous timing mechanism remains synchronized to the exogenous environment through the influence of timing cues (zeitgebers), such as light via a process known as entrainment. The studies presented here describe the functional and mechanistic assessment of the p42/44 mitogen-activated protein kinase (MAPK) cascade as a putative input pathway to the SCN. The following hypotheses are tested using a variety of behavioral, cellular, and biochemical techniques. 1) Light-induced behavioral phase shifting in mice is coupled via a MAPK dependent mechanism. 2) Light activation of the MAPK pathway is stringently regulated with respect to the time course of activation / inactivation and subcellular localization of ERK within neurons. 3) Light-induced phosphorylation of p90 ribosomal S6 kinases (RSKs) within the SCN is phase restricted to the subjective night and is dependent upon activation of the MAPK pathway. 4) Light-induced phosphorylation of mitogen- and stress-activated kinases (MSKs) within the SCN is dependent on a signaling cassette consisting of the neuromodulator pituitary adenylate cyclase activating polypeptide (PACAP) and the MAPK pathway. 5) Light-induced phase advances, but not phase delays, are attenuated in mice lacking MSKs. Conversely, light-induced phase delays, but not phase advances, are attenuated in mice lacking RSKs. The data presented herein demonstrate that functional coupling between photic stimuli and behavioral phase shifting occurs via a MAPK signaling pathway. Furthermore, expression profiles for maximal light-induced activation of two MAPK substrates, RSK1 and MSK1, suggest that these kinases may occupy divergent functional roles within the entrainment mechanism. Preliminary data testing this possibility indicates that RSK and MSK signalling may function in a partially compensatory and complimentary manner rather than exclusively distinct pathways.
Advisors/Committee Members: Obrietan, Karl.
Keywords: MAPK; circadian; entrainment; RSK; MSK; SCN
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3.
Cao, Yu.
Morphological and functional characterization of the neurotransmitter GABA in adult rat taste buds.
Degree: PhD, Neuroscience, 2006, Ohio State University
► GABA is among a broad array of neuroactive substances, which include several…
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▼ GABA is among a broad array of neuroactive substances, which include several neurotransmitters and neuropeptides that have been identified in mammalian taste buds. The present study is the first to characterize the morphological features, distribution patterns and functional consequences of GABAergic taste receptor cells (TRCs) in adult rat posterior lingual epithelium. Subsets of TRCs were identified as the endogenous source of GABA in taste buds of foliate or circumvallate papillae, as demonstrated by localization of immunoreactivity to both GABA and its synthetic enzyme, glutamate decarboxylase (GAD). Double labeling immunofluorescent studies revealed complex co-expression patterns of GAD with TRC population-specific protein markers (i.e. taste-specific G-protein gustducin á subunit, neural cell adhesion molecule and protein gene product 9.5), the presynaptic membrane-specific protein marker synaptosomal-associated protein of 25 kDa (SNAP-25) and neuropeptides (i.e. cholecystokinin and vasoactive intestinal polypeptide), implying that GABAergic TRCs may have diverse functions in taste buds. GABA receptor subtypes, GABAA and GABAB, were also localized to subsets of TRCs in rat foliate and circumvallate papillae. GABAB receptor R1 subunit-immunoreactivity was observed in a group of TRCs separate from the GAD-containing cells in the same bud, arguing a paracrine role for GABA. Interestingly, peptidergic TRCs appeared to receive differentially distributed modulatory input mediated by the GABAB receptor. Possible physiological effects of GABA in the taste buds were examined by patch clamp recordings of TRCs acutely dissociated from rat foliate and circumvallate papillae. GABA was demonstrated to enhance chloride currents and inwardly rectifying potassium currents by acting on the GABAA and GABAB receptor subtype, respectively. Therefore electrical properties of TRCs may be modulated by GABA. In summary, GABA produced endogenously in the taste buds may modulate functions of various populations of TRCs by acting on specific receptor subtypes. The results of the present study add GABA to a growing list of recently characterized neuroactive substances in the taste buds. These neuroactive substances mediating cell-to-cell communication within the taste buds are capable of shaping the final output of chemosensory TRCs and therefore may play important roles in peripheral gustatory signal processing.
Advisors/Committee Members: Herness, M Scott.
Subjects: Biology, Neuroscience
Keywords: taste receptor cells, GABA, paracrine, co-transmission, modulation
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4.
Choi, Yong-Jin.
Function of commissureless and related genes in drosophila neural development.
Degree: PhD, Neuroscience, 2003, Ohio State University
► Commissureless (Comm) and Roundabout (Robo) are key regulators of axon guidance at…
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▼ Commissureless (Comm) and Roundabout (Robo) are key regulators of axon guidance at the Drosophila CNS midline. Robo encodes a receptor for the midline repellent Slit and prevents ipsilaterally projecting axons from crossing the midline. Comm encodes a novel transmembrane protein that is required for commissural axons to cross the midline. Genetic studies suggest the function of Comm is to regulate Robo receptor activity. The broad goal of this work is to understand how Comm functions. First, how does Comm regulate Robo? Second, what are the functions of Comm family members? Third, how does Comm function in neuromuscular synaptogenesis? Using a cell culture assay, we demonstrate that Comm forms a complex with Robo and facilitates clearance of Robo from the cell surface. This activity requires a defined region of the Comm cytoplasmic domain for clearance activity and the transmembrane domain region for complex formation. Similarly, the Robo transmembrane and juxtamembrane regions are required for complex formation and Comm-mediated clearance. The identification of lysine residues in the juxtamembrane region of Robo as important for Comm-mediated clearance suggests that ubiquitination of Robo may be required for internalization of the Robo-Comm complex. We have identified two additional Comm family members (Comm2, Comm3) and tested their ability to regulate different Robo family members. We find that Comm can clear all three DRobos (DRobo, DRobo2, DRobo3), while Comm2 only clears DRobo efficiently, and Comm3 does not efficiently clear any of the Robo family members. As a first step in our genetic analysis of comm2, we isolated two P-element insertions in the 5’-UTR of comm2. Molecular genetic studies indicate that these insertions in comm2 influence the transcription of comm, despite residing approximately 25kb 3’ of comm. This is consistent with other data that suggests Comm cis-regulatory regions are large and complex. Comm is expressed by all muscles in the periphery and is required for initiation of neuromuscular synaptogenesis. Our findings suggest that the conserved tyrosine residues identified as important for endocytosis of Comm and for Comm-mediated Robo clearance in S2 cells are not absolutely essential for Comm function in muscles.
Advisors/Committee Members: Seeger, Mark A.
Subjects: Biology, Neuroscience
Keywords: Axon guidance; Commissureless; Roundabout; Comm2; Comm3; Synaptogenesis; Neural development
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5.
Congdon, Erin Elizabeth.
Insights into the mechanism of Tau polymerization and the effects of small molecules.
Degree: PhD, Neuroscience, 2007, Ohio State University
► Alzheimer’s disease and related tauopathies are characterized by the loss of neurons…
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▼ Alzheimer’s disease and related tauopathies are characterized by the loss of neurons occurring in parallel with the formation of filamentous lesions composed of the tau protein. Though macroscopic analysis has provided insights into the development of tau lesions, the mechanism by which filaments assemble has remained unknown. The first stage in clarifying the reaction pathway was to characterize the partially folded intermediate species and determine conditions which promote intermediate stabilization. Data indicate that intermediate species contain increased secondary and tertiary structure. Several planar aromatic dyes including Congo red, thiazin red, thioflavin S known to bind β-structure, were capable of triggering filament formation. They were also capable of dramatically reducing critical concentration and nucleation rate relative to other inducers. In the presence of β sheet binding dyes assembly time courses were sigmoidal and reached plateau within 8 hours. Reaction kietics were utilized to estimate nucleus cluster size as well as several of the rate contstants governing the reaction. These estimates along with data from polymerization time courses were used to create a mathematical model of the tau polymerization reaction. These methods were further utilized to examine the effects of alternative splicing on tau polymerization. The effects of individual exons on both nucleation and elongation rates were determined through analysis of reaction kinetics. Finally, the effects of a previously described inhibitor of tau polymerization, N744 were examined over a wide concentration range. Results revealed a biphasic effect with inhibitory activity at low dye concentrations followed first by relief of inhibition, and then enhancement. Greater than 50% inhibition was seen over only a narrow concentration range. Changes in activity parallel changes in dye aggregation state, with dimers predominant under inhibitory concentrations. In the presence of tau protein the dimerization constant for N744 was decreased over an order of magnitude relative to controls. These results suggest that ligand aggregation may play an important role in the development of effective fibrillization inhibitors.
Advisors/Committee Members: Kuret, Jeff A.
Keywords: Alzheimer disease; Tau; Intermediate; Thiazin red; Protein polymerization; Nucleation; Mathematical simulation; Tau isoform; Alternative splicing; Cyanine dye; Fibrillization inhibitor; Dye aggregation; Dose response
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6.
Davidson, Adam G.
Bilateral actions of the reticulospinal tract in the monkey.
Degree: PhD, Neuroscience, 2004, Ohio State University
► The motor output of the primate pontomedullary reticular formation (PMRF) was investigated…
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▼ The motor output of the primate pontomedullary reticular formation (PMRF) was investigated with spike- and stimulus triggered averaging (SpikeTA, StimulusTA) in monkeys during reaching. The first study employed StimulusTA for ipsilateral arm and shoulder muscles and bilateral trapezius muscles. The second study used StimulusTA and SpikeTA for 24 muscles. Muscles studied on the ipsilateral (i) and contralateral (c) side were extensor carpi ulnaris (ECU), flexor carpi radialis (FCR), brachioradialis (Brac), biceps (Bic), triceps-long head (TrLo), triceps-lateral head (TrLa), anterior deltoid (ADlt), posterior deltoid (PDlt), latissimus dorsi (Lat), pectoralis major (PMj), middle trapezius (MTr), and upper trapezius (UTr). Average onset was significantly earlier for post-stimulus facilitation (PStF) than for post-stimulus suppression (PStS). The average duration of PStS was longer than the average duration of PStF, and response magnitude was significantly larger for PStF. A clear pattern of PStF and PStS was observed among all muscles. In the ipsilateral arm, flexors were facilitated and extensors were suppressed. In the contralateral arm, extensors were facilitated and flexors were suppressed. Shoulder girdle muscles demonstrated similar proportions for responses: iUTr, cMTr, and cPMj were suppressed; cUTr , iMTr, and iPMj were facilitated. Lat was the only muscle to demonstrate the same response (PStS) bilaterally. Reciprocal, cofacilitation, and cosuppression responses were observed between anatomical antagonists within a limb and bilateral homologues at individual stimulus sites. These responses were usually reciprocal and matched the most prevalent response for each member of the pair. Overall, 9 of 368 cells produced post-spike effects (PSpEs). 8 of the 11 total PSpEs were post spike facilitation (PSpF). 4 PSpEs matched the corresponding PStE obtained at the same site. Overall, StimulusTA and SpikeTA of bilateral arm and shoulder muscles revealed motor patterns that implicate the reticulospinal tract in the control of voluntary reaching movements and the coordination of bilateral movements.
Advisors/Committee Members: Buford, John A.
Subjects: Biology, Neuroscience
Keywords: Reticular Formation, Electromyogram, Motor Control, Non-Human Primate
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7.
Detloff, Megan Ryan.
Supraspinal Sensory Perception after Spinal Cord Injury and the Modulatory Factors Associated with Below-Level Allodynia.
Degree: PhD, Neuroscience, 2009, Ohio State University
► Spinal cord injury (SCI) impairs sensory systems causing debilitating chronic allodynia, neuropathic…
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▼ Spinal cord injury (SCI) impairs sensory systems causing debilitating chronic allodynia, neuropathic pain elicited from an innocuous stimulus. While inflammation can cause allodynia under some conditions, no ameliorative cure exists. Our rat spinal cord contusion model emulates the pathology of human SCI but its validity as a model of allodynia remains debatable. Hence, our goals were: to validate and extend behavioral assessments of below-level allodynia for experimental SCI, to identify the anatomical and functional connections involved in processing sensation after SCI, and to characterize the patterns of glial activation and pro-inflammatory cytokine production in sensory processing centers of the lumbar spinal cord. To test for allodynia in experimental SCI, we validated current paradigms and developed a new assessment of sensation that did not rely on hindlimb or postural control. We validated these techniques in >150 rats with SCI and demonstrate that Up-Down methods provide a quantitative assessment of perceptual threshold. With the new sensory test, thresholds collected prior to recovery of hindlimb weight support predicted chronic thresholds with 75-89% accuracy. Subsequently, we showed that anatomical connections between L5 and supraspinal centers remain intact after moderate SCI. Mechanistically, the activation of microglia and p38 MAP kinase in L5 cord predicted allodynia. Tumor necrosis factor-α and interluekin-1β increased in the L5 dorsal horn by 7 dpo and interleukin-6 was elevated chronically. These data suggest that remote microglial activation is pivotal in SCI-induced allodynia. Fractalkine, a microglial activator, and astrocytes were not primary modulators of pain. Finally, we showed supraspinal processing of below-level stimuli occurs after moderate SCI using functional MRI and somatosensory evoked potentials (SSEP). SSEPs delineated pain-specific delays in S1 cortical depolarization. Importantly, we show that fMRI captures cortical activation in the rat brain elicited by the same noxious pinprick stimulus used in clinical practice to classify below-level sensation in people. Taken together, the behavioral, perceptual, and inflammatory markers of below-level allodynia established in this dissertation define a profile of SCI-induced allodynia that can be applied to differentiate and diagnose below-level allodynia in the laboratory and the clinic.
Advisors/Committee Members: Basso, D. Michele.
Subjects: Behaviorial sciences; Biomedical research
Keywords: cytokines; functional magnetic resonance imaging; functional recovery; microglia; p38; rats; somatosensory evoked potentials
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8.
Emch, Gregory Simon.
EFFECTS OF TUMOR NECROSIS FACTOR-ALPHA ON DORSAL VAGAL COMPLEX NEURONS THAT EXERT REFLEX CONTROL OF THE GASTROINTESTINAL TRACT.
Degree: PhD, Neuroscience, 2002, Ohio State University
► The results of the experiments presented in this thesis have shown that…
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▼ The results of the experiments presented in this thesis have shown that injection of tumor necrosis factor-alpha (TNF) into the dorsal vagal complex [DVC; made up of the area postrema (AP), the sensory nucleus of the solitary tract (NST), and the dorsal motor nucleus of the vagus (DMN)] has mixed results on neuronal activity in this medullary brainstem area. In the NST, microinjection of TNF causes a significant and dose-dependent increase in neuronal firing rate (FR) as compared to injection of saline controls. Subsequently, some NST neurons exhibit a potentiated response to afferent stimulation following pre-exposure of the neurons to TNF. Conversely, microinjection of TNF significantly inhibits the FR of most neurons in the DMN. Immunohistochemical studies show that the protein product of the proto-oncogene c-Fos (a marker of neuronal activation) is increased in response to systemic administration of lipopolysaccharide (LPS; bacterial cell coat component that induces endogenous production of TNF) in the DVC. Additionally, protein expression is independent of the integrity of the vagus nerve(s). That is, surgical section of the vagi does not inhibit the increase in number of c-Fos labeled neurons. Direct injection of TNF into the NST causes a significant elevation of Fos-labeled neurons, and protein expression is dependent on glutamate neurotransmission since glutamate receptor antagonists abolish any significant increase in Fos-positive neurons evoked by injection of TNF alone. Therefore, it was concluded that tumor necrosis factor-alpha causes gastrointestinal stasis by removing cholinergic excitation to the stomach. TNF alters vago-vagal reflexes by acting directly on neurons at the level of the dorsal vagal complex in the medullary brainstem.
Advisors/Committee Members: Bishop, Georgia A.
Keywords: NST; TNF; VAGAL; c-Fos; NEURONS; gastric; DMN
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9.
Gensel, John Carib.
Modeling and treatment of rat cervical spinal cord injury.
Degree: PhD, Neuroscience, 2007, Ohio State University
► Spinal cord injury (SCI) is a long lasting, debilitating condition with no…
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▼ 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, but only topiramate was found to protect neurons after SCI. More small and medium sized neurons were spared in the topiramate treated group compared to control 48 hours after SCI. NBQX treatment increased white matter sparing compared to control, but resulted in worse motor function compared to topiramate. Both treatments were only effective when applied after moderate-severe injury and not after mild injury.
Advisors/Committee Members: Bresnahan, Jacqueline C.
Subjects: Biology, Neuroscience
Keywords: spinal cord injury; cervical; contusion; model; gray matter; neuroprotective; grooming; topiramate; minocycline; methylprednisolone; unilateral; hemicontusion; neuroprotection; translational research; excitotoxicity; glutamate; AMPA; excitotoxic; rat
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10.
Ghai, Kanika.
Notch-Signaling in Retinal Regeneration and Müller glial Plasticity.
Degree: PhD, Neuroscience, 2009, Ohio State University
► Eye diseases such as blindness, age-related macular degeneration (AMD) and glaucoma are…
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▼ Eye diseases such as blindness, age-related macular degeneration (AMD) and glaucoma are highly prevalent in a rapidly aging population. These sight-threatening diseases all involve the progressive loss of cells from the retina, light-sensing neural tissue in the eye. Thus, developing strategies to replace dying retinal cells or prolonging neuronal survival is essential to preserving sight. This dissertation elucidates the properties of the primary support cell in the chicken retina, known as the Müller glia, which have been shown to possess stem-cell like properties, with the potential to form new neurons in damaged retinas. However, the mechanisms that govern this stem-cell like ability are less well understood. Here, we analyze the role of one of the key developmental processes, i.e., the Notch-Signaling Pathway in regulating proliferative, neuroprotective and regenerative properties of Müller glia that bestow them with this plasticity. The first part of this dissertation, we find that inhibition of γ-secretase activity associated with Notch-signaling and silencing of the bHLH effectors Hes1 and Hes5 have distinctly different outcomes on cell-fate specification of cultured chicken retinal progenitors. Further, our studies reveal that Notch-signaling plays a limited but important role during retinal regeneration. Components of the Notch-signaling pathways are transiently upregulated in proliferating Müller glia after damage in a chicken retina and blocking Notch after damage enhances some neural regeneration from glial-derived progenitors. In the second part of this dissertation, we analyze the role of the Notch pathway in the postnatal retina in the absence of damage. We find that components of the Notch-signaling pathway are expressed at low levels in most Müller glia in undamaged retina. Further, Notch-signaling influences the phenotype and function of Müller glia in the mature retina; low levels of Notch-signaling diminish the neuroprotective capacity of Müller glia, but are required to maintain their ability to become progenitor-like cells. We also find that there is cross-talk between Notch and MAPK pathways – FGF2, a secreted protein that activates the MAPK pathway, also induces the expression of Notch pathway genes. Our data indicate that Notch-signaling is down-stream of and is required for FGF2/MAPK- signaling to drive the proliferation of Müller glia. The last part of this dissertation describes the patterning of the immature zone of cells present at the retinal margin, called the circumferential marginal zone (CMZ). Additionally, we describe the morphological and mechanistic properties of a unique subset of interneurons we discovered in the retina, called the serotonin-accumulating bipolar cells. Our data indicates that these cells perform glial functions by actively transporting and degrading serotonin that is synthesized in neighboring amacrine cells. Taken together, the data presented in this dissertation furthers understanding of Müller glial plasticity. This information could be applied to stimulating neural regeneration, harnessing Müller glia as a localized source of stem cells, developing therapies targeted to glia and countering neuronal death in eye diseases. Additionally, our studies on serotonin-accumulating bipolar cells have implications for understanding the mechanisms of melatonin biosynthesis and retinal circadian rhythms, dysfunctions of which lead to photoreceptor degeneration and loss of vision.
Advisors/Committee Members: Fischer, Dr. Andy.
Subjects: Biology; Molecular biology; Ophthalmology
Keywords: retina; Müller glia; plasticity; regeneration; serotonin; bipolar cells; CMZ; proliferation; cell death
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11.
Hill, Caitlin E.
Contusive Spinal Cord Injury: Endogenous Responses of Descending Systems and Effects of Acute Transplantion of Glial Restricted Precursor Cells.
Degree: PhD, Neuroscience, 2002, Ohio State University
► Contusive spinal cord injury (SCI) in the rat mimics many of the…
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▼ Contusive spinal cord injury (SCI) in the rat mimics many of the aspects of human injury. It provides a good model for examination of endogenous responses to injury, and alterations that occur following therapeutic manipulations. Damage to the spinal cord, results in cell death at the injury site and the development of a chronic cystic lesion cavity, separated into chambers by tissue bridges, and from the spared white matter by a glial and molecular scar. Transplantation of stem cells and immature cells can ameliorate tissue damage, induce axonal regeneration, and improve locomotion. However, unless these cells are pushed down a neuronal lineage, the majority of cells become glia; suggesting that the alterations observed are potentially glially mediated. Glial restricted precursor (GRP) cells-a precursor cell population restricted to oligodendrocyte and astrocyte lineages-offer a novel way to examine the effects of glial cells after injury. The studies performed within, examine the endogenous responses of decending axons from the cortex and brainstem to SCI, and how they respond to acute transplantation of GRP cells. The survival and differentiation of GRP cells, and their ability to modulate the development of the lesion is also examined. GRP cells isolated from a transgenic rat that ubiquitously expresses human placental alkaline phosphatase (hPLAP) were used to specifically detect transplanted cells. Following transplantation, GRP cells retained their differentiation potential. Transplanted GRP cells altered the lesion environment, reducing astrocytic scarring and the expression of inhibitory proteoglycans. After SCI descending systems from the cortex and brainstem initiated endogenous sprouting responses after injury, but these responses were limited and delayed. Transplanted GRP cells supported modest axonal growth from corticospinal tract (CST) and raphespinal axons, and altered the morphology of CST axons towards that of growth cones, suggesting that GRP cells can support axonal growth, however, a longer time course may be required for more extensive growth. The recent isolation and characterization of GRP cells means that many questions remain to be answered about this precursor cell population. The results of this initial qualitative study indicate that GRP cells may be useful in repairing the spinal cord after injury.
Advisors/Committee Members: Bresnahan, Prof. Jacqueline.
Keywords: Spinal cord injury; contusion; precursor cells; GRP cells; Glial restricted precursor cells; regeneration; corticospinal tract; reticulospinal tract; serotonin; proteoglycans; CSPG; histology; gliosis; astrocytes; anterograde tracer; endogenous repair
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12.
Hoschouer, Emily Laurel.
Evaluating Sensory Abnormalities in Mice after Spinal Cord Injury and the Anatomical Evidence for Likely Mechanisms.
Degree: PhD, Neuroscience, 2010, Ohio State University
► Spinal cord injury (SCI) results in devastating losses in motor and sensory…
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▼ Spinal cord injury (SCI) results in devastating losses in motor and sensory function. In addition to the loss of function, a large proportion of individuals with SCI also suffer from neuropathic pain, dysesthesias, and paresthesias, which have more detrimental impact on quality of life. Several animal models of neuropathic pain, including those specific to SCI, have been developed, leading to a much broader understanding of chronic pain mechanisms. However, the potential of transgenic mice to contribute to the understanding of the mechanisms of development of chronic pain after SCI remains largely untapped, in part due to the lack of sensory measures applicable to and characterized in spinal cord injured mice. The overarching goal of this research was to document practical assessments of mouse sensory dysfunction, including evoked and spontaneous dysfunctions, to characterize aberrant responses, and to evaluate the likely anatomical substrates of neuropathic pain. In the first set of experiments, we hypothesized that the L1 cell adhesion molecule would contribute to sensory fiber sprouting and therefore altered sensory responses after SCI. To test this, we compared sensory responses and histology in L1 knockout (KO) and wild-type (WT) littermates after SCI. We found that KO and WT mice developed hypersensitivity to thermal stimuli after SCI, but that KO mice recovered normal responsiveness by 4 weeks post-injury. Anatomically, L1 KO mice had diminished sprouting of small-diameter nociceptive fibers, and increased protein kinase C γ (PKCγ) expression in the dorsal horn of the lumbar spinal cord. These results suggest that L1 is necessary for the maintenance of thermal hyperalgesia, and that it acts through sprouting and PKCγ-related mechanisms. For the second set of experiments, we hypothesized that patterns of sensory dysfunction in mice after SCI would depend on lesion severity, testing modality, and body area tested. We found that in the hind paws, hypersensitivity to thermal stimuli developed independent of injury severity. In contrast, hind paw mechanical sensitivity decreased after mild, moderate, or complete transection injuries; but after severe contusion with limited axonal sparing, there was enhanced sensitivity to mechanical stimuli. On the dorsal trunk, mechanical and pin prick testing demonstrated diminished sensitivity at and below the injury level, while responses above the level of the injury were largely unchanged. In the next set of experiments, we tested the hypothesis that sensory stimulation prior to SCI could induce overgrooming, an indication of neuropathic pain or dysesthesia after SCI. We found that both mechanical and nociceptive stimulation were capable of producing pathological overgrooming when combined with SCI. Finally, we analyzed anatomical evidence of likely pain substrates after SCI. We hypothesized that small diameter afferent sprouting and PKCγ upregulation would correspond with the thermal hyper-responsiveness evident at all injury severities, while microglia and astrocytes would increase corresponding with mechanical allodynia, and would only be present in the lumbar spinal cord after the most severe injuries. We found that small-diameter afferent sprouting and increased microglial presence corresponded with mechanical sensitivity, while astrocyte activation and PKCγ upregulation had no relation to thermal hyper-responsiveness or mechanical sensitivity.
Advisors/Committee Members: Jakeman, Lyn B.
Subjects: Neurology
Keywords: allodynia; hyperalgesia; neuropathic pain; sensory testing; mice; spinal cord injury
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13.
Jones, T. Bucky.
The effects of T-lymphocytes on secondary neurodegeneration and recovery of function after experimental spinal contusion injury.
Degree: PhD, Neuroscience, 2004, Ohio State University
► Spinal cord injury (SCI) disrupts nerve fibers carrying information between the brain…
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▼ Spinal cord injury (SCI) disrupts nerve fibers carrying information between the brain and the body. The initial trauma activates secondary degenerative processes that continue for days to weeks, causing further loss of neurons and glia and expanding the region of tissue damage. The protracted nature of secondary injury provides an opportunity to intervene and rescue cells that may otherwise undergo secondary cell death. Cells of the peripheral immune system, including T-lymphocytes reactive with myelin proteins, infiltrate the injured spinal cord and contribute to post-injury sequelae. These cells can cause demyelination and axonal transection in the CNS yet also produce neurotrophic factors that may promote neuronal survival after injury. To clarify the role of myelin-reactive T-cells in SCI, transgenic (Tg) mice with a T-cell repertoire biased toward recognition of myelin proteins, were evaluated for their ability to recover from spinal contusion injury. Recovery of overground locomotor ability and reflex function were significantly impaired in Tg mice compared with non-Tg littermates. Motor deficits were associated with reduced myelin sparing at the impact site and exacerbation of neuropathology over the rostro-caudal spinal cord. Because the kinetics and magnitude of the T-cell response to SCI differ between mice and rats, the myelin-reactive T-cell response to SCI in Lewis rats was boosted by immunization with myelin basic protein (MBP). Similar to Tg mice, immunized rats demonstrated enhanced functional deficits and exacerbated neuropathology. Interestingly, rats that were immunized with adjuvants in the absence of myelin antigen demonstrated enhanced recovery of hind limb function compared with PBS-treated controls. These results raise the possibility that other T-cells, responsive to an undefined constituent of the adjuvant confer benefit to the injured spinal cord. In conclusion, the data suggest that myelin-reactive T-cells that infiltrate the injured spinal cord contribute to secondary neurodegeneration and loss of function. However, T-cells of other antigen specificities, as yet undefined, could confer benefit in the injured spinal cord. Thus, effective neuroprotection may be achieved by limiting deleterious T-cell functions, for example by inhibiting the autoimmune response to SCI, while promoting reparative functions of T-cells in the environment of the injured spinal cord.
Advisors/Committee Members: Popovich, Phillip G.
Keywords: spinal cord injury; T-lymphocytes; neuroinflammation; secondary injury
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14.
Karelina, Ekaterina.
MECHANISMS OF SOCIAL NEUROPROTECTION AFTER CEREBRAL ISCHEMIA.
Degree: PhD, Neuroscience, 2010, Ohio State University
► Social isolation has long-term physiological and psychological consequences. The benefits associated with…
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▼ Social isolation has long-term physiological and psychological consequences. The benefits associated with social support are well described in cerebrovascular disease patients; however, the mechanisms by which social interactions influence disease outcome are unknown. The present body of work examined the effects of social interaction on stroke outcome in mice. The goals of this dissertation are to describe the phenomenon and consequences of social interaction-mediated neuroprotection in a mouse model of cerebral ischemia, as well as to describe a neuroendocrine basis by which social interactions may mediate stroke-induced neuroinflammation and functional outcome. Social housing conditions influence measures of stroke outcome in a mouse model of transient focal cerebral ischemia. Male mice housed with an ovariectomized female have attenuated ischemic injury, improved post-stroke survival rate and enhanced functional recovery. Importantly, this neuroprotective effect requires the physical contact component of social interaction, as removal of this component using a barrier (while preserving all other sensory stimuli associated with social interactions), eliminates both the neuroprotection and locomotor recovery in socially housed mice. Additionally, the reduction in ischemic damage in socially housed mice is accompanied by an anti-inflammatory response, characterized by altered central and systemic markers of inflammation. Specifically, interleukin-6, a cytokine that is both modified by social interactions and predicts stroke outcome, is differentially regulated in socially housed and isolated mice, suggesting that social housing may alter the trajectory of ischemia outcome in part by attenuation of inflammation. Finally, the role of oxytocin, a neuropeptide released during social contact, was assessed as a potential mediator of social neuroprotection. Administration of oxytocin to socially isolated animals reproduces the neuroprotection conferred by social housing, and blockade of oxytocin action via administration of an oxytocin receptor antagonist blocks these effects in socially housed animals. Importantly, oxytocin receptors on microglia, critical immune effectors in ischemia, appear to modulate microglia activation in response to an inflammatory stimulus. These findings support the hypothesis that oxytocin is neuroprotective against physiological and behavioral consequences of cerebral ischemia, and provide insight into the mechanism by which social influences impact stroke outcome.
Advisors/Committee Members: DeVries, Courtney.
Subjects: Neurology
Keywords: social interaction; stroke; oxytocin
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15.
Lee, Bo Young.
Signaling events in activity dependent neuroprotection, neurodegeneration, and synaptic plasticity.
Degree: PhD, Neuroscience, 2007, Ohio State University
► CREB-(cAMP response element binding protein) dependent gene transcription within the context of…
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▼ CREB-(cAMP response element binding protein) dependent gene transcription within the context of physiological and patho-physiological conditions is a central focus of my dissertation. CREB is a transcription factor that plays a role in many activity-dependent neuronal processes, such as learning and memory, neuroprotection and neurotransmission. Initially, in chapter 1, I examined cellular and molecular signaling events that couple excitotoxic and nontoxic levels of NMDA receptor stimulation to activation of the CREB/cAMP response element (CRE) pathway in cultured cortical neurons. In this study, I report that the temporal regulation of CREB activation is an essential cue that controls the efficacy of NMDA as a regulator of CRE-mediated transcription. In chapter 2, I examined the role of the CREB/CRE-dependent signaling pathway under pathological conditions elicited by status epilepticus (SE). First, to characterize how seizure activity regulates the activation state of the CREB/CRE pathway in both glia and neurons of the hippocampus. I found that SE triggers two waves of CREB-mediated gene expression, a transient wave in neurons and a long-lasting wave in reactive glial cells, and that CREB couples SE to COX-2 expression. In chapter 3, I examined the role of the CREB/CRE pathway as a signaling intermediate that couples a BDNF-evoked preconditioning stimulus to protection against SE-induced neuronal death in the striatum. I found that SE evoked cell deaths were dramatically attenuated by BDNF infusion directly into striatum 24 hr prior to SE. I found MAPK-CREB transcription pathway is essential for BDNF mediated neuroprotection and one of CREB target genes, PGC-1 alpha may play a role in this BDNF mediated neuroprotection through CREB transcription signaling pathway. In chapter 4, I redirected my focus on the analysis of signaling pathways that couple excitatory neurotransmission to entrainment of the circadian clock. The mammalian circadian pacemaker located in the suprachiasmatic nuclei (SCN) drives a vast array of biochemical and physiological processes with 24 hr periodicity. I examined the role of protein kinase C (PKC) in clock entrainment. I found that PKC may influence clock entrainment via posttranslational mechanisms that influence clock protein stability.
Advisors/Committee Members: Obrietan, Karl.
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16.
Lim, Jeong-Eun.
Regulatory genetic variants in mental illness: focus on serotonin-related genes.
Degree: PhD, Neuroscience, 2007, Ohio State University
► Genes encoding the serotonin transporter (SERT) and tryptophan hydroxylase 2 (TPH2) were…
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▼ Genes encoding the serotonin transporter (SERT) and tryptophan hydroxylase 2 (TPH2) were the particular focus of my studies since disruption of brain serotonergic systems has been implicated in a variety of mental illnesses, including major depression (MD), anxiety disorders, schizophrenia, alcoholism, drug abuse, aggression and suicidal behavior. Most of the serotonin in the brain is produced by serotonergic neurons located in the raphe nuclei of the pons and brain stem. To identify functional genetic variants that influence the mRNA expression, I measured expression of mRNA in an allele-specific manner in post-mortem human pons sections containing the dorsal and median raphe nuclei. Any difference in the expression of one allele over the other indicates the presence of cis-acting (i.e, local) elements that differentially affect transcription and/or mRNA processing and turnover. Using a marker SNP in the 3’ untranslated region of SERT mRNA, statistically significant differences in allelic mRNA levels were detected in nine out of 29 samples heterozygous for the marker SNP. While the allelic expression differences were relatively small (15–25%), they could nevertheless be physiologically relevant. In contrast to previous results, positive correlation was not observed between SERTLPR and allelic expression ratios, implying regulation of SERT mRNA is not dependent of SERTLPR. In TPH2, significant allelic expression imbalance (AEI) was detected ranging from 1.2 to 2.5-fold in 19 out of the 27 samples using two marker SNPs markers: rs7305115 (located in exon 7) and rs4290270 (located in exon 9), suggesting the existence of cis-acting polymorphisms that differentially affect TPH2 mRNA levels in pons. The minor A-allele yielded higher levels of TPH2 mRNA expression than the G-major allele. By genotyping twenty additional TPH2 SNPs, I identified a haplotype block comprising five tightly linked SNPs for which heterozygosity is highly correlated with AEI. My studies have demonstrated the utility of a novel genetic approach to finding functional polymorphisms in genes of interest. Widely applied, this method should increase the ability to demonstrate the association of specific genes with mental disorders and provide a mechanistic explanation for the role of these genes in the etiology of mental illness.
Advisors/Committee Members: Saffen, David.
Subjects: Biology, Neuroscience
Keywords: serotonin, serotonin transporter, tryptophan hydroxylase 2, allelic expression imbalance, raphe nuclei
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17.
McCarthy, Michael J.
Regulation of the endogenous opioid system by acute nicotine and nicotine withdrawal.
Degree: PhD, Neuroscience, 2004, Ohio State University
► Nicotine addiction emerges as a result of long-term plastic changes in the…
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▼ Nicotine addiction emerges as a result of long-term plastic changes in the brain including altered intracellular signaling, gene transcription and receptor function. The endogenous opioids may contribute to aspects of nicotine’s addictive psychopharmacological properties. Presently, the response to both acute nicotine and chronic nicotine withdrawal was evaluated with respect to effects on the regulation of opioid peptides, opioid receptor function and the signaling events that link these processes. Acute nicotine biphasically increased striatal dynorphin content with peaks at 1 hr and 18hr after injection. The mRNA for prodynorphin (PD), as well as the immediate early genes c-fos, c-jun and egr-1 was increased from 30 min to 12 hr following acute injection. Increased p-CREB immunoreactivity and CREB-PD promoter binding was observed in the early stages after acute nicotine. Antagonist pre-treatments revealed that dopamine and muscarinic receptors contribute to the 1 hr and 18 hr dynorphin increases after acute nicotine. For withdrawal studies, mice were treated with nicotine four times daily for 14 days and killed at 0-96 hr after the last injection. During nicotine withdrawal, PD mRNA was increased in the striatum, whereas dynorphin was decreased for 72 hr. Analysis of CREB, adenylyl cyclase and the PD promoter suggest these are coordinated in an atypical manner, resulting in decreased adenylyl cyclase activity concomitant to an increased CREB activity. Preliminary data suggesting a role for the transcriptional repressor protein, DREAM in this interaction is presented. Analysis of the delta (DOR) and kappa (KOR) opioid receptors was assessed for altered function during nicotine withdrawal. While changes in DOR and KOR binding were subtle, evidence for DOR and KOR uncoupling from intracellular signaling pathways was observed. Data suggest that regulation of G-proteins and adenylyl cyclase during nicotine withdrawal may contribute to these functional alterations in the DOR and KOR.Taken together, nicotine engages signaling mechanisms that regulate PD transcription. Perturbations of this interaction may disrupt dynorphin release in the striatum during nicotine withdrawal. Alterations in DOR and KOR function were observed during withdrawal. These findings together provide a substrate by which the endogenous opioid system could mediate aspects of the nicotine withdrawal syndrome.
Advisors/Committee Members: Neff, Maria H.
Subjects: Biology, Neuroscience
Keywords: dynorphin; opioid; CREB; DREAM; striatum; nucleus accumbens; caudate-putamen; kappa opioid receptor; delta opioid receptor; nicotine withdrawal; immediate early gene; dopamine; muscarinic; adenylyl cyclase
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18.
Miller, Brandon Andrew.
The effects of excitotoxicity and microglial activation on oligodendrocyte survival.
Degree: PhD, Neuroscience, 2007, Ohio State University
► The nervous system transmits information over long distances by action potentials carried…
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▼ The nervous system transmits information over long distances by action potentials carried by neurons. In both the central and peripheral nervous system, neurons are insulated by myelin which improves the conduction of action potentials. In the peripheral nervous system, myelin is produced by Schwann cells. Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS). Both mature OLs and oligodendrocyte progenitor cells (OPCs) are lost in CNS disease and injury. Two contributing factors to OL and OPC cell death are inflammation and excitotoxicity. These studies were designed to better understand how OLs and OPCs respond to excitotoxicity and inflammatory stimuli. The glutamate receptor agonist kainic acid (KA) was used to induce excitotoxic cell death in OLs from optic nerve. We found that the pro-inflammatory cytokine tumor necrosis factor-alpha increased the susceptibility of optic nerve OLs to KA. Subsequent experiments tested the response of cortical OLs at different developmental stages to KA and revealed that mature cortical OLs were also vulnerable to KA-induced excitotoxicity. In the final set of experiments, we used combined culture of OLs or OPCs and microglia (MG) to study the effects of activated MG on OPC and OL survival. We found that MG activated with lipopolysaccharide induced OPC cell death, but MG, regardless of activation state, protected mature OLs from apoptotic cell death. We also observed that MG cell death occurs as a consequence of activation. Taken together, these studies demonstrate that both excitotoxicity and inflammatory stimuli can induce OL and OPC death but that MG can also support the survival of OLs.
Advisors/Committee Members: Popovich, Phillip G.
Keywords: oligodendrocyte, microglia, excitotoxicity, inflammation
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19.
Neigh, Gretchen N.
Neural and immune changes that occur following psychological and physical stressors.
Degree: PhD, Neuroscience, 2004, Ohio State University
► Exposure to stressors can influence the onset and progression of both physical…
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▼ Exposure to stressors can influence the onset and progression of both physical and mental disease, and the effects of stressors on physiology and behavior are, at least in part, mediated by the hypothalamic pituitary adrenal (HPA) axis. The hippocampus is a component of the HPA axis that is susceptible to stressor-induced damage and alterations in the cytoarchitecture of the hippocampus can alter HPA axis function and subsequently immune function. The first series of experiments examined the role of stressor-induced energetic shortage, as signaled by increased concentrations of glucocorticoids, in suppression of immune function and neurogenesis. Mice supplemented with pyruvate, a potent producer of cellular energy, had a lower cumulative exposure to elevated concentrations of glucocorticoids and did not exhibit the restraint-induced suppression of immune function that was evident in restrained mice that did not receive pyruvate supplementation. Pyruvate was not protective against stressor-induced changes in neurogenesis. However, exposure to stressors increased the proportion of proliferating astrocytes in the hippocampus, as compared to neurons. The second set of experiments examined the effects of damage to the hippocampus, by cardiac arrest and resuscitation, on behavior as well as immune function. Cardiac arrest and resuscitation increased anxiety-like behavior, decreased social interaction, and impaired spatial memory. In addition, prior exposure to a restraint stressor augmented post-arrest anxiety-like behavior. The behavioral deficits observed were attributed to hippocampal damage, a reduction in dendritic spines, and an increase in the reactive microglia in the hippocampus. Furthermore, hippocampal damage following cardiac arrest and resuscitation altered HPA axis activity and augmented cell-mediated immune function as compared to mice that were exposed to cardiac arrest and resuscitation but did not sustain brain damage. In addition, the relationship between hippocampal damage and immune function appeared to be bidirectional, as survival following cardiac arrest and resuscitation was compromised in mice that were immunized with a novel protein prior to the cardiac arrest procedure. In conclusion, the work described in this dissertation adds to the body of literature that describes the relationship between the HPA axis and the immune system.
Advisors/Committee Members: Nelson, Randy J.
Keywords: stress; hippocampus; HPA axis; cardiac arrest; psychoneuroimmunology; corticosterone; housing; pyruvate
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20.
Nelson, Christopher L.
Prefrontal cortical modulation of posterior parietal acetylcholine release: a study of glutamatergic and cholinergic mechanisms.
Degree: PhD, Neuroscience, 2004, Ohio State University
► Attentional processing is a crucial early component of cognitive functions and capacities.…
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▼ Attentional processing is a crucial early component of cognitive functions and capacities. The cognitive consequences of abnormal regulation of attentional processing are evident in neuropsychiatric diseases, including Alzheimers disease and schizophrenia, where subjects are characterized by attentional and cognitive impairments. Attention is subject to top-down regulation by areas of the cortex (prefrontal cortex [PFC]) associated with knowledge-driven and executive functions, leading to the processing of selected target stimuli, and filtering of others, for further cognitive processing. This top-down regulation involves modification of input processing in other cortical areas, such as the posterior parietal cortex (PPC). As cortical cholinergic inputs, originating from the basal forebrain cholinergic system (BFCS) have been demonstrated to mediate important aspects of attentional processing, and as these neurons are innervated by prefrontal outputs, a set of experiments investigated the pharmacological interactions between the BFCS and the PFC and PPC. Dual probe in vivo microdialysis was utilized for a series of experiments designed to demonstrate glutamatergic and cholinergic actions between the PFC and PPC, either through the BFCS and/or cortico-cortical interactions. The first set of experiments demonstrated a uni-directional increase in PFC and PPC acetylcholine (ACh) efflux following AMPA administration to the PFC, antagonized by co-administration of the AMPA receptor antagonist DNQX. The second set of experiments demonstrated that nicotine and the mixed cholinergic agonist carbachol both produced increases in local (PFC) ACh efflux, but only carbachol increased PPC ACh efflux. This PPC effect of carbachol was uni-directional, and attenuated by co-administration of a muscarinic antagonist (atropine), and also moderately attenuated by DNQX and the nicotinic antagonist mecamylamine. Collectively, these studies demonstrate the capacity of the PFC to regulate ACh efflux in distal cortical areas (PPC) via glutamatergic and cholinergic mechanisms, and that this is a uni-directional effect. These studies begin to elucidate neurochemical mechanisms underlying the top-down regulation of attentional functions, and will contribute to an understanding of the consequences of PFC dysfunction on attentional processing. Attentional processing is a crucial early component of cognitive functions and capacities. The cognitive consequences of abnormal regulation of attentional processing are evident in neuropsychiatric diseases, including Alzheimers disease and schizophrenia, where subjects are characterized by attentional and cognitive impairments. Attention is subject to top-down regulation by areas of the cortex (prefrontal cortex [PFC]) associated with knowledge-driven and executive functions, leading to the processing of selected target stimuli, and filtering of others, for further cognitive processing. This top-down regulation involves modification of input processing in other cortical areas, such as the posterior parietal cortex (PPC). As cortical cholinergic inputs, originating from the basal forebrain cholinergic system (BFCS) have been demonstrated to mediate important aspects of attentional processing, and as these neurons are innervated by prefrontal outputs, a set of experiments investigated the pharmacological interactions between the BFCS and the PFC and PPC. Dual probe in vivo microdialysis was utilized for a series of experiments designed to demonstrate glutamatergic and cholinergic actions between the PFC and PPC, either through the BFCS and/or cortico-cortical interactions. The first set of experiments demonstrated a uni-directional increase in PFC and PPC acetylcholine (ACh) efflux following AMPA administration to the PFC, antagonized by co-administration of the AMPA receptor antagonist DNQX. The second set of experiments demonstrated that nicotine and the mixed cholinergic agonist carbachol both produced increases in local (PFC) ACh efflux, but only carbachol increased PPC ACh efflux. This PPC effect of carbachol was uni-directional, and attenuated by co-administration of a muscarinic antagonist (atropine), and also moderately attenuated by DNQX and the nicotinic antagonist mecamylamine. Collectively, these studies demonstrate the capacity of the PFC to regulate ACh efflux in distal cortical areas (PPC) via glutamatergic and cholinergic mechanisms, and that this is a uni-directional effect. These studies begin to elucidate neurochemical mechanisms underlying the top-down regulation of attentional functions, and will contribute to an understanding of the consequences of PFC dysfunction on attentional processing.
Advisors/Committee Members: Bruno, John P.
Subjects: Biology, Neuroscience
Keywords: acetylcholine; attention; glutamate; microdialysis; prefrontal cortex; basal forebrain; posterior parietal cortex
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21.
Nout, Yvette Stephanie.
Novel method to study autonomic nervous system function and effects of transplantation of precursor cells on recovery following spinal cord contusion injury.
Degree: PhD, Neuroscience, 2006, Ohio State University
► Disruption of bladder and sexual function are major complications following spinal cord…
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▼ Disruption of bladder and sexual function are major complications following spinal cord injury (SCI). To investigate these behaviors in a rat model of SCI, we developed a method to monitor micturition and erectile events by telemetry. Pressure monitoring has been described for recording penile erections in awake rats and involves placement of a catheter into the corpus cavernosum of the penis. We developed a variation on this technique involving pressure monitoring within the bulb of the corpus spongiosum penis (CSP). Using this technique we can record both erectile and micturition events. This technique was validated in 10 male rats and we demonstrated that telemetric recording of CSP pressure provides a quantitative and qualitative assessment of both penile erections and micturitions. Subsequently we monitored CSP pressures in 7 male rats subjected to SCI. We demonstrated that monitoring of CSP pressure in conscious rats is a valuable and reliable method for assessing recovery of autonomic function. Although recovery of micturition occurs in rats following incomplete SCI, recovery is limited and voiding remains inefficient. Moreover, changes consistent with spasticity and/or hyperreflexia were determined through waveform analysis. To repair the injured spinal cord cell transplant strategies are being developed since they appear to reduce secondary damage and promote regeneration. We examined the effect of transplanting glial restricted precursor (GRP) cells and elevating cyclic adenosine monophosphate (cAMP) concentrations on recovery of autonomic functions following SCI in 53 rats. When compared to an operated control group no beneficial effects of this cell transplantation technique were found with regards to behavioral outcomes. Histopathological analysis showed survival, migration, and differentiation of GRP cells within the spinal cord. Transplanted GRP cells were well integrated in the spared host tissue and animals that had received GRP cells had more tissue throughout the lesion region and at the lesion center. Although elevation of cAMP appeared to reduce the area of spinal cord occupied by graft tissue, cAMP favored differentiation of GRP cells into oligodendrocytes. The transplantation technique used here did not affect serotonergic input to the neurons in the lumbosacral spinal cord that regulate micturition and sexual behavior.
Advisors/Committee Members: Bresnahan, Jacqueline C.
Subjects: Biology, Neuroscience
Keywords: spinal cord injury; autonomic nervous system; micturition; urinary function; erection; sexual function; cAMP; transplantation; precursor cells
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22.
Peterson, John Wesley.
Inflammation and neuronal pathology in multiple sclerosis.
Degree: PhD, Neuroscience, 2003, Ohio State University
► Our concept of multiple sclerosis (MS) has expanded from an inflammatory demyelinating…
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▼ Our concept of multiple sclerosis (MS) has expanded from an inflammatory demyelinating disease of the central nervous system (CNS) to one incorporating the concept of MS having an inflammatory mediated neurodegenerative component causing extensive neuronal damage resulting in permanent neurological disability. The majority (80-90%) of typical MS patients have a relapsing-remitting (RR) disease course. Early in the disease, RR-MS patients often benefit from anti-inflammatory therapeutics and recover neurological function with resolution of inflammation and edema. Eventually, many patients enter the secondary progressive phase of the disease characterized by increasing neurological disability, minimal recovery and poor efficacy of anti-inflammatory therapeutics. Why is the progression of RR-MS biphasic? Demyelination and inflammation certainly cause reversible neurological disability and may cause permanent neurological disability in MS. However, neurological decline doesn’t always associate with inflammatory lesions in MS and recent evidence indicates chronically demyelinated axons are capable of conducting signals suggesting irreversible neurological disability is due to additional mechanisms. We identified significant amounts of axonal transection in WM lesions from MS patients with short disease duration, indicating axonal transection occurs from disease onset. Additionally, we identified numerous cortical lesions in MS brains containing extensive neuronal pathology characterized by transected axons, transected dendrites, and apoptotic neurons. Widespread cortical pathology in MS brains identifies another component in the physiopathogenesis of MS and further implicates neuronal pathology in the development of irreversible neurological disabilities. We along with others suggest recovery early in the disease from neurological disability is due to resolution of inflammation and edema, remyelination, and the capacity of the CNS to compensate for neuronal injury. Eventually, accumulation of neuronal damage surpasses the capability of the CNS to compensate resulting in permanent neurological disability. Both inflammation and demyelination were associated with the neuronal pathology identified in the MS lesions. Identification of VCAM-1 on a subset of microglia at lesion edges contacting oligodendrocytes further supports the hypothesis that microglia target oligodendrocytes in MS brains and cause oligodendrocyte death and demyelination. Further characterization of MS lesions using microarray analysis was done to identify pathways activated or inhibited during lesion formation in an effort to better understand MS pathogenesis. Our concept of multiple sclerosis (MS) has expanded from an inflammatory demyelinating disease of the central nervous system (CNS) to one incorporating the concept of MS having an inflammatory mediated neurodegenerative component causing extensive neuronal damage resulting in permanent neurological disability. The majority (80-90%) of typical MS patients have a relapsing-remitting (RR) disease course. Early in the disease, RR-MS patients often benefit from anti-inflammatory therapeutics and recover neurological function with resolution of inflammation and edema. Eventually, many patients enter the secondary progressive phase of the disease characterized by increasing neurological disability, minimal recovery and poor efficacy of anti-inflammatory therapeutics. Why is the progression of RR-MS biphasic? Demyelination and inflammation certainly cause reversible neurological disability and may cause permanent neurological disability in MS. However, neurological decline doesn’t always associate with inflammatory lesions in MS and recent evidence indicates chronically demyelinated axons are capable of conducting signals suggesting irreversible neurological disability is due to additional mechanisms. We identified significant amounts of axonal transection in WM lesions from MS patients with short disease duration, indicating axonal transection occurs from disease onset. Additionally, we identified numerous cortical lesions in MS brains containing extensive neuronal pathology characterized by transected axons, transected dendrites, and apoptotic neurons. Widespread cortical pathology in MS brains identifies another component in the physiopathogenesis of MS and further implicates neuronal pathology in the development of irreversible neurological disabilities. We along with others suggest recovery early in the disease from neurological disability is due to resolution of inflammation and edema, remyelination, and the capacity of the CNS to compensate for neuronal injury. Eventually, accumulation of neuronal damage surpasses the capability of the CNS to compensate resulting in permanent neurological disability. Both inflammation and demyelination were associated with the neuronal pathology identified in the MS lesions. Identification of VCAM-1 on a subset of microglia at lesion edges contacting oligodendrocytes further supports the hypothesis that microglia target oligodendrocytes in MS brains and cause oligodendrocyte death and demyelination. Further characterization of MS lesions using microarray analysis was done to identify pathways activated or inhibited during lesion formation in an effort to better understand MS pathogenesis.
Advisors/Committee Members: Beattie, Michael S.
Keywords: Multiple sclerosis; inflammation; demyelination; axonal transection; dendritic transection; neuronal apoptosis; neuronal pathology; microarray; gene chips; gene expression analysis
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23.
Pyter, Leah M.
Seasonal plasticity of physiological systems, brain, and behavior.
Degree: PhD, Neuroscience, 2006, Ohio State University
► Seasonal adaptations have evolved in animals and are believed to promote survival…
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▼ Seasonal adaptations have evolved in animals and are believed to promote survival and reproduction through yearly changes in the environment. These seasonal responses are physiological, morphological, and behavioral and are coordinated by day length (photoperiod) information in non-tropical rodents. In the laboratory, short days promote a winter phenotype, whereas long days promote a summer phenotype. This dissertation was designed to examine the effects of photoperiod on adult plasticity of physiology, brain, and behavior in male white-footed mice (Peromyscus leucopus) that may represent seasonal adaptations to the changing environment. Recent evidence suggests that significant plasticity occurs in adult systems including the central nervous system. The first studies examined the effects of photoperiod on angiogenesis in the periphery and the brain. Short days altered expression of angiogenesis genes in testes and brain and decreased cerebral blood flow compared with long days. The next set of studies was based on the finding that short days decreased brain mass and impaired spatial learning and memory compared with long days. The hippocampus is involved in spatial learning and memory and is one of the few brain regions associated with significant adult plasticity. Short days decreased hippocampal volume, altered hippocampal dendritic spine density, modified the effects of learning experience on neurogenesis, and dampened long-term potentiation compared with long days. Photoperiod alters concentrations of various hormones, some of which affect the hippocampal morphology and function. Testosterone reversed the short-day impairment of spatial learning and memory indirectly of hippocampal steroid receptors, but did not affect long-day performance. Corticosterone altered spatial learning and memory depending on photoperiod and duration of exposure and short days altered the hypothalamic-pituitary-adrenal axis compared with long days. The effects of photoperiod on the other brain region characterized by significant adult plasticity, the olfactory bulbs, and olfaction was examined. Neurogenesis increased in the caudal olfactory bulbs of short-day mice. Finally, I tested the effects of photoperiod and testosterone on depressive- or anxiety-like behaviors and observed few differences. Taken together, photoperiod appears to coordinate adult plasticity within the endocrine and nervous system that result in behavioral changes hypothesized to be adaptive to a seasonally-changing environment.
Advisors/Committee Members: Nelson, Randy J.
Keywords: photoperiod; seasonality; learning and memory; hippocampus; hypothalamic-pituitary-adrenal axis; hypothalamic-pituitary-gonadal axis; adult brain plasticity
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24.
Schonberg, David L.
Formation of New Oligodendrocytes in the Spinal Cord Following Macrophage Activation.
Degree: PhD, Neuroscience, 2009, Ohio State University
► Spinal cord injury (SCI) causes devastating functional deficits including upper and lower…
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▼ Spinal cord injury (SCI) causes devastating functional deficits including upper and lower limb paralysis, sexual dysfunction, and loss of bladder and bowel control. These problems arise when nerve fibers become damaged, thus preventing information from being transmitted between the brain and the rest of the body. As a result neurons, which process this information, and oligodendrocytes, which enhance conduction of these signals, become vulnerable and undergo cell death. Loss of these cells then leads to further neurological and functional problems. Therefore, replenishing these cell populations in the adult central nervous system (CNS) provides a potential therapy for ultimately improving the lives of injured patients. Cell renewal, particularly of the oligodendrocyte lineage, requires proliferation and maturation of immature cells that can develop into oligodendrocytes. This process can be influenced by activated macrophages, an immune cell that responds to brain and spinal cord pathologies. In addition to releasing a variety of immune-related molecules, macrophages secrete iron and the main iron storage protein, ferritin. Iron is of great importance since it is one of the most tightly regulated elements in the CNS. It can be toxic if its levels are too high yet at the same time is required for a number of critical functions. Iron is necessary for the synthesis of neurotransmitters (dopamine and norepinephrine), oligodendrocyte cell membrane constituents (lipids and cholesterol) and genetic material such as DNA. Since iron is also essential for proper cell cycle regulation, there is a critical need for a complete understanding of its metabolism during oligodendrocyte lineage progression. Activated macrophages can greatly influence iron balance and therefore indirectly affect oligodendrocyte function since these cells need iron for forming myelin wraps around nerve fibers. For instance, macrophages attempt to prevent the spread of bacterial infections by sequestering iron. In addition, activated macrophages can secrete ferritin-bound iron which can be safely internalized by oligodendrocytes and function to promote their survival. Thus, macrophages may contribute to oligodendrocyte survival and renewal by removing potentially toxic amounts of excess iron and then releasing iron in a controlled fashion when it is safely bound to ferritin. Determining the extent to which macrophages regulate iron availability and indirectly contribute to new oligodendrocyte formation is important given the essential role of iron in many physiological functions. Specifically, the experiments discussed in this dissertation reveal that macrophages, depending on how they are activated, can promote oligodendrogenesis and this phenomenom is due in part by iron accumulation in new oligodendrocytes. Furthermore, proving our hypothesis that the source of ferritin comes from activated macrophages which is required for promoting new oligodendrocyte formation would have enormous relevance in CNS diseases where oligodendrocytes are lost (e.g. SCI and multiple sclerosis).
Advisors/Committee Members: McTigue, Dana.
Subjects: Biology; Biomedical research
Keywords: oligodendrocyte, macrophage, iron, toll-like receptor, spinal cord injury, neurodegeneration
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25.
Shan, Xiu.
Investigation of mRNA oxidation in Alzheimer's disease.
Degree: PhD, Neuroscience, 2005, Ohio State University
► Oxidative modifications to vital cellular components have been described in association with…
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▼ Oxidative modifications to vital cellular components have been described in association with Alzheimer’s disease (AD). Cytoplasmic RNA oxidation is a prominent feature of vulnerable neurons in AD affected regions. However, the role of RNA oxidation in the pathogenesis of AD is unknown. This dissertation examined the magnitude of oxidized mRNAs in AD, identified oxidized mRNA species, and characterized the consequence of mRNA oxidation. An immunoprecipitation method was developed to isolate, characterize and quantify oxidized mRNAs in AD brain. The data showed that 30-70% of mRNAs are oxidized in frontal cortices of AD as compared to age-matched normal control. Identification of oxidized mRNA species revealed that mRNA oxidation in AD is not random but selective. Many identified oxidized mRNA species have been implicated in the pathogenesis of AD. Quantitative analysis revealed that some mRNA species are more susceptible to oxidative damage for which the relative amounts of oxidized transcripts reach 50-70%. To understand whether oxidation of mRNAs is involved in the pathogenesis of AD, the consequence of mRNA oxidation was studied using in vitro translation system and cell lines. mRNA oxidation may have deleterious effects by interfering with normal translational process or by a toxic gain-of-function. Examination of the protein expression from oxidized mRNAs revealed that mRNA oxidation causes a decrease of protein level and associated activity, which may result from the abnormal association of polyribosomes with oxidized mRNAs during the process of translation. Furthermore, we observed that microinjection of oxidized mRNAs into neuronal cells caused cell death, suggesting that increased mRNA oxidation could be lethal to cells. Studies in primary neuronal cultures revealed that RNA oxidation is an early event far preceding cell death induced by insults associated with AD. Neurons are specifically susceptible to RNA oxidation. Some mRNA species highly oxidized in AD brain are also present in oxidized mRNA pool of oxidative insult-treated cultures. A decrease of protein level was observed to oxidized mRNA species in cultures. Taken together, these studies indicate the possibility of oxidized mRNAs to interfere with physiological functions of cells and also implicate the potential contribution of RNA oxidation in the pathogenesis of AD.
Advisors/Committee Members: Lin, Chien-liang Glenn.
Keywords: Alzheimer's disease, neurodegenerative disease, neurodegeneration, oxidative stress, RNA oxidation, hydroxyl radical, 8-oxo-7,8-dihydroguanosine
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26.
Sun, Fang.
Investigation of the stimuli inducing delayed oligodendrocyte apoptosis after rat spinal cord contusion injury.
Degree: PhD, Neuroscience, 2006, Ohio State University
► After spinal cord injury (SCI), oligodendrocyte (OL) apoptosis was first revealed in…
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▼ After spinal cord injury (SCI), oligodendrocyte (OL) apoptosis was first revealed in a rat contusion model and later confirmed in human. A prominent feature of OL apoptosis is its association with long tract axon degeneration. The two events are often coextensive in areas distal to the lesion, which is seemingly unaffected by other components of the trauma. Thus, it has been postulated that OL apoptosis is a result of axon degeneration: apoptotic stimulus could either be the deprivation of axon derived signals, or the cytotoxic effect of microglial cells which are activated by the degenerating axons. However, the feasibility of the above notions has not been tested. In the present studies, we directly tested this issue by using a dorsal rhizotomy model. This model produced axon degeneration and microglial activation similar to that after SCI. However, OL apoptosis was not detected by a variety of indicators including pyknotic nuclei and cleaved caspase-3. Instead, rhizotomy induced OL progenitor cell (OPC) proliferation, new OL generation and OL cell number increase. In contrast to rhizotomy, OL apoptosis and cell loss were found in the area of SCI- produced axon degeneration, although OPC proliferation and new OL generation also existed. Taken together, these results highly suggest that OL apoptosis is not stimulated by axon degeneration per se but by trauma produced stimuli. Multiple lines of evidence suggest that oxidative stress could be one of these stimuli. We investigated this issue by examining the vulnerable OLs for the presence of oxidative damaged nucleic acids. Immnofluorescence and immunoprecipitation were performed by using an antibody recognizing both oxidized DNA and RNA. RNA oxidation but not DNA oxidation was significantly increased in the vulunerable OLs after SCI; neither of them was found after rhizotomy where OL apoptosis was absent. This series of studies provided strong evidence against a long held hypothesis. The impact produced by SCI is more profound than previously estimated; it induces significant degeneration and regeneration of the OL lineage cells even in areas distant to the lesion site. Degenerative drive of oxidative stress may have initiated OL apoptosis and cell loss.
Advisors/Committee Members: Beattie, Michael.
Keywords: spinal cord injury; axonal degeneration; oligodendrocyte; oligodendrocyte progenitor cell; apoptosis; oxidative stress
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27.
Tripathi, Richa Balmiki.
Oligodendrogenesis Following Experimental Spinal Cord Injury.
Degree: PhD, Neuroscience, 2008, Ohio State University
► Spinal cord injury (SCI) results in demyelination and loss of oligodendrocytes (OLs),…
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▼ Spinal cord injury (SCI) results in demyelination and loss of oligodendrocytes (OLs), the myelinating cells of the central nervous system (CNS). However, the adult CNS has a population of endogenous oligodendrocyte progenitor cells (OPC) identified by NG2 expression, which following proliferation, can give rise to myelinating oligodendrocytes. Previously, our laboratory showed that OPCs undergo enhanced proliferation following SCI. To better understand the role of OPCs following SCI and the possibility that they differentiate into oligodendrocytes, better characterization of the proliferation and fate of these OPCs after spinal trauma is needed. Also, since tissue adjacent to lesion cavities is exposed to different mediators compared to outlying spared tissue, we used a rat SCI model to compare NG2 cell proliferation and OL genesis adjacent to lesion cavities with that in spared tissue closer to meninges. NG2 cells proliferated throughout the first week post-injury and accumulated along lesion borders, especially within gray matter. By 3d post-injury (dpi), new OLs were detected throughout the cross-sections; between 4-7dpi, however, oligogenesis was restricted to lesion borders. New OLs derived from cells proliferating during 1-7dpi increased dramatically by 14dpi; most were located along lesion borders and in spared gray matter. Oligogenesis continued along lesion borders during the second week post-injury. Overall OL numbers were reduced at 3dpi in spared tissue, but rebounded to normal levels by 14dpi. Surprisingly, lesion borders maintained normal OL numbers at 3dpi, which then rose to exceed pre-injury levels at subsequently. These results indicate that oligogenesis after SCI leads to increased OL numbers and most new OLs are formed in regions of greatest NG2 cell proliferation. Thus, the adult spinal cord spontaneously develops a dynamic gliogenic zone along lesion borders. To elucidate mechanisms responsible for this post-traumatic oligodendrogenesis we chose examine ciliary neurotrophic factor (CNTF). Since CNTF, an astrocyte-derived growth factor, promotes OPC proliferation and differentiation into OLs and is upregulated in several CNS disorders, we hypothesized that CNTF expression is increased after SCI, especially in the regions of enhanced oligogenesis. Using a rat spinal contusion model, we quantified CNTF protein after SCI using Western blots. This revealed that CNTF expression continually rises between 5d and 28d post-injury (dpi). Using immunohistochemistry, we next determines CNTF distribution in tissue sections spanning the lesions at 3-28 dpi. CNTF was significantly increased in spared WM and GM at 5, 7, 14 and 28dpi compared to uninjured controls. At 7dpi, CNTF was equally high along lesion borders and outer spared tissue; by 28dpi CNTF was significantly elevated along lesion borders compared to spared tissue. Since CNTF can potentiate fibroblast growth factor-2 (FGF-2) expression which also promotes OPC proliferation; we quantified FGF-2+ve cells in the same regions as above. Indeed, significantly higher FGF-2+ve cells were noted along lesion borders and in spared GM suggesting that CNTF may promote FGF-2 expression in these regions. Since CNTF is upregulated in regions of prominent oligogenesis, CNTF may play a direct and/or indirect role in OL replacement after SCI. Collectively, these data elucidate a potential previously un-appreciated mechanism for CNS endogenous repair.
Advisors/Committee Members: McTigue, Dana.
Subjects: Biomedical research; Cellular biology; Molecular biology; Pathology
Keywords: oligodendrocyte, progenitor, NG2, CNTF, FGF, spinal cord injury
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28.
Venugopal, Sharmila.
Role of inhibition and hyperpolarization-activated membrane properties in a lick/gape central pattern generator.
Degree: PhD, Neuroscience, 2008, Ohio State University
► The interplay between intrinsic and synaptic properties is an important determinantof the…
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▼ The interplay between intrinsic and synaptic properties is an important determinantof the outputs of a central pattern generating network (CPG). The studies presented in this thesis are focused towards understanding the intrinsic and synaptic mechanisms underlying a brainstem central pattern generator, orchestrating taste-induced ingestion and rejection responses. A combination of computational and mathematical modeling with whole cell electrophysiology are used for these studies. Using mathematical and computational methods, we show that the magnitude and kinetics of inhibitory synaptic currents can be critical for the strength and patterning of the motor outputs of taste-induced licks (ingestion) and gapes (rejection). Using whole cell electrophysiology, we explore the hyperpolarization-activated intrinsic properties of the potential CPG neurons in a brainstem slice preparation. We classify these neurons based on hyperpolarization-induced facilitation or suppression of spikes. Additionally, we show the existence of a hyperpolarization-induced inward cation current (Ih), a transient A-type potassium current (IA) among these neurons. We conclude that the hyperpolarization-induced changes in excitability do not arise by mere existence or absence of one type of ionic current. Rather, overlapping combinations of currents dynamically interact to lend specific groups of neurons more or less excitable as they recover from hyperpolarization/inhibition. We speculate that the intrinsic firing properties observed in these neurons may play a role during lick-gape pattern generation. In addition to being the first studies to reveal various intrinsic and synaptic mechanisms of lick/gape pattern generation at both single cell and network level, these studies have laid the foundation for several future experimentation and mathematical modeling to understand the workings of the CPG under study.
Advisors/Committee Members: Travers, Joseph.
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29.
Weil, Zachary M.
Social And Temporal Determinants Of Brain, Behavior And Immune Function.
Degree: PhD, Neuroscience, 2008, Ohio State University
► In this dissertation, I will consider the consequences (physiological, behavioral, and susceptibility…
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▼ In this dissertation, I will consider the consequences (physiological, behavioral, and susceptibility to injury) associated with adaptations to both changing biological times and alterations in the social environment. To that end This dissertation is divided into three sections. Section I (chapters 2 and 3) describe a series of experiments that investigate how the social environment regulates inflammatory and behavioral responses to acute administration. Those experiments were designed to determine how animals parse competing behavioral and physiological priorities in order to maximize fitness and survive infection. Section II (chapters 4 and 5) describe the first photoperiodism experiments in this dissertation (see below). Briefly, photoperiodism is the use of day length to regulate seasonal changes in physiology and behavior. Cell-mediated immune responses are typically enhanced in short winter-like day lengths. These experiments were designed to address the role of photoperiod exposure early in life and also the modulatory effects of social housing on photoperiod-mediated changes in the immune system. Section III (chapters 6-9) includes four experiments that investigated temporal and social factors that regulate functional outcomes following cardiac arrest and cardiopulmonary resuscitation. This final set of experiments was conducted to describe and investigate natural fluctuations in ischemic outcomes. I investigated ischemic outcomes at different times of day (chapter 6), after differential social housing (chapter 7), and after sleep deprivation (chapter 8). All of these experiments focused on the role of social and temporal variables in the regulation of inflammatory responses to ischemia.
Advisors/Committee Members: Nelson, Randy.
Subjects: Biomedical research
Keywords: neuroscience, neuroendocrinology, inflammation, cardiac arrest, seasonality, circadian rhythms, photoperiodism, sickness behaviors.
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30.
White, Robin Elaine.
Manipulation of Astrocytes After Spinal Cord Injury Using Transforming Growth Factor Alpha.
Degree: PhD, Neuroscience, 2009, Ohio State University
► Spinal cord injury results in paralysis and loss of sensation. Astrocytes, prominent…
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▼ Spinal cord injury results in paralysis and loss of sensation. Astrocytes, prominent glial cells in the central nervous system, respond by proliferating, migrating to the site of injury, and forming the glial scar, a physical and chemical barrier to regeneration. Although traditionally viewed as detrimental to recovery, astrocytes also perform tasks that are vital for repair. Because of this dual role after injury, we hypothesized that if astrocytes can be stimulated after injury to enhance their beneficial, rather than detrimental characteristics, then axonal growth can be achieved. In order to manipulate astrocytes, we must better understand the normal astrocyte response to injury. Astrocytes of the glial scar can arise from endogenous adult spinal cord neural progenitor cells (ASCNPCs) and also mature astrocytes present near the injury. We determined that early proliferating cells accumulate at the lesion border in the first week after injury, and that approximately half of those progenitors chronically differentiate into astrocytes. We predicted that those progenitors destined to be astrocytes could be identified prior to differentiation using developmental markers of radial glia. Using the astrocyte-specific radial glial marker brain lipid binding protein (BLBP), we identified possible astrocyte precursors in the parenchyma surrounding the injury site and in the cells surrounding the central canal early after injury. These studies show that manipulation may be best induced in the first week after injury to expand upon this population of astrocyte progenitors. To promote a growth-supportive astrocyte response to injury, we used transforming growth factor α (TGFα), a ligand for the epidermal growth factor receptor (EGFR). We found that an intrathecal infusion of TGFα into the injured mouse spinal cord results in increased astrocyte and axonal infiltration into the lesion, a reponse we predicted was due to a direct activation of the EGFR on astrocytes. Indeed, early after injury, we found that astrocytes and cells surrounding the central canal were the primary expressors of the EGFR. Using a battery of in vitro assays, we showed that TGFα has direct, potent effects on ASCNPCs and astrocytes, and that these effects result in an axonal growth-supportive phenotype. To better target TGFα to the site of injury, we used an adeno-associated virus (AAV) that increases TGFα. Using this technique, we have shown that a short-term administration of the virus results in increased astrocyte and axonal presence within the lesion core. However, when administered chroncially, mice that receive TGFα-AAV do not exhibit infiltration of astrocytes or axons into the lesion, possibly due to chronic EGFR activation on astrocytes and other non-astrocytic cells. In completing these studies, we have shown that there are astrocyte-specific precursors present early after injury that may be manipulated to improve repair, and that EGFR activation via TGFα is a successful method for promoting a growth-supportive astrocytic phenotype. Thus, using EGFR activation, we may be able to target specific astrocytic populations to acquire a pro-reparative phenotype and improve regeneration after SCI. This dissertation provides necessary information that lays a foundation for future studies employing the growth-supportive aspects of astrocytes to promote repair.
Advisors/Committee Members: Jakeman, Lyn.
Subjects: Biochemistry; Biomedical research; Neurology
Keywords: spinal cord injury; astrocytes; central nervous system; transforming growth factor α
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