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1.
AIR, ELLEN LOUISE.
THE MECHANISMS THROUGH WHICH INSULIN AND AN INSULIN-MIMETIC REGULATE FOOD INTAKE AND BODY WEIGHT.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2002, University of Cincinnati
► Insulin has long been recognized to play an important role in the…
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▼ Insulin has long been recognized to play an important role in the regulation of energy balance. It is secreted from the pancreas in direct proportion to adipose stores and acts in the hypothalamus to decrease food intake and body weight. However, little progress has been made in elucidating the brain systems through which insulin exerts these effects. The studies presented here identify the melanocortin system as a key mediator of insulin's actions in the brain. First, insulin receptors were localized to pro-opiomelanocortin (POMC) neurons. Second, i.c.v. administration of insulin stimulated POMC expression in the hypothalamus. Third, antagonism of melanocortin receptors blocked insulin-induced hypophagia. Leptin, a hormone that also reduces body weight, has previously been found to act through the melanocortin system. Therefore, the interaction between leptin and insulin was also characterized and found to be sub-additive, indicating redundancy between these two hormones. Although insulin promotes weight loss through its actions in the central nervous system (CNS), increased insulin signaling in the periphery is associated with weight gain. Therefore the ability of a small, lipophilic, non-peptidyl, insulin-mimetic compound (L-783,281) to regulate energy balance was assessed. The data presented here illustrate that L-783,281 acts in the CNS to reduce food intake and body weight and increase energy expenditure. These effects were independent of visceral illness. In addition, L-783,281 was found to increase POMC expression and decrease the expression of the orexigenic compound, Neuropeptide Y. These studies, in concert with the fact that an analog of L-783,281 prevents diet-induced obesity when administered orally, suggest that the insulin system may be an appropriate target for the treatment of obesity.
Advisors/Committee Members: Woods, Dr. Stephen C.
Keywords: obesity; Central Nervous System; therapeutics; Type 2 Diabetes Mellitus; food intake; body weight; melanocortins
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2.
BALFOUR, MARGARET E.
SEXUAL BEHAVIOR CAUSES ACTIVATION AND FUNCTIONAL ALTERATIONS OF MESOLIMBIC SYSTEMS: NEUROBIOLOGY OF MOTIVATION AND REWARD.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2003, University of Cincinnati
► There is increasing evidence that the various drugs of abuse converge upon…
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▼ There is increasing evidence that the various drugs of abuse converge upon common reward pathways in the brain. While it is clear that these circuits are involved in drug-induced reward and reinforcement, less is known about how these systems function when activated by normal motivated behaviors such as sexual behavior. Like drugs of abuse, sexual behavior is a rewarding and reinforcing behavior. Sexual behavior, however, is generally not considered an ìaddictiveî behavior. Thus, understanding how neural circuits are activated by normal motivated behaviors may lead to a better understanding of the pathology of drug addiction. The first set of studies investigated the mechanisms by which sexual behavior activates the mesolimbic dopamine (DA) system ñ a critical component of the neural circuitry regulating motivation and reward. These studies found that both sexual experience and sex-associated environmental cues cause endogenous opioid release and activation of DA producing neurons in the ventral tegmental area (VTA). In addition, a large population of non-dopaminergic neurons was activated by sexual behavior. Therefore, the second set of studies explored the anatomical relationship between these sex-activation neurons and other components of the limbic system. These studies suggest that the medial prefrontal cortex (mPFC) may contribute to the activation of this cell population. The final set of studies investigated whether repeated endogenous activation of the mesolimbic system causes similar functional changes as repeated administration of drugs of abuse. Indeed, sexually experienced animals displayed a robust sensitization to the locomotor effects of amphetamine. Taken together, these studies suggest that sexual behavior activates the mesolimbic DA pathway and that repeated endogenous activation of this system results in long-term changes in its function.
Advisors/Committee Members: Coolen, Dr. Lique M.
Keywords: sexual behavior; drug addiction; dopamine; opioids; behavioral sensitization
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3.
FORADORI, CHAD D.
THE ROLE OF ENDOGENOUS OPIOID PEPTIDES IN THE OVINE ESTROUS CYCLE.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2003, University of Cincinnati
► Gonadotropin releasing hormone (GnRH) neurons play a central role in the control…
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▼ Gonadotropin releasing hormone (GnRH) neurons play a central role in the control of mammalian reproductive function. Changes in the pulsatile secretion of GnRH and luteinizing hormone (LH) are critical for the regulation of events leading to ovulation, as well as to inhibition of ovulation prior to puberty and during other physiological periods of infertility. Based on recent data, we have developed a working hypothesis for the control of pulsatile GnRH/LH secretion by endogenous opioid peptides (EOP). This hypothesis states that one of the EOP systems in the brain, the dynorphin-kappa receptor system, mediates the inhibitory effect of progesterone on GnRH pulse frequency during the luteal phase of the ovine estrous cycle. We first tested one prediction of this hypothesis by determining whether or not dynorphin neurons contain progesterone receptors. We found that a very high percentage of dynorphin neurons in the arcuate nucleus of the hypothalamus, as well as in the anterior hypothalamic area and the preoptic area, contained immunoreactive nuclear progesterone receptors. We then asked whether or not progesterone could act upon these neurons to increase the transcription of dynorphin by using in situ hybridization to measure changes in the levels of mRNA encoding the precursor for dynorphin. We found that ovariectomy significantly decreased the number of PPD mRNA-expressing cells in the ARC, POA and AHA; progesterone replacement increased the number of cells back to those levels seen in intact luteal phase animals in the POA and AHA but not in the ARC, suggesting that in the latter nucleus, estradiol also plays a role in maintaining dynorphin levels. In the same experiment CSF dynorphin was found to be elevated in the progesterone treated group. We further determined that a very large proportion of dynorphin cells colocalize another neuropeptide, neurokinin B, previously shown to be sexually dimorphic and contain estradiol receptors. Finally, we implicated a novel opioid peptide, orphanin FQ/nociceptin, in the control of GnRH secretion by finding almost total colocalization of this peptide with GnRH cells and fibers.
Advisors/Committee Members: Lehman, Dr. Michael N.
Subjects: Biology, Neuroscience
Keywords: progesterone; luteal phase; dynorphin; kappa opioid receptors; neurokinin B
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4.
Hnasko, Robert Michael.
Isolation and Characterization of a Prolactin-Requlating Factor (PRF) from a Mouse Pituitary Intermediate Lobe Cell Line.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2000, University of Cincinnati
► Prolactin (PRL) is regulated by inhibitory and stimulatory factors from the hypothalamus…
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▼ Prolactin (PRL) is regulated by inhibitory and stimulatory factors from the hypothalamus and pituitary. Dopamine is the primary PRL-inhibitory factor, but acute elevations in PRL require stimulation by a PRL-releasing factor (PRF). PRF from the rat pituitary rapidly stimulated PRL release and localized to the intermediate lobe (IL). Partial purification of multiple PRF species from IL tumors differed in size and chromatographic properties. However, the primary structure of PRF has not been resolved. Our hypothesis was: a subpopulation of IL cells secretes a novel peptide that functions as a PRF. Transgenic POMC-Tag mice that develop IL tumors were used to investigate the following objectives: 1) determine if POMC-Tag mice with IL tumors develop hyperprolactinemia, 2) establish and characterize an IL cell line the produces PRF, 3) determine the biochemical properties of PRF, 4) purify PRF and determine its structure. Hyperprolactinemia was not observed in POMC-Tag mice from 20 to 120 days. Cells from two IL tumors were cloned into mIL cell lines that differed in cellular characteristics. As assessed by RT-PCR the mIL39, but not mIL5, cells expressed POMC and D2R gene products, characteristic of IL melanotrophs. The cell lineage of mIL5 cells remains undefined. Only the mIL5 cells, co-cultured with GH3/luc cells, stimulated PRL gene expression and release. PRF from mIL5 was secreted and bound heparin. Two heparin-binding proteins, FGF2 and HB-EGF, identified in mIL5 cells were potent PRL inducers. However, neither significantly contributed to the PRF activity from mIL5 as judged by Western blotting, heparin-affinity and immunoneutralization. Purification of PRF from mIL5 by heparin-affinity chromatography indicated multiple species that differed in chromatographic properties. Sequential chromatography was used to isolate PRF from cell extract and sequencing identified a peptide identical to an internal sequence of heparin-interacting protein (HIP/L29). The expression of HIP protein was ubiquitous and two HIP antibodies were ineffective in the attenuation of PRF activity from mIL5 cells. Isolated PRF from conditioned media was subjected to mass spectrometry that revealed a mass of 14,968 Da. N-terminal sequence analysis failed to resolve the primary structure of PRF.
Advisors/Committee Members: Ben-Johnson, Nira.
Keywords: Prolactin; Pituitary; Cell Liens; Heparin-Binding Growth Factors
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5.
KINZIG, KIMBERLY PEACOCK.
MULTIPLE ROLES OF THE CNS GLUCAGON-LIKE PEPTIDE-1 SYSTEM.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2002, University of Cincinnati
► Central administration of glucagon-like peptide-1 (GLP-1) has been proposed to contribute to…
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▼ Central administration of glucagon-like peptide-1 (GLP-1) has been proposed to contribute to the regulation of food intake, as it causes anorexia in the rodent. However, GLP-1 also causes symptoms of visceral illness. Whether GLP-1- induced anorexia is due to a role in energy balance or if it is secondary to visceral illness is a matter of debate. These studies demonstrate that GLP-1 is involved in both the regulation of food intake and mediating the response to visceral illness. When injected into the fourth ventricle, GLP-1 reduces food intake with no concomitant conditioned taste aversion (CTA). This is in contrast to the effects of GLP-1 injected directly into the central nucleus of the amygdala. In this case, there is no reduction in food intake, however rats developed a CTA. These results indicate that GLP-1 a flexible system that can be activated under different circumstances to alter the ingestion of nutrients and/or produce other visceral illness responses depending on the ascending pathways of the GLP-1 system that are recruited. Recent data also imply the involvement of GLP-1 with the hypothalamic-pituitary-adrenal (HPA) axis. Administration of interoceptive stressors such as lithium chloride (LiCl) increases neuronal activity in GLP-1-containing neurons, and administration of GLP-1 increases neuronal activity in the hypothalamic paraventricular nucleus (PVN). We therefore hypothesized that GLP-1 mediates the HPA response to interoceptive stressors. We further hypothesized that the GLP-1 system would not be involved in the response to psychogenic stressors, as GLP-1-producing neurons originate in the hindbrain and the processing of psychogenic stressors is largely independent of hindbrain activity. We show that central GLP-1 increases levels of the stress-activated hormones ACTH and corticosterone, and increases levels of anxiety as measured by the elevated plus maze. The endocrine response is preferentially activated by GLP-1 administration in the PVN while the anxiety response is preferentially activated by administration in the CeA. Furthermore, GLP-1 antagonists block increases in stress hormones associated with the toxin LiCl and both the endocrine and anxiety responses to vertical heights. Therefore, the current data implicate a role for the GLP-1 system as a critical mediator of multiple stress responses.
Advisors/Committee Members: Seeley, Dr. Randy J.
Subjects: Biology, Neuroscience
Keywords: glucagon-like peptide-1; conditioned tast aversion; stress; visceral illness; energy balance
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6.
LACHEY, JENNIFER LYNN.
THE ROLE OF THE CENTRAL GLUCAGON-LIKE PEPTIDE-1 IN MEDIATING VISCERAL ILLNESS.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2002, University of Cincinnati
► Central administration of glucagon-like peptide-1 (GLP-1) produces responses similar to those produced…
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▼ Central administration of glucagon-like peptide-1 (GLP-1) produces responses similar to those produced by a toxic LiCl dose, the prototypical visceral illness-inducing agent. These responses include anorexia, conditioned taste aversion (CTA) learning and distinct Fos activation. Importantly, in the rat, LiCl administration Fos activates a significant number of preproglucagon-producing cells. Additionally, in the rat, pretreatment with a GLP-1 receptor (GLP-1R) antagonist attenuates these illness responses. Together, these data led to the hypothesis that the central GLP-1 system mediates visceral illness. To further describe GLP-1 action in visceral illness, we determined LiCl ability to elicit anorexia, CTA learning and Fos activation in mice lacking GLP-1 signaling (GLP-1R -/-) expecting these responses would be absent or attenuated. Consistent with this prediction, GLP-1R -/- mice exhibit reduced Fos activation in brain regions downstream of GLP-1R signaling compared to +/+ controls. In contrast to our prediction, GLP-1R -/- mice are anorectic and form a CTA in response to LiCl. These data support the idea that there is a species difference between mouse and rat for the visceral illness system or that unknown interactions for GLP-1 and/or its antagonists exist. Our finding that central GLP-1 administration is able to support CTA learning in mouse as it does in rat does not support species differences as the primary explanation for the discrepant pharmacological and genetic data. Furthermore, GLP-1 is not able to support a CTA in GLP-1 -/- mice. This result supports the contention that these effects are mediated by the sole identified GLP-1 receptor. Taken together, these results raise the possibility that developmental compensation occurs in GLP-1 -/- mice such that alternate systems mediate the effects of LiCl to produce visceral illness responses.
Advisors/Committee Members: Seeley, Dr. Randy J.
Subjects: Biology, Neuroscience
Keywords: visceral illness; glucagon-like peptide-1; nucleus of the solitary tract; emesis; lithium chloride
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7.
LAU, JOAN M.
IMAGING MEMBRANE PROTEINS USING ATOMIC FORCE MICROSCOPY TECHNIQUES.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2002, University of Cincinnati
► Thousands of different membrane proteins exist in the human body and reside…
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▼ Thousands of different membrane proteins exist in the human body and reside in the membranes of cells. Structural information regarding these proteins can provide insight into the function of these proteins. Acquiring membrane protein structural information is difficult, especially when preparation techniques that are traditionally used for soluble proteins such as crystallizing and isolating proteins are not easily adapted for membrane proteins. The atomic force microscope (AFM) provides an alternative for imaging membrane proteins. The preparation required does not require crystallizing or isolating proteins, and can imagine membrane proteins in their native environment. Techniques are explored that can utilize the AFM for imaging proteins, including examining isolated cell membrane patches and membrane surfaces. One technique utilizes plasma membrane from Xenopus laevis oocytes as a model system to study membrane. A novel technique is developed to isolate oocyte membranes by bursting the oocyte and depositing its membrane on a flat mica substrate. The flat surface membrane preparation allows high-resolution AFM images to be obtained, revealing a novel structure of densely packed particles. These particles exhibit a regular, repeating pattern of a lattice-like array with orderly packing, and are thus termed “lattice-like array particles” (LAPs). The LAPs are orderly yet imperfectly packed, are located in depressed pools, occur with a low frequency on the oocyte membrane surface, and have not previously been seen using other isolation and imaging methods. Histogram analysis of the center-to-center distance between LAPs suggest their size to be about 44 nm in diameter, considerably larger than other reported size estimates of IMPs. These results indicate that LAPs represent a novel membrane particle organization, which merits further study. Future developments using this method or further studies to develop alternative membrane preparations may help elucidate membrane protein structure.
Advisors/Committee Members: Yu, Dr. Lei.
Keywords: atomic force microscopy; membrane proteins; lattice array particles
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8.
LEE, HAN SUNG.
CHARACTERIZATION OF CIRCADIAN RHYTHMS OF PHOSPHORYLATED MAP KINASE IN THE HAMSTER SCN.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2003, University of Cincinnati
► The suprachiasmatic nucleus (SCN) has long been recognized as the anatomical locus…
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▼ The suprachiasmatic nucleus (SCN) has long been recognized as the anatomical locus of the mammalian circadian pacemaker. Despite recent advances in the understanding of the molecular mechanisms, it remains unclear how the tissue level properties of the SCN contribute to the function of the SCN as the “master” oscillator of the circadian system. Chapter 2 of this thesis provides a review of the heterogeneity that is inherent to the structure and function of the SCN. The SCN can be viewed as a multi-component structure, with its endogenously rhythmic properties localized to regions of the nucleus that form a “shell” appearance, and the non-rhythmic and light-responsive properties largely overlapping in a central region of the nucleus, forming a “core” appearance. Chapter 3 provides evidence of how the patterns of rhythmic MAP kinase phosphorylation in hamsters contribute to this view of SCN organization. In characterizing the two rhythms of phophorylated MAP kinase (pERK) in the SCN, we further discovered that the presence of the eye is necessary for one rhythm to persist, as enucleation abrogated pERK in the core region. The neurochemical phenotype of pERK cells and their involvement in putative intercellular interactions were then characterized in chapter 4. In chapter 5, the role of retinal activity in mediating the eye’s influence on the core pERK rhythm was demonstrated using the sodium-channel inhibitor, tetrodotoxin. Finally, in chapter 6, I have provided evidence that the expression of a clock gene, Per1, is also influenced by ocular input, as enucleation resulted in changes of its immunoreactivity within the hamster SCN. Together, these studies provide anatomical evidence of a role for the eye in influencing circadian properties of the SCN that is distinct from its role in transducing photic information.
Advisors/Committee Members: Lehman, Dr. Michael.
Subjects: Biology, Neuroscience
Keywords: circadian; suprachiasmatic nucleus; MAP kinase; phosphorylation; eye
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9.
McQUADE, JILL MARIE SLANE.
THE INVOLVEMENT OF DFF45 AND c- fos IN HIPPOCAMPAL PLASTICITY AND FUNCTION.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2002, University of Cincinnati
► Neuroplasticity is an important aspect of neurodevelopment and function. The hippocampus is…
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▼ Neuroplasticity is an important aspect of neurodevelopment and function. The hippocampus is an area of the brain that undergoes many types of plasticity during development and in adulthood, including neurogenesis, apoptosis and changes in synaptic strength due to changes in gene expression. Hippocampal functions such as learning and memory and regulation of the stress response rely on this plasticity. To study how changes in plasticity might affect hippocampal function, we generated two knockout mice, the first of which lacks a component of the apoptotic pathway, DFF45. The cells of the mice are resistant to apoptotic stimuli and the mice have an increased number of dentate gyrus granule cells. When hippocampal-dependent learning was tested in these mice we found that they display enhanced spatial and non-spatial learning abilities. The second model we used is a hippocampal specific knockout of c-fos, an immediate early gene and part of the AP-1 transcription factor complex. The spatial learning abilities are normal in these mutant mice. The mice have more severe kainic-acid induced seizures than wild-type mice and greater CA3 cell death following seizures. While the mice have a normal response to acute restraint stress, they display enhanced habituation to chronic restraint stress. Female mutants also display less anxious behavior in the elevated plus maze than wild-types. Studies to discover the underlying molecular causes for these differences revealed changes in the expression of receptors including GluR6, GR, and ERa. Increased CA3 apical dendritic length was also found in the mutant mice.
Advisors/Committee Members: Xu, Dr. Ming.
Subjects: Biology, Neuroscience
Keywords: hippocampus; learning; stress; c-fos; DFF45
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10.
McQUADE, JOHN-ANDREWS MORRISON.
THE INVOLVEMENT OF THE DOPAMINE-3 RECEPTOR IN THE REGULATION AND REWARD OF FOOD INTAKE.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2002, University of Cincinnati
► The DA receptors (DA-R) have been identified as potential targets for understanding…
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▼ The DA receptors (DA-R) have been identified as potential targets for understanding processing of reward related behavior. The dopamine-3 receptor (D3-R) is expressed in the midbrain dopaminergic circuitry suggesting DA signaling at the D3-R may be vital to inhibition of reward processing. Mice lacking the D3-R (D3-R -/-) and wild-types (D3-R +/+) were given 3-month access to standard rodent chow or a preferable, high-fat (HF) diet. Following 3-months of access, mice were sacrificed and body weight, adiposity, food intake, plasma insulin and leptin, and metabolic measures were evaluated. D3-R -/- became obese on the preferable, HF diet but lacked an overt food intake phenotype. Thus, it was hypothesized that signaling at the D3-R enables an animal to integrate signals about peripheral energy availability and adjust food intake appropriately. Mercaptoacetate (MA), 2-deoxy-d-glucose (2-DG) and insulin were ineffective at increasing food intake in D3-R -/- mice, however peripheral glucose and fatty acids were elevated normally in response to the drugs. In contrast, the mutant mice were hyper-responsive to the anorectic effects of leptin and amylin. To further characterize reward-related behavior the D3-R -/- and +/+ mice were given access to increasing concentrations of ethanol. Ethanol intake is of interest because dopaminergic circuitry has been hypothesized to mediate consumption and is a caloric source with psycho-pharmacological properties. There was a genotypic based increased consumption by the D3-R -/- mice. To assess the hypothesized inhibitory role of the D3-R on food intake we administered the D3-R agonist (7-OH-DPAT) to rats with access to chow or HF diet in three different feeding regimens of varying levels of deprivation. In a final group of experiments animals with access to chow or HF diet were food restricted. On the test day 7-OH-DPAT was administered to animals that received the diet that was expected or the diet that violated expectancy (positive and negative expectancy). 7-OH-DPAT reduced intake of the positive contrast without reducing intake in the other conditions. To characterize central populations of D3-Rs that may influence this effect 7-OH-DPAT was administered directly into the nucleus accumbens (NAcc) or the lateral hypothalamus (LH) in the same behavioral paradigm.
Advisors/Committee Members: Seeley, Dr. Randy.
Subjects: Biology, Neuroscience
Keywords: dopamine; food intake; ethanol consumption; reward; learning
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11.
MURPHY, ERIN KATHLEEN.
STEROID RECEPTOR ACTION IN THE HIPPOCAMPUS IN STRESS AND AGING.
Degree: MS, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2002, University of Cincinnati
► Stress and aging are modulators of steroid receptor action in the hippocampus…
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▼ Stress and aging are modulators of steroid receptor action in the hippocampus of rodents and humans. The glucocorticoid receptor (GR) is highly expressed in the hippocampus and shows marked alterations in function during aging. In particular, we have demonstrated age-related deficits in GR translocation from the cytosol to the nucleus as well as deficits in GR binding to DNA in the nucleus. The purpose of this study was to determine if these age-related decreases are specific to the GR or if another hippocampally expressed steroid receptor sharing structural and functional characteristics with GR, such as the androgen receptor (AR), was also affected. Additionally we wanted to determine if these age-related deficits would persist following an acute stressor. Thus we investigated cytosolic and nuclear protein levels and DNA binding of the GR and AR in the hippocampus in 3, 15, and 30-month Fisher 344 x Brown Norway F1 hybrid rats following 30 minutes of restraint stress. Additionally, we also investigated protein levels of 3 essential chaperone proteins (HSP-90, HSP-70, HSC-70) that are responsible for the proper activation and translocation of these receptors. We found no age-related deficits in translocation of the AR or GR in the control or stressed condition. We also found no age-related deficits in DNA binding for either receptor in the control or stress condition. Additionally, no age-related deficits were found for HSP-90, HSC-70 or HSP-70 protein levels in the cytosol or nucleus. Thus, we conclude that age-related deficits are population specific and we have uncovered a population of animals that exhibit normal steroid receptor function at all ages. This may help to determine protective molecular mechanisms responsible for successful aging.
Advisors/Committee Members: Herman, Dr. James P.
Subjects: Biology, Neuroscience
Keywords: glucocorticoid receptor; androgen receptor; hippocampus; Fischer 344 x Brown Norway F1 hybrid rats; aging
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12.
Pettigrew, David Brent.
THE EFFECTS OF AGE AND GEOMETRY ON AXONAL GROWTH AND REGENERATION: A TISSUE SECTION CULTURE APPROACH.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2000, University of Cincinnati
► Axonal growth is reduced with aging in several models of brain plasticity.…
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▼ Axonal growth is reduced with aging in several models of brain plasticity. These reductions are assumed to contribute to corresponding reductions in behavioral plasticity that occur with aging. Specifically of interest was whether the aged brain is a less permissive substrate for axonal growth in the absence of injury. To assess the baseline substrate properties of the aged brain, explants of sympathetic ganglia were cultured onto cryostat sections of young and aged forebrain and the extent of neurite outgrowth from these explants was measured. The extent of growth varied significantly between brain regions but was not reduced with aging. These data suggest that age-related reductions in axonal growth within the brain are due to age-related changes in the interactions between living cells rather than reduced baseline substrate properties. Axonal regeneration is limited in the CNS following injury. Previous investigations have identified axon-growth inhibitors associated with myelin, inspiring the hypothesis that myelinated fiber tracts cannot support axonal growth. Other studies, however, have shown that white matter can support axonal growth in vivo. We sought to reconcile these contrasting lines of evidence by reassessing the capacity of white matter in cryostat sections of brain and spinal cord to support neurite growth from cultured sympathetic neurons. White matter was found to support long neurite growth oriented in parallel with the fiber tract and inhibit non-parallel growth. This geometric growth constraint is likely due to myelin-associated inhibitors since neurites extending on myelin-deficient tracts or on myelinated tracts in the presence of factors known to deactivate these inhibitors were significantly less parallel. To assess the effects of injury-induced tissue disruption on axonal growth in the absence of glial scarring, spinal cord or sciatic nerve was crushed and immediately frozen to prevent glial scarring. When longitudinal cryostat sections were used as substrata for sympathetic neurons, neurites extended on uncrushed tissue, crossed crushed gray matter but did not cross crushed white matter or crushed sciatic nerve. These data suggest that injuries to fiber tracts are barriers to axonal regeneration in the absence of glial scarring and that restoration of tissue organization is key in permitting axonal regeneration.
Advisors/Committee Members: Crutcher, Ph.D, Keith A.
Subjects: Biology, Neuroscience
Keywords: Axonal Regeneration; Aging; White Matter; Glial Scarring; Axon Guidance
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13.
RANGWALA, FATIMA ABDULLA.
RAS SIGNALING IN SCHWANN CELL TUMOR FORMATION: NEUROFIBROMATOSIS TYPE 1.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2003, University of Cincinnati
► Patients with Neurofibromatosis Type 1 (NF1) carry a germline mutation in the…
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▼ Patients with Neurofibromatosis Type 1 (NF1) carry a germline mutation in the NF1 gene and have an increased risk for developing a variety of benign and malignant tumors. Neurofibromin, the protein encoded by the NF1 gene, is a GTPase activating protein that negatively regulates Ras activity. NF1 -deficient tumors display elevated levels of Ras-GTP suggesting that inappropriate Ras activation contributes to tumor formation. While many abnormal phenotypes of NF1 mutant cells can be ascribed to H-, N-, and K-Ras-GTP excess, Ras-independent phenotypes have been described. The major objective of this work is to explore the contribution of Ras-dependent and Ras-independent signaling pathways to tumor formation in neurofibromin deficient cells. The first set of studies demonstrates that Schwann cells derived from Nf1 null mice have enhanced migration in comparison to wildtype controls. Nf1 -/- mouse Schwann cell migration is not reversed by inhibition of the classical Ras proteins, suggesting that migration is independent of their increased H-, N-, and/or K-Ras activation. We find that TC21/R-Ras2 and its downstream effectors play a role in the migration of neurofibromin-deficient Schwann cells. These studies are the first to implicate TC21 activity in benign tumor formation. The second set of studies investigates Ras signaling in the context of malignant transformation in NF1. NF1 patients are at a greater risk for the development of malignant peripheral nerve sheath tumors (MPNST) than the general population. We hypothesize that a NF1 -specific pathway contributes to the pathogenesis of NF1-associated MPNST. To better understand the molecular events involved in MPNST formation, we characterize 6 NF1-associated MPNST cell lines, 2 sporadic MPNST lines, and 7 normal human Schwann cell samples. We demonstrated that NF1-associated MPNSTs, but not sporadic MPNSTs, had elevated levels of Ras-GTP and loss of p16 INK4a expression. Ras-GTP levels of NF1-associated MPNSTs correlate with their rates of proliferation. In addition, we identify a molecular signature that distinguishes NF1-associated MPNSTs from sporadic MPNSTs. Taken together, these data reveal that each of the Ras isoforms contributes to different aspects of NF1 tumor formation.
Advisors/Committee Members: Ratner, Dr. Nancy.
Keywords: neurofibromatosis Type 1; Schwann Cell; RAS; MPNST; microarray
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14.
TANG, YANG.
BLOOD GENOMIC FINGERPRINTS OF NEUROLOGICAL DISEASES - MICROARRAY STUDIES.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2002, University of Cincinnati
► Gene expression profiling has the power to sensitively reflect a myriad of…
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▼ Gene expression profiling has the power to sensitively reflect a myriad of biological states and perturbations. This is highlighted by the recent progress in molecular classification of various cancers using DNA microarray technology. However, the application of this technology in studying most other human diseases is likely to be slow because of the paucity of biopsy and postmortem samples. The studies presented here sought to determine whether global expression profiling of blood cells could provide peripheral markers for diseases or phenotypes that do not involve the hematological system. This hypothesis was addressed by the following experiments. Firstly, rat models of brain ischemia, intracerebral hemorrhage, seizure, hypoglycemia and hypoxia were used to investigate whether each disease model produced characteristic blood genomic expression fingerprints. At the same time, brain gene expression changes were also surveyed to study the mechanisms of brain injuries associated with each condition. Secondly, rat models were used to determine whether there is a common blood genomic expression pattern that correlates with the occurrence of various neuronal injuries. Finally, neurofibromatosis type 1 was used as a test case to examine whether blood expression profiling is capable of diagnosing clinical diseases. The effects of common confounding factors - age and gender - on blood genomics were also characterized. These results were consistent with the suggestion that diseases and phenotypes may produce unique expression signatures in blood cells and blood expression profiling can be used in diagnostic, mechanistic, and therapeutic assessment of these disease states.
Advisors/Committee Members: Sharp, Dr. Frank R.
Subjects: Biology, Neuroscience
Keywords: blood; white cell; genomics; microarray; gene expression profiling
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15.
VAN HOOREN, DANIELLA CHRISTINE.
GluR5 IS INVOLVED IN REGULATION OF THE HPA AXIS.
Degree: MS, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2004, University of Cincinnati
► Excitatory and inhibitory signals are summated at the paraventricular nucleus of the…
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▼ Excitatory and inhibitory signals are summated at the paraventricular nucleus of the hypothalamus (PVN) and translated into a decision to initiate the hypothalamic pituitary adrenocortical (HPA) axis response to stress. The mechanism of action behind this initiation is still unknown, but the excitatory neurotransmitter glutamate is suspected to play a role. Glutamate receptors have been localized to PVN neurons. Ionotropic glutamate receptors (iGluRs) containing the GluR5 subunit have been localized to the region of the PVN known to initiate the HPA axis. The present study is a test of the hypothesis that iGluRs containing the GluR5 subunit are involved in activation of the HPA axis. We investigate this through microinfusion of a GluR5 agonist (ATPA), and antagonist (LY382884), directly into the PVN. We found that both LY382884 and ATPA activate the HPA axis, and suggest that these compounds may be functioning on fundamentally different receptors at different neuroanatomical locations.
Advisors/Committee Members: Herman, Dr. James P.
Subjects: Biology, Neuroscience
Keywords: GluR5, Ionotropic Glutamate Receptors, Paraventricular Nucleus of the Hypothalamus (PVN), Corticotropin Releasing Hormone (CRH), Corticosterone, ACTH, HPA Axis
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16.
Walsh, Ryan Robert.
Functional Neuroanatomic Analysis of the Response of the Nucleus Accumbens to Acute and Chronic Drugs of Abuse.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2003, University of Cincinnati
► The nucleus accumbens is a key limbic region implicated in mechanisms underlying…
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▼ The nucleus accumbens is a key limbic region implicated in mechanisms underlying reward and addiction. Evidence for involvement of the Nacc in responses to drugs of abuse (including cocaine and morphine) has partly come from studies using Fos as a marker for neuronal activation. While previous reports have consistently shown that Nacc neurons are activated following acute administration of cocaine, studies of morphine-induced activation have produced variable results. In the present study, we used two markers of neural activation, phosphorylation of the MAP-kinase, ERK, and expression of Fos, to investigate Nacc activation in response to either cocaine or morphine. In addition, we used a combination of retrograde tract tracing and immunocytochemistry to investigate whether activated Nacc neurons send projections to the ventral pallidum (VP), a major efferent target of the Nacc. Whereas cocaine induced neural activation at ten minutes, one hour, and two hours following drug administration, morphine only induced activation two hours following injection. Furthermore, while cocaine-activated neurons were present at all rostral-caudal Nacc levels, morphine-activated neurons were restricted to the rostral Nacc. Finally, cocaine induced activation of a subset of VP-projecting neurons in all rostral-caudal levels of the Nacc, while morphine did not. Thus, cocaine and morphine induce different temporal and regional patterns of activation in the Nacc, with cocaine producing more rapid and widespread activation than morphine. The only area of overlap in the patterns of activation produced by either drug was in the rostral Nacc, suggesting that this subdivision may be particularly important in reward and addiction.
Advisors/Committee Members: Lehman, Dr. Michael.
Subjects: Biology, Neuroscience
Keywords: accumbens; morphine; cocaine; ventral pallidum
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17.
WORTMAN, MATTHEW DARYL.
PARTICIPATION OF NEURONAL METABOLISM IN THE REGULATION OF ENERGY BALANCE.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2003, University of Cincinnati
► Central or peripheral administration of the FAS inhibitor C75 reduces food intake…
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▼ Central or peripheral administration of the FAS inhibitor C75 reduces food intake and body weight in rodents. We and others have reported that the CNS is a critical site of action. Despite being anorexic, C75 administration in lean mice leads to a hypothalamic neuropeptide profile similar to the fed state (elevated POMC/CART, decreased NPY/AgRP) suggesting a specific influence on hypothalamic regulatory pathways. Of interest is that obese animals and animals on a high fat diet are sensitive to the effects of C75 suggesting its actions are upstream of systems like leptin and insulin that can become desensitized in obesity. We hypothesized that carbohydrate utilization, rather than fatty acid oxidation, is important for C75's effects. To test this hypothesis we placed animals on a high-fat ketogenic diet and, after confirming they were ketotic, tested the efficacy of C75 to reduce food intake and body weight. Consistent with our hypothesis, there was no difference between C75 and vehicle in ketotic animals. To confirm metabolic state, and not diet content, was responsible for C75 resistance, we allowed each animal to consume either a sucrose or saccharin solution in addition to the ketogenic diet. C75 sensitivity was completely restored in animals that received the sucrose solution while animals that received the saccharin solution remained insensitive. These results suggest that C75's effect is mediated by carbohydrate utilization in brain and that some aspect of glycolysis or glucose oxidation is capable of influencing endogenous energy sensing mechanisms.
Advisors/Committee Members: Woods, Dr. Stephen.
Subjects: Biology, Neuroscience
Keywords: obesity; metabolism; neuroscience
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18.
XIE, WENRUI.
BLOCKADE OF ECTOPIC ACTIVITY AT THE INITIAL STAGE OF PERIPHERAL NERVE INJURY PREVENTS NEUROPATHIC PAIN.
Degree: PhD, Medicine : Interdisciplinary (Medical Science Scholars, Neuroscience), 2003, University of Cincinnati
► Following a nerve injury, there is evidence that there is a large…
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▼ Following a nerve injury, there is evidence that there is a large increase in the level of spontaneous firing in the afferent neurons linked to the injury site. The development of this ectopic activity may be particularly important for the development of hyperalgesia, allodynia and ongoing pain associated with nerve injury. In the present study, the relationship between ectopic activity at the very beginning of peripheral nerve injury and neuropathic pain behavior (thermal hyperalgesia and mechanical allodynia) was examined. We used either chronic constriction injury (CCI) or spare nerve injury (SNI) on the sciatic nerve to produce neuropathic pain in rats. In some animals, the injured nerve activity was blocked initially with either bupivacaine or TTX for 5-7 days and 24 hours per day. Animal neuropathic pain behaviors, thermal hyperalgesia and mechanical alodynia, were checked from the first to 2 to 5 months post operation. During this time, there were no significant neuropathic pain behaviors observed on the rats with sciatic nerve injury and initial nerve blockade. We also checked the ectopic activity in rat sciatic nerve with CCI. Initial nerve blockade prevented the subsequent ectopic activity in injured nerve. However, 10 days following CCI or SNI, when rats already presented robust thermal hyperalgesia and mechanical allodynia, this blockade only relieved naturopathic pain temporarily during the blockade. These results suggested that ectopic activity occurring at the early stage of peripheral nerve injury was essential for the development of chronic neuropathic pain.
Advisors/Committee Members: Yu, Dr. Lei.
Subjects: Biology, Neuroscience
Keywords: ectopic activity; neuropathic pain; peripheral nerve injury
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