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1.
Bronson, Stefanie L.
Neurobehavioral Consequences of Prenatal Exposure to Maternal Immune Activation.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2011, University of Cincinnati
► Schizophrenia is a chronic and pervasive neurodevelopmental disorder that devastates the lives…
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▼ Schizophrenia is a chronic and pervasive neurodevelopmental disorder that devastates the lives of nearly 1% of the population. The disorder is most commonly recognized by the manifestation of hallucinations, delusions, and bizarre or disorganized behavior. These psychotic symptoms are only one facet of this complex illness. Individuals with schizophrenia also experience disabling cognitive, affective, and social impairments. Dysfunction of brain dopamine systems, and the mesocorticolimbic system in particular, is suspected to underlie these impairments. Despite recognition of the illness throughout history, there are currently no effective interventions ameliorating the full spectrum of the illness, and the origins of schizophrenia remain unclear. Although genetic factors contribute substantially to the etiology of schizophrenia, it is clear that environmental factors have a significant pathophysiological role. Epidemiologic evidence suggests that the prenatal period represents a critical window of vulnerability to environmental insult. Multiple prenatal exposures are associated with elevated schizophrenia risk in later life, including maternal infection, psychosocial stress, malnutrition, and obstetric complications. It is theorized that a mechanism common to these diverse insults may disrupt fetal development, therefore leading to psychiatric illness. One such common factor of these prenatal events is activation of the maternal inflammatory response during pregnancy. The objective of the following work was to determine the consequences of maternal immune stimulation during pregnancy on behaviors mediated by the mesocorticolimbic dopamine system in exposed progeny. Mesocorticolimbic dopamine neurotransmission is thought to underlie psychosis symptoms, as well as their exacerbation by psychomimetic agents and psychosocial stress. Thus, these studies test the overarching hypothesis that prenatal immune activation would enhance the behavioral response to psychomimetic drugs and stressful stimuli. The following work provides data evidencing complex effects on mesocorticolimbic sensitivity to these stimuli that vary depending on the specific immunostimulatory agent and environmental exposures in offspring. These data support a relationship between the maternal inflammatory response and fetal maldevelopment, and implicate intermediary mechanisms downstream of bacterial-like immune activation.
Advisors/Committee Members: Richtand, Neil.
Subjects: Neurology
Keywords: prenatal; immune; schizophrenia; glutamate; dopamine; stress
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2.
Choi, Derrick L.
The role of orexin in reward-based feeding behaviors.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2011, University of Cincinnati
► The regulation of food intake involves the coordinated action of multiple mechanisms…
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▼ The regulation of food intake involves the coordinated action of multiple mechanisms including energy balance and mechanisms independent of caloric needs. In the case of the latter, referred to as non-homeostatic regulation, hedonic value of palatable foods and the motivation to obtain them are an important component. The mesolimbic reward pathway, a major component of drug addiction neurobiology, is implicated in the control of reward-based feeding behaviors. The lateral hypothalamic orexin system modulates a variety of systems including arousal, food intake and reward-related behaviors. Due to its extensive projections to many brain regions and diverse roles in behavioral systems, orexin is a prime candidate for the regulation of mesolimbic function and reward-based feeding behaviors. Moreover, orexin is well positioned to serve as a feed-forward system to integrate metabolic and visceral signals from the basal hypothalamus with learned reward-stimulus associations to affect mesolimbic function. However, this possibility remains to be understood. In these studies, we hypothesized that orexin promotes reward-based feeding behaviors and does so by acting on the mesolimbic circuit. First, we assessed the hypothesis that orexin is a critical promoter of reward-based feeding in models of conditioned and unconditioned responding for palatable food using behavioral pharmacology in rats. These data demonstrate that orexin signaling is necessary for promoting reward-based feeding under conditioned and unconditioned responding paradigms independent of energy status. Conditioned expectation of both palatable food and drug reinforcers activates the hypothalamic orexin system and stimuli previously associated with palatable food intake induce overconsumption in rodents. We hypothesized that context dependent expectation of palatable food and chow-meal feeding differentially activate the orexin system and its target regions. We assessed cue induced neuronal activation in orexin neurons as well as target substrates of the orexin system. Results demonstrate that expectation of chocolate activates both orexin neurons and several of its target regions including the medial prefrontal cortex, paraventricular thalamus (PVT) and ventral tegmental area, all of which are implicated in reward function. The PVT can regulate mesolimbic dopamine neurochemistry through direct connections with the nucleus accumbens. In addition, the PVT modulates the processing of attention and cognitive arousal information, suggesting that the PVT may represent a unique brain region with the capacity to integrate orexinergic effects of arousal and reward function. We then assessed the necessity of PVT orexin signaling for reward-based feeding by selectively reducing the expression of the orexin-1 receptor (OX1R) in PVT neurons. To accomplish this, we utilized an adeno-associated virus, containing a shRNA directed towards OX1R, that was injected into the PVT of rats. The PVT OX1R knockdown rats were then assessed behaviorally in models of conditioned and unconditioned responding for food rewards. Results from these studies suggest that orexin signaling in the PVT promotes unconditioned, but not conditioned or high work-requirement, reward-based feeding behaviors. Together, these results present new possibilities in the integration of a generalized orexin arousal system capable of promoting reward function through a novel HTS circuit and provides new supporting evidence of a significant role for orexin in reward-based feeding.
Advisors/Committee Members: Benoit, Stephen.
Subjects: Neurology
Keywords: orexin; food reward; mesolimbic dopamine; high fat feeding; paraventricular thalamus; progressive ratio
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3.
de Kloet, Annette D.
The Renin-Angiotensin System and the Neuroendocrine Regulation of Energy Balance.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2011, University of Cincinnati
► The renin-angiotensin system (RAS) is best-known as an endocrine system that regulates…
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▼ The renin-angiotensin system (RAS) is best-known as an endocrine system that regulates hydromineral balance and cardiovascular function. More recently, it has become evident that the RAS acts in an autocrine or paracrine fashion within many tissues to influence obesity and its comorbidities. The goal of these studies was to test specific hypotheses relating to how angiotensin-II (Ang-II; an end-product of the RAS) influences energy and glucose homeostasis. The overall hypothesis is that Ang-II acts in the brain to promote negative energy balance and peripherally to enhance energy storage. To assess the role of the RAS in energy and glucose homeostasis, body weight and composition, food intake and glucose tolerance were examined in rats given captopril. Captopril is an angiotensin-converting enzyme (ACE) inhibitor that prevents circulating Ang-II from being formed but does not readily access the brain. Rats fed either high-fat or low-fat diet and given captopril weighed less, had less body fat, and had improved glucose tolerance relative to controls. Rats given captopril also ate significantly less than free-fed controls, and comparisons to pair-fed controls indicated that the reduced weight gain and adiposity and improved glucose tolerance were due primarily to decreased food intake. Because systemic captopril elevates plasma and consequently brain angiotensin-I (Ang-I; the precursor for Ang-II and substrate for ACE), but does not itself enter the brain, we further hypothesized that still-active brain ACE would convert the increased Ang-I into Ang-II, and that the increased central Ang-II would contribute to systemic captopril-induced negative energy balance. Consistent with this, the reduction in food intake elicited by peripheral captopril was reversed by co-administration of the ACE inhibitor into the brain. These results suggest that captopril protects against diet-induced obesity, in part by elevating central Ang-II levels. These studies were extended by directly evaluating the role of RAS in the CNS regulation of energy balance. Osmotic minipumps were used to chronically administer Ang-II to rats in order to examine the effect of increased brain Ang-II signaling on energy balance. Chronic elevation of central Ang-II signaling resulted in reduced food intake, body weight gain and adiposity. The decrease in body weight and adiposity occurred relative to free-fed and pair-fed controls, implying that reduced food intake, in and of itself, does not underlie all of these effects. Consistent with this, rats administered Ang-II exhibited increased energy expenditure and enhanced expression of indices of adipose tissue sympathetic activation. Moreover, chronic icv Ang-II increased the anorectic corticotrophin-releasing and thyroid-releasing hormones within the hypothalamus. This hypothalamic gene expression profile coupled with the abundant angiotensin type-1 receptor expression within the paraventricular nucleus of the hypothalamus (PVN) led to the hypothesis that the PVN angiotensin type-1 receptor population may contribute to some of these processes. This hypothesis is discussed in the final chapter. Collectively, the experiments included in this dissertation support the overall hypothesis that Ang-II acts within the CNS to promote negative energy balance, and suggest that some contributing mechanisms include reduced food intake, elevated energy expenditure and enhanced sympathetic activation of adipose tissue.
Advisors/Committee Members: Woods, Stephen.
Subjects: Neurology
Keywords: Angiotensin; Obesity; Adipose; Neural
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4.
Dickerson, Jonathan W.
Neuroprotective and neurorestorative effects of neuregulins in the injured and aged dopaminergic nigrostriatal system.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2010, University of Cincinnati
► Parkinson’s disease (PD) is a progressive neurological disorder characterized by motor deficits…
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▼ Parkinson’s disease (PD) is a progressive neurological disorder characterized by motor deficits associated with nigrostriatal dopaminergic degeneration. Normal aging is the highest risk factor for developing PD. Current pharmacological and surgical treatments for PD are effective in improving symptoms, but do not prevent the progression of the disease. Neuregulins (NRGs) are pleiotrophic growth factors that are neurotrophic for dopamine cells in vitro and in vivo. In the present series of studies, the neuroprotective and neurorestorative roles of NRGs in the injured and aging nigrostriatal system were investigated. In the first study, rats received 6-hydroxydopamine (6-OHDA) neurotoxin lesions to create an experimental model of PD, followed two weeks later by an infusion of the NRGs glial growth factor (GGF2) or neuregulin-2β (NRG-2β). The animals were assessed for cell survival and behavioral outcomes. The second study investigated age-related changes in NRG1 and its ErbB receptors in the chronologically aging rat mesostriatal system by Western blot and in situ hybridization. Animals were also infused with GGF2 in an aged model of PD to determine if NRG treatment was a potential therapy for the injured aged nigrostriatal system. The third study tested the hypothesis that reduction of ErbB4 receptor availability in the substantia nigra will exacerbate the detrimental effects of neurotoxin-induced damage upon the nigrostriatal system. ErbB4 expression was reduced in the substantia nigra using RNA interference followed by a striatal 6-OHDA lesion. The animals were then assessed for possible worsening of neurotoxin-induced motor dysfunction and dopaminergic cell death. Results from the first study showed that infusion of either GGF2 or NRG-2β into the substantia nigra two weeks after striatal 6-OHDA injections significantly promoted functional recovery of motor function. In addition, both NRGs significantly increased the number of tyrosine hydroxylase (TH) neurons in the substantia nigra when compared to their appropriate controls. These findings demonstrate the neuroprotective and neurorestorative effects of NRGs administered after the establishment of experimental parkinsonism and identify NRG-2β as a novel neurotrophic agent for the dopaminergic nigrostriatal system. Results from the second study revealed a significant decrease in mRNA and protein for the functional NRG receptor ErbB4 and the dopaminergic biosynthetic enzyme TH in the substantia nigra of aging animals. The decrease in ErbB4 preceded that of TH. Reduced ErbB1 receptor protein was also observed in the ventral midbrain of aged rats. Despite the diminished availability of ErbB4 and ErbB1 receptors in the aging midbrian, supranigral GGF2 infusion was able to significantly protect against the morphological and behavioral deficits due to 6-OHDA lesion in an aging model of PD. These findings suggest that GGF2 administration may overcome the possible decline of NRG/ErbB trophic support for dopaminergic neurons in the injured aged midbrain. In the final study, knockdown of ErbB4 in vivo in the SNpc was achieved using a lentiviral vector-driven siRNA construct. This knockdown of ErbB4, however, did not exacerbate motor dysfunction or dopaminergic cell death in a model of experimental parkinsonism. Overall, the results of this research demonstrate the neuroprotective and neurorestorative effects of NRGs in the injured and aged dopaminergic nigrostriatal system. Moreover, these findings indicate the potential therapeutic use of NRGs for the treatment of PD.
Advisors/Committee Members: Seroogy, Kim.
Subjects: Neurology
Keywords: neurotrophic factor; neuregulin; substantia nigra; aging; Parkinson's disease
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5.
Flak, Jonathan N.
Chronic Stress, Neurotransmitter Plasticity, and Body Weight.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2011, University of Cincinnati
► Chronic stress exposure is associated with the manifestation of many diseases and…
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▼ Chronic stress exposure is associated with the manifestation of many diseases and disorders, which may be due in part to changes in neural structure and function via the activation/ recruitment of neural circuits altering synaptology, morphology, and gene expression. However, the neural dysfunction associated with chronic stress- related pathology is believed to be plastic and returns to normal following a combination of sufficient recovery, coping, pharmaceuticals, and/or therapy. Thus, the changes in neural organization by chronic stress and factors that alter how chronic stress can regulate neuronal structure/function are integral to our understanding of chronic stress- related pathology. Thus, the studies within this dissertation attempt to further our understanding of both the effects and regulatory factors in chronic stress- related pathology. The data in chapter 2 demonstrated that chronic stress increases the number of excitatory neurotransmitter inputs to mpPVN CRH neurons, the cells that trigger HPA axis response to stress. The experiment in chapter 3 identified several regions known to project into the PVN as being recruited by unpredictable chronic stress, but not a predictable regimen. The study in chapter 4 indicated that the PVN- projecting noradrenergic neurons are necessary for appropriate responses to acute, but not chronic stress. Collectively, the studies included in chapter 5 demonstrated that changes in body weight homeostasis are sufficient to alter the physiological indices of chronic stress, perhaps via opposing regulation of the PVN. These investigations have laid the groundwork for subsequent analyses, progressing toward deciphering the neural circuits that regulate responses to chronic stress and how these changes contribute to the manifestation of disorders such as depression and PTSD.
Advisors/Committee Members: Herman, James.
Subjects: Neurology
Keywords: Chronic Stress; CRH; PVN; Norepinephrine; HPA Axis; Glucocorticoids
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6.
Hemmerle, Ann M.
Effects of stress-induced depression on Parkinson’s disease symptomatology.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2011, University of Cincinnati
► Parkinson’s disease (PD) is a chronic neurodegenerative disorder that primarily affects dopaminergic…
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▼ Parkinson’s disease (PD) is a chronic neurodegenerative disorder that primarily affects dopaminergic neurons of the nigrostriatal pathway resulting in debilitating motor symptoms. Parkinson’s patients also have a high risk of comorbid depression, though this aspect of the disorder is less well studied. Understanding the underlying pathology of the comorbidity is important in improving clinical treatments and the quality of life for PD patients. To address this issue, we have developed a new model combining the unilateral striatal 6-hydroxydopamine lesion model of PD with the chronic variable stress model (CVS) of depression. Dysfunction of the hypothalamic-pituitary-adrenal axis and its relationship to depression symptomatology is well established. Stress dysfunction may also have a role in the etiology of preclinical PD non-motor symptoms, and later in the course of the disease, may worsen motor symptoms. The combined model allows us to test the hypothesis that experimental depression exacerbates PD symptoms and to ascertain the mechanisms behind the increased neuronal loss. In the first study, we examined several temporal paradigms of the combined model. Motor behavior was assessed using the forelimb asymmetry test (cylinder test) and loss of dopamine neurons was evaluated via immunohistochemical labeling of tyrosine hydroxylase and unbiased stereological cell counting. We found that animals administered CVS concomitant with the lesion exhibited worsened motor deficits and increased neurodegeneration of the dopaminergic neurons in the substantia nigra pars compacta. The second study examined potential glucocorticoid-related mechanisms behind the increased neurodegeneration. We hypothesized that glucocorticoids played a key role in the exacerbated dysfunction and neuronal loss. Animals received the glucocorticoid corticosterone (CORT) alone in a similar regimen as the flanking CVS paradigm. The administration of CORT alone did not worsen either the motor deficits or neurodegeneration. In the second part of this study, animals were administered the glucocorticoid receptor antagonist RU486 prior to CVS concomitant with the lesion. This course of action also did not affect the behavioral deficits or neuronal loss in the combined model. Both of these experiments indicate that glucocorticoids do not have a prominent role in the worsened neuronal loss. To further explore potential mechanisms, the role of neurotrophic factors was preliminarily examined. Animals were exposed to two weeks of CVS prior to sacrifice. Messenger RNA levels of neurotrophic factors known to be neuroprotective for dopaminergic neurons were examined in brain regions involved in depression and PD. Select neurotrophic factors were altered in many regions, including the nigrostriatal pathway. The effects of chronic administration of the antidepressant desipramine on trophic factor expression were also examined. Alterations occurred in both stress and PD circuitry, though not in a complimentary fashion to the CVS changes. This study indicates possible trophic factor involvement in the increased neuronal vulnerability to injury. Overall, the primary findings from this work indicate that CVS combined with experimental parkinsonism results in exacerbated behavioral deficits and accelerated nigral cell degeneration. These results emphasize the need for early detection of depression in PD and for development of better treatments for both the affective and motor components of the disorder.
Advisors/Committee Members: Seroogy, Kim.
Subjects: Neurology
Keywords: chronic stress; glucocorticoid; neurodegeneration; neurotrophic factor; Parkinson's disease; substantia nigra
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7.
Hufnagel, Robert B.
The Role of Basic Helix-Loop-Helix Transcription Factors in Early Retinal Neurogenesis.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2010, University of Cincinnati
► The retina converts visual information into neural signals that are processed and…
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▼ The retina converts visual information into neural signals that are processed and transmitted to the brain. During retinal development, seven major cell types, six neuronal and one glial, are generated from a common neuroepithelium during discrete but overlapping time periods. Here, we study the retinal expression and function of three basic helix-loop-helix (bHLH) transcription factors: Atoh7/Math5 (atonal homologue 7), Neurog2/Neurogenin2, and Ascl1/Mash1 (achaete-scute complex like 1). Proneural bHLH transcription factors are critical for neuronal differentiation and cell type specification in the retina. Atoh7 and Neurog2 are expressed at the initiation of retinal development, and Atoh7 is critical for the generation of the first-born cell type, retinal ganglion cells (RGCs), which transmit visual information to the brain via the optic nerve. Ascl1 is expressed later in retinogenesis, and is required for normal bipolar interneuron and Müller glial genesis, two later-born cell types. First, I explored the regulation of Atoh7 expression, using GFP-expressing transgenes under control of Atoh7 regulatory DNA, which expressed GFP in Atoh7-expressing progenitor cells and nascent RGC axons as they sent projections into the optic nerve and established connections with the brain. In addition to the visual system, Math5-GFP transgenic expression was observed ectopically in developing auditory and proprioceptive systems in the developing brain, spinal cord, and inner ear that normally express Atoh1/Math1, the other atonal semi-orthologue. I found similarities in the genetic regulation of the proximal 2.1 Kb of 5’ Atoh7 DNA and the Atoh1 3’ enhancers, and concluded that these highly-related bHLHs share common regulatory features that, during evolution from a common precursor, were restricted to nonoverlapping expression domains by as of yet unknown DNA repressor elements. Second, I examined the function of Neurog2 at the initiation of retinal neurogenesis. Neurog2 and Atoh7 expression was observed sequentially in progenitor cells that give rise to the first neurons in the central retina. I determined that Neurog2, but not Atoh7, is essential for the peripheral expansion of neurogenesis and RGC genesis. In Neurog2 mutant mice, neurogenesis was delayed until the onset of retinal Ascl1/Mash1 expression, but by birth the proportions of early-born cell types are returned to normal. Ascl1 replacement of Neurog2 rescued the delay in both neural differentiation and RGC genesis, signifying that retinal development proceeds as overlapping waves of neurogenesis regulated by these bHLH factors. Finally, I further explored the interchangeability of bHLH transcription factors. To test the hypothesis that Ascl1 and Atoh7 have distinct functions in cell cycle exit and fate specification in retinal progenitor cells, I used a previously constructed mouse model, the Atoh7Ascl1KI allele, which misexpresses Ascl1 in Atoh7-lineage cells. Ascl1 replacement of Atoh7 did not rescue RGC development but increased bipolar interneuron and decreased Müller glia number in adult eyes. During the initiation of neurogenesis, ectopic Ascl1 prolonged proliferation of Atoh7-expressing cells that normally exit the cell cycle, dominant to endogenous Atoh7 function. In sum, this thesis provokes new mechanisms for the divergence of bHLH regulation and function in mouse retinal development. Neurog2 and Atoh7 have separate roles in early retinal progenitor cells during the initiation of neurogenesis. While Ascl1 can compensate for neural differentiation defects in Neurog2 mutant mice, it does not promote cell cycle exit or rescue RGC specification in terminally mitotic Atoh7-lineage cells. Together, bHLH factors have overlapping and distinct functions in the mammalian retina, defined by a combination of evolutionary homology, phase of cell cycle expression, and developmental timing.
Advisors/Committee Members: Brown, Nadean.
Subjects: Neurology
Keywords: retina; n eurogenesis; retinal ganglion cell; Neurog2; Atoh7; Ascl1
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8.
Johnson, Erica M.
Neuroprotection and Cognitive Enhancing Training Strategies: Environmental Enrichment and Motor Skills Training.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2011, University of Cincinnati
► Environmental enrichment (EE) provides many neurological benefits including increased cortical weight, neuronal…
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▼ Environmental enrichment (EE) provides many neurological benefits including increased cortical weight, neuronal density, dendritic branching, and angiogenesis. These changes manifest as improved cognitive performance. In a rodent model, EE is used successfully as a therapy following traumatic brain injury (TBI) to reduce functional deficits in motor function, spatial memory, and learning. The objective of this work is to exploit the benefits of EE to identify training mechanisms that can be applied to healthy adults to enhance cognitive performance and provide neuroprotection. Two experiments were conducted. The first experiment explored EE as a neuroprotective strategy against cognitive deficits induced by traumatic neurological insults. Adult male rats were placed in an enriched environment for 15 days before medial prefrontal cortex injury via controlled cortical impact. Animals were behaviorally tested to assess memory, anxiety, and sensory neglect. Lesion-induced deficits in spatial memory were significantly attenuated in EE rats. In addition, sensory neglect was reduced in EE rats relative to non-enriched animals. The second experiment was aimed at identifying a specific mode of EE that could be realistically applied to healthy human adults to improve cognitive performance. Motor skills training (MST) is a specific form of exercise that offers neurological benefits including synaptogenesis, cerebellar angiogenesis, motor cortex strengthening and reorganization, and hippocampal neurogenesis. Adult male rats were trained for four weeks then behaviorally tested to assess memory, anxiety, and exploratory behavior. MST significantly improved subsequent performance on tasks of spatial memory. MST also reduced anxiety-like behavior. Both EE and MST experiments provide behavioral data to support non-invasive, non-pharmaceutical training techniques that provide numerous functional benefits. Various biomarkers of stress, plasticity and inflammation were explored as potential mechanisms of neuroprotection and cognitive enhancement; however no candidate proteins were identified. Future work is necessary to identify and understand target mechanisms that can lead to functional improvements. This work provides simple, inexpensive training solutions to both military and civilian populations that can be used to lessen the severity of TBI in populations at increased risk of injury due to occupational hazards.
Advisors/Committee Members: Herman, James.
Subjects: Neurology
Keywords: environmental enrichment; motor skills training; traumatic brain injury; cogntive performance; exercise
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9.
Jury, Nicholas J.
Alterations in Peripheral and Central Serotonin Physiologies during Lactation: Relevance to Mood during the Postpartum Period.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2012, University of Cincinnati
► The discovery of a novel serotonergic system within the mammary gland has…
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▼ The discovery of a novel serotonergic system within the mammary gland has led us to investigate central and peripheral serotonergic systems during lactation in an intact, non-depressed phenotype mouse model. During lactation we observed significant changes in both central and peripheral serotonergic physiologies. Platelet serotonin (5-HT) was elevated in lactating dams when compared to virgin animals. 5-HT immunostaining was significantly lower in the dorsal raphe of lactating mice than nulliparous mice. These findings are what led us to probe the serotonergic systems with a selective serotonin reuptake inhibitor (SSRI), citalopram. Lactating, nulliparous, and postpartum/non-lactating mice were all given a subchronic treatment regimen with SSRI and then subjected to behavioral tasks to assess mood-related behavior. Strikingly, only lactating dams responded to SSRI treatment with an improvement of mood-related behaviors. Locomotor and home-cage activity tasks indicated that these changes in behavior were specific to mood-related behaviors, and not due to an alteration of sensorimotor function. The novel findings from these studies are that lactating mice exhibit an elevated mood-related behavioral phenotype and respond to SSRI treatment that is ineffective in non-lactating mice. The current study shows that there is an interaction between lactation status and responsiveness to SSRIs, which has important implications for the treatment of postpartum depression (PPD). The immunostaining and behavioral results provide evidence of the potential enhancement of serotonergic activity into the projection fields of the brains of lactating mice. Using Palkovits micropunch technique we determined that there were changes in 5-HT and 5-HIAA activity within the posterior basolateral amygdala (PBLA), a brain region that may participate in mood regulation, of lactating mice. Furthermore, treatment with SSRI significantly reduced 5-HIAA content and increased 5-HT content within the PBLA of lactating dams. These results support the hypothesis that there is altered serotonergic activity within limbic projection fields. Again these changes were induced only within brains of lactating mice. The elevations in platelet 5-HT that were observed in lactating mice from our initial study led us to hypothesize that the upregulated serotonergic system within the mammary gland was responsible. Using a mammary specific knockout and overexpression mouse model of tryptophan hydroxylase, the rate limiting enzyme in 5-HT biosynthesis, we demonstrated that the mammary gland is the source of the elevated platelet 5-HT observed in lactating mice. Taken together these findings have significant clinical implications for the treatment of PPD. The clinical literature often does not address the breastfeeding (lactation) status of women when reporting or conducting studies in PPD. These data show that lactation is important and that there should be renewed interest in researching the interaction between breastfeeding and responsiveness to SSRI treatment during the postpartum period.
Advisors/Committee Members: Gregerson, Karen.
Subjects: Neurology
Keywords: postpartum depression; serotonergic; antidepressants; selective serotonin reuptake inhibitors; mood regulation; lactation
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10.
Krawczewski Carhuatanta, Kimberly A.
CNS and peripheral mechanisms by which voluntary running wheel exercise affects adiposity and glucose metabolism.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2011, University of Cincinnati
► The worldwide increase in the prevalence of obesity and its co-morbidities, such…
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▼ The worldwide increase in the prevalence of obesity and its co-morbidities, such as Type 2 Diabetes (T2D), has heightened the urgency for the discovery of effective therapies. Increased physical activity and exercise reduce adiposity and risk of co-morbidities. Peripheral signals are integrated in the brain to maintain energy balance and defend body weight, controlling feeding behavior and energy expenditure. However, when fat stores decrease due to exercise, the increased energy expenditure during exercise is not necessarily accompanied by compensatory changes in resting energy expenditure or feeding. Therefore, we hypothesize that exercise acts on neuronal circuits involved in the control of energy balance to lower the defended fat store. Moreover, CNS mechanisms by which exercise prevents or reduces diet-induced obesity (DIO) remain unknown. Here, we show that voluntary exercise promotes leanness via increased energy expenditure, and prevents the obesigenic effects of high-fat diet (HFD), greatly attenuating fat mass gain. Additionally, exercised animals display improvements in their metabolic profile and glucose metabolism. We tested the hypothesis that exercise improves insulin sensitivity and glucose metabolism in mice fed HFD independent of its body weight effects. We found that prevention of HFD-induced weight and fat gain by both exercise and calorie restriction (CR) improves glucose tolerance despite having little effect in attenuating HFD-induced insulin resistance. Using a marker for chronic neuronal activation, we identify novel neural circuits involved in the beneficial effects of exercise. We show that exercise induces plastic changes in arcuate (ARC) and ventromedial hypothalamic (VMH) neurons as well as increasing chronic neuronal activation in leptin-receptor positive neurons in the VMH, whereas HFD decreases it. Leptin is a peripheral signal, released from fat that acts in the hypothalamus to curb appetite and increase energy expenditure when fat stores increase, exerting a negative feedback on the expansion of fat mass. However, HFD and a sedentary lifestyle can cause obesity and leptin resistance. In our experiments, the use of voluntary wheel running (VRW) prevents DIO and preserves the anorectic and weight-reduction effects of leptin. The prevention of DIO in sedentary mice using CR to match the body weight and fat to exercised mice, resulted in partial preservation of the anorexic effect of leptin, indicating that weight regulation by exercise can improve CNS leptin action independent of the effects of exercise on body weight reduction. Using exercise and CR to prevent HFD-induced weight and fat gain, we find that exercise preserves leptin-induced neuronal activation in the ARC and VMH, while CR prevents HFD-induced leptin resistance only in the ARC. Since the ARC and VMH play pivotal roles in the energy homeostasis control, the preservation of leptin action in these areas could be essential to maintain lower adiposity during consumption of HFD. Future studies will determine whether improved central leptin action in these nuclei is required for the beneficial effects of exercise on body composition. Thus, our findings provide overwhelming support for beneficial exercise-induced central effects, supporting exercise as an intervention strategy for the prevention and treatment of obesity and related impaired glucose homeostasis.
Advisors/Committee Members: Obici, Silvana.
Subjects: Neurology
Keywords: exercise; leptin; diet induced obesity; HFD; glucose metabolism
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11.
Loftspring, Matthew C.
Brain injury mechanisms in hemorrhagic stroke.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2011, University of Cincinnati
► Strokes are the third most common cause of death in the United…
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▼ Strokes are the third most common cause of death in the United States. Stroke is caused by occlusion (ischemic stroke) or rupture of cerebral blood vessels (hemorrhagic stroke). Although hemorrhagic strokes comprise less then 20% of all strokes, they are associated with worse mortality and morbidity than ischemic strokes. A better understanding of how brain injury occurs in subarachnoid and intracerebral hemorrhages may suggest alternative therapies. For this reason, the research that comprises this dissertation focuses on brain injury mechanisms in hemorrhagic stroke, with an emphasis on intracerebral hemorrhage (ICH). In these experiments we study two putative mechanisms of injury: 1) the blood degradation products, unconjugated bilirubin (UBR) and bilirubin oxidation products (BOXes), and 2) inflammation. Moreover, we ask whether there is an interaction between these two mechanisms. This question has not been previously addressed in the literature, and it represents a significant contribution of this dissertation. Chapters 1 and 2 introduce this research by reviewing relevant literature. Before asking what contributions UBR and BOXes have in ICH, we first address gaps in the understanding of how UBR is oxidized to BOXes (Chapter 3). Our data indicate that more than one mechanism exists for conversion of UBR to BOXes. Both cytochrome oxidase and reactive oxygen species produce BOXes in vitro. In Chapter 4, we design a mouse model of intracerebral hemorrhage and determine the profile of inflammatory cell infiltration into the brain after stroke. We found that, compared to saline injection, ICH was associated with an increase in neutrophils at 1 and 4 days and CD4+ T cells at 4 days (Figures 4.3 and 4.4). In Chapter 5, we show that UBR potentiates inflammation and edema after ICH. We observed an increase in brain water content (77% to 77.5%, p< 0.05, Figure 5.1) when 450 mcM UBR was infused with blood. UBR was associated with increased neutrophil counts assessed by immunofluorescence and flow cytometry (Figures 5.2 and 5.6) and also activated neutrophils in vitro and that this activation was PKC dependent (Figure 5.3). Finally, we found that UBR-treated animals had increased ICAM-1-positive blood vessels (Figure 5.9) and suggest this as a mechanism by which UBR produced an increase in neutrophil inflammation. BOXes were associated with neutrophil activation in vitro (Figure 5.4) but we did not observe changes in inflammation in BOXes-treated mice (Figure 5.8). Chapter 6 asks whether neutrophil depletion improves outcome after ICH. We depleted neutrophils using an antibody to the surface marker GR-1. Compared to control, animals receiving anti-GR-1 had profoundly reduced blood neutrophils (50.3 ± 8.3% vs. 1.5 ± 0.34% of CD45+ cells, p< 0.01, Figure 6.2), but neutrophils in the brain were only reduced by 50% (Figure 6.3). We observed reduced astrocyte reactivity in neutrophil-depleted animals but did not observe changes in behavioral data or brain edema. Taken together, our results suggest that UBR and neutrophils contribute to brain injury after ICH (Chapter 7). More detailed studies that incorporate sensitive behavioral data are needed before suggesting potential therapies.
Advisors/Committee Members: Clark, Joseph.
Subjects: Neurology
Keywords: stroke; neuroinflammation; intracerebral hemorrhage; bilirubin
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12.
Murphy, Brian L.
Aberrant hippocampal granule cell neurogenesis and integration in epilepsy.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2010, University of Cincinnati
► The data from the present studies suggest that granule cells in different…
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▼ The data from the present studies suggest that granule cells in different stages of neuronal differentiation may be differentially susceptible to changes in their cellular structure and survival following an epileptogenic stimulus. Recent work in the field has focused on the development of dendritic abnormalities with respect to immature neurons or newly generated neurons following exposure to an epileptogenic stimulus. In Chapter 2, we show for the first time that fully differentiated granule cells are capable of dendritic rearrangement. Specifically, we have shown that previously established apical dendrites shift to the basal portion of the cell as the somata of these cells radially migrate up an adjacent primary dendrite towards the dentate molecular layer. In doing so, dendritic branches on this dendrite become a new primary dendrite. We also propose that this migration underlies the dispersion of the granule cell layer, which was previously suggested by other laboratories; however, the utility of organotypic explant cultures made from Thy1-YFP mice allowed us for the first time to observe fully differentiated granule cell migration and their contribution to the dispersion of the granule cell layer. Granule cell dispersion and distortions to granule cell dendritic structure are common pathologies of the epileptic brain. Both phenomena also occur in adult animal models of epilepsy. Using bi-transgenic Gli-CreERT2+/-;Green fluorescent protein (GFP) reporter+/- mice, data from Chapter 3 suggests that the pool of hippocampal subventricular zone and/or subgranular cell layer neural progenitor cells active several days prior to a prolonged seizure become disrupted following early-life seizure activity. Specifically, fewer cells within the dentate gyrus were labeled with GFP, and associated with decreased numbers of progenitor cells, immature and mature granule cells. Additionally, we are the first laboratory to show that early-life seizures disrupt the integration of granule cells, which has been a ‘hot’ topic in studies using adult models of epilepsy. In Chapter 4, we used the same bi-transgenic mice, but in an adult model of epilepsy. From this study, we found that the pool of subgranular zone progenitor cells producing progeny following seizures become disrupted, and at later time points, give birth to fewer new granule cells. Additionally, this study implicates that granule cells born during the first week following a seizure may exhibit an accelerated rate of maturation. The results of these studies will hopefully spur further research into the underlying cellular signaling pathways involved in the formation of basal dendrites on dentate granule cells, etcopic localization of granule cells to the hilus and dentate molecular layers and granule cell layer dispersion. Additionally, future studies of cell-fate mapping in the early-life seizure and adult model of epilepsy should include the use of alternate tamoxifen injection time points to determine if progenitors active before or after an epileptogenic stimulus respond differently than the conditions tested here.
Advisors/Committee Members: Danzer, Steve.
Subjects: Neurology
Keywords: plasticity; dentate granule cell; recurrent basal dendrite; epilepsy; neurogenesis; early-life seizure
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13.
Paumier, Katrina Lee.
Chronic Antidepressant Treatment in the Nigrostriatal System: the Impact of Antidepressant-Mediated Neuroplasticity.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2011, University of Cincinnati
► The studies in this dissertation are designed to address whether antidepressant-mediated neuroplasticity…
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▼ The studies in this dissertation are designed to address whether antidepressant-mediated neuroplasticity can benefit Parkinson’s disease (PD). The first aim investigates whether antidepressants are neuroprotective to dopamine (DA) neurons in the 6-OHDA rat model of PD. The second aim examines whether antidepressant therapy can increase neurotrophic factors relevant to DA neuron survival in the intact and degenerating nigrostriatal system. The final aim extends the scope of the previous two aims to determine whether antidepressants have disease-modifying effects in a population of early PD patients. Findings from these studies show the tricyclic antidepressant (TCA) amitripyline (AMI) partially protects DA neurons of the injured nigrostriatal system. Furthermore, results show divergent regulation of brain derived-neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) occurs within the nigrostriatal system in response to AMI treatment before and after 6-hydroxydopamine lesion. Taken together, these results suggest that AMI treatment elicits significant trophic changes important to DA neuron survival within both the intact and injured nigrostriatal system. Additionally, results from our patient-level meta-analysis indicate TCAs have disease-modifying effects in an early population of PD. Further, they suggest that untreated mild depression is associated with a higher probability to begin therapy compared to subjects taking antidepressants or non-depressed subjects. Interestingly, there was no impact on annualized UPDRS scores for antidepressant treatment or depression severity. These results suggest tricyclic therapy may provide additional therapeutic benefit for PD patients beyond the treatment of depressive symptoms. Additionally, they highlight the importance of treating depression in PD. Overall, the studies in this dissertation show that antidepressants mediate neuroplastic changes that extend beyond the mesolimbic system, which may have important consequences in PD. They also point to a need for more widespread therapies that address both the motor and non-motor symptoms that contribute to the overall disability experienced by PD patients.
Advisors/Committee Members: Collier, Timothy.
Subjects: Neurology
Keywords: Parkinson's disease; Antidepressants; Neuroprotection; animal models; retrospective study; neurotrophic factors
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14.
Sarria, Ignacio.
Molecular mechanisms and regulation of cold sensing.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2012, University of Cincinnati
► TRPM8 is the principal sensor of cold temperatures in mammalian primary sensory…
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▼ TRPM8 is the principal sensor of cold temperatures in mammalian primary sensory neurons. Cold temperatures 28~8°C and the cooling compound menthol activate TRPM8. TRPM8 is expressed on nociceptive and non-nociceptive primary sensory neurons and mediates innocuous and painful cold sensations. Using calcium imaging, I examined menthol responses and role of protein kinases in two functionally distinct populations of cold-sensing DRGs that use TRPM8 receptors to convey innocuous (menthol-sensitive/capsaicin-insensitive, MS/CI) and noxious (menthol-sensitive/capsaicin-sensitive, MS/CS) cold sensation. PKC activation decreased menthol response in all neurons. MS/CI neurons had larger menthol responses with greater adaptation and adaptation was attenuated by blocking PKC and CaMKII. In contrast MS/CS neurons had smaller menthol responses with less adaptation that was not affected by blocking PKC or CaMKII. In both MS/CI and MS/CS neurons, menthol responses were not affected by PKA activation or inhibition. Taken together, these results suggest that TRPM8-mediated responses are different between non-nociceptive-like and nociceptive-like neurons (Chapter II). Calcium influx causes a feedback regulation of TRPM8 currents that when analyzed under whole-cell voltage-clamp exhibit a Ca2+-dependent functional downregulation with two distinctive phases, a shorter, faster acute desensitization and a prolonged tachyphylaxis. Using acutely dissociated rat DRGs I examined TRPM8 whole-cell currents while pharmacologically manipulating several intracellular targets. TRPM8 acute desensitization is caused by calmodulin and requires phosphatidylinositol 4,5-bisphosphate (PIP2). Conversely, tachyphylaxis is mediated by hydrolysis of PIP2 and activation of PKC/phosphatase 1,2A. Consequently, I set out to determine the mechanisms underlying the mentioned findings by studying inside-out recordings of TRPM8 channels stably expressed in HEK 293 cells. PIP2 switches TRPM8 channel gating to a high open probability state with short closed times and Ca2+-calmodulin reverses the effect of PIP2, switching channel gating to a low open probability state with long closed times. Thus, through gating modulation, Ca2+-calmodulin provides a mechanism to rapidly regulate TRPM8 functions in the somatosensory system (Chapter III). It is not well understood how cooling temperatures have multiple sensory effects ranging from generating cooling or painful cold sensation to modifying sensory modalities like touch, itch and pain. With electrophysiology I studied how temperature modulates excitability in DRGs. Cooling temperatures differentially modify the excitability of non-nocicepetive and nociceptive neurons. Cold aborts repeated action potential firing in non-nociceptive neurons by increasing the voltage-dependent inactivation of TTXs Na+ channels and reducing A-type K+ currents. Cooling temperatures also inhibit IA in nociceptive-like neurons, which possessed TTXr Nav 1.8 channels, but these neurons largely retain or increase firing rate. Cold had less inhibition on TTXr Na+ channels, allowing nociceptive neurons to fire at painful cold temperatures. Like cold, IA blocker 4-AP reduced IA-K+ currents in TTXs and TTXr cells, but this led to higher spike frequency only in the latter. Finally, the molecular determinants for neuron excitability under cooling temperatures play a role in defining temperature threshold and ranges for which innocuous and noxious cold directly elicit impulses in nociceptive and non-nociceptive cold-sensing neurons respectively, providing a molecular mechanism for sensory distinction between innocuous and noxious cold stimuli (Chapter IV).
Advisors/Committee Members: Gu, Jianquo.
Subjects: Neurology
Keywords: Cold; TRPM8; calmodulin; nociception; menthol; action potential
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15.
Spieles-Engemann, Anne L.
The Neuroprotective Potential of Subthalamic Nucleus Deep Brain Stimulation in the 6-OHDA Rodent Model of Parkinson’s Disease.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2011, University of Cincinnati
► The studies in this dissertation are designed to examine the effects of…
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▼ The studies in this dissertation are designed to examine the effects of subthalamic nucleus deep brain stimulation (STN DBS) in the 6-hydroxydopamine (6-OHDA) rodent model of Parkinson’s disease (PD). The first study examines whether STN DBS can provide neuroprotection to the dopaminergic neurons of the substantia nigra (SN) in the face of previous large-scale dopamine neuron loss, similar to what patients have upon initial diagnosis. The second study examines the effects of STN DBS on trophic factors within the STN itself and its target structures in both unlesioned and 6-OHDA lesioned animals. Findings from these studies demonstrate that STN DBS can provide neuroprotection to remaining dopaminergic neurons in the SN. Furthermore, the results show that STN DBS can upregulate brain-derived neurotrophic factor (BDNF) within the SN, striatum, globus pallidus interna, and M1 motor cortex. Taken together, these results demonstrate that STN DBS has the potential to be a disease-modifying therapy for PD, with important effects on cell survival and plasticity within the basal ganglia and motor cortex. They also suggest the need for further study of the use of STN DBS as a treatment for early stage PD as well as its use in other disorders in which downregulation of BDNF has been implicated. Finally, the more through understanding of STN DBS gained by these types of studies may aid in the risk-benefit analysis when deciding upon STN DBS as a treatment option.
Advisors/Committee Members: Herman, James.
Subjects: Neurology
Keywords: Parkinson's disease; Deep brain stimulation; Subthalamic nucleus; Neuroprotection; Trophic factors
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16.
Stefater, Margaret.
Vertical Sleeve Gastrectomy: Mechanisms for Weight Loss and Lessons for Obesity Therapy.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2011, University of Cincinnati
► Bariatric surgery has emerged as a superior treatment for obesity because of…
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▼ Bariatric surgery has emerged as a superior treatment for obesity because of its ability to produce potent, durable weight loss. Vertical sleeve gastrectomy (VSG) is one bariatric procedure that is gaining popularity as an obesity therapy. It is less invasive and as effective as other bariatric procedures including the Roux-en-Y gastric bypass (RYGB). Here, we perform VSG in rats and demonstrate dramatic, long-term weight loss in rats following surgery. This weight loss was a specific loss of fat mass. Initial weight loss was due to early postsurgical reductions in food intake and was maintained a lack of compensatory hyperphagia in response to the postoperative weight loss. Ingestive behavior after the surgery was characterized by smaller, more frequent meals than in sham-operated controls. Importantly, we demonstrated that VSG does not impair ability to overeat in response to additional weight loss but instead appears to reduce motivation to overeat. Energy expenditure was unaffected by VSG, substantiating the idea that changes to food intake are primary determinants of a newly defended, postsurgical body fat level. Because leptin resistance is a feature of obesity that often precludes the maintenance of diet-induced weight loss, we initially hypothesized that enhanced leptin sensitivity contributes to defended body weight after VSG. Food intake reduction following an exogenous dose of leptin was greater in VSG- than sham-operated rats. However, because the response after VSG was comparable to the anorexia elicited in pair-fed rats, we concluded that behavioral sensitization to leptin after surgery is secondary to weight loss and is unlikely to drive reduced motivation of VSG-operated rats to overeat. This conclusion is supported by the absence of changes in the expression of genes in the mediobasal hypothalamus that regulate activity of the melanocortin axis. Highlighting the power of VSG as a treatment not only for obesity but also for obesity-related comorbidities, we show that the procedure produces significant, weight-independent improvements to lipid homeostasis. This benefit is primarily a postprandial phenomenon. Our data indicate that lower postprandial plasma lipid levels are due to reduced intestinal triglyceride secretion in the absence of any changes to hepatic triglyceride production. We did not detect any changes to the expression of genes regulating lipid transport and/or triglyceride production in either the proximal intestine or the liver. We hypothesize that changes to intestinal biology following VSG are not due to permanent, transcriptional changes but, rather, to altered patterns of intestinal nutrient delivery after surgery. Meal patterns and/or gastric emptying might elicit these changes. We also report weight-related enhancement of plasma bile acid levels, leading us to propose that bile acids may mediate some weight-dependent metabolic benefits to weight loss following VSG and potentially other bariatric procedures. Together, these data provide exciting promise for the use of VSG as a metabolic surgery for obese populations. Although it is unclear what mechanism(s) may suppress hyperphagic behavior and thus lower defended body fat level after VSG, our data contribute significantly to the understanding of the cascade of metabolic changes elicited by VSG. Additionally, we provide the first evidence that VSG induces weight-independent changes to lipid homeostasis. Therefore, VSG is a procedure that holds the potential to treat not only obesity, but obesity-related comobidities which may include atherosclerosis and hyperlipidemia. Further understanding the mechanisms for these improvements, including the role of intestinal nutrient sensing, is an important area for future research.
Advisors/Committee Members: Seeley, Randy.
Subjects: Surgery
Keywords: Obesity; Bariatric Surgery; Vertical Sleeve Gastrectomy; Hypothalamus; Leptin; Triglyceride
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17.
Terpstra, Brian T.
Purine Nucleoside Mediated Neuroprotection in the 6-Hydroxydopamine Rodent Model of Parkinson's Disease.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2011, University of Cincinnati
► Parkinson’s Disease (PD) is a progressive, neurodegenerative disorder characterized by bradykinesia, akinesia,…
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▼ Parkinson’s Disease (PD) is a progressive, neurodegenerative disorder characterized by bradykinesia, akinesia, and resting tremor. While dopamine replacement therapy effectively eliminates symptoms in the early stages, as the disease progresses, therapeutic effects lessen and side effects emerge. The lack of long-term therapies highlights the need for compounds that slow the progression of the disease. Inosine is neuroprotective in models of stroke and nerve transection; however, its effect in a model of PD has not been investigated. Chapter 1 examined the neuroprotective potential of peripherally administered inosine in the 6-hydroxydopamine rodent model of PD. These experiments show that inosine is both neurotrophic and neuroprotective in vitro. Peripheral inosine treatment increased nigral and striatal inosine levels and protected nigral dopamine neurons against intrastriatal 6-hydroxydopamine infusion. Peripherally administered inosine is extensively metabolized. Chapter 2 determined the compound responsible for inosine-mediated neuroprotection in the 6-hydroxydopamine rodent model of PD by inhibiting the enzymatic metabolism of inosine. The results of this study show that inhibiting the final step in rodent inosine metabolism (uric acid→allantoin) abolished the functional and morphological neuroprotection seen with systemic inosine treatment. Systemic allantoin treatment resulted in a level of neuroprotection similar to that seen with systemic inosine, indicating that allantoin is responsible for inosine-mediated neuroprotection. To confirm that allantoin is responsible for inosine-mediated neuroprotection, Chapter 3 examined the levels of plasma purines following systemic inosine, inosine/potassium oxonate (urate oxidase inhibitor; KOx) and allantoin. These results showed that inosine and allantoin administration both significantly elevated allantoin, without altering any other plasma purines. Concurrent administration of KOx significantly reduced the increase in plasma allantoin following inosine treatment. These results confirm that allantoin is responsible for inosine-mediated neuroprotection in our model. The 6-hydroxydopamine rodent model of PD requires direct intracerebral infusion, severely compromising the blood brain barrier (BBB). To determine the bioavailability of peripheral allantoin, Chapter 4 examined the effects of subcutaneous (s.c.) and oral allantoin on plasma and whole brain levels of allantoin in animals with intact BBBs. Both s.c. and oral allantoin significantly elevated plasma allantoin, but only s.c. allantoin significantly elevated whole brain allantoin. These results show that allantoin may be a viable peripherally administered treatment in PD. Oxidative stress is thought to play a role in the current model and previous evidence (Gus’kov et al., 2001 and 2004) shows antioxidant effects of systemic allantoin, therefore we sought to determine appropriate markers of oxidative stress for our model. Chapter 5 determined the effects of our lesion on levels of protein carbonyls and Thiobarbituric Acid Reactive Substances (TBARs) in the striatum 24 hours post-lesion. Our lesion had no effect on protein carbonyls or TBARs. Chapter 6 examined the effect of systemic allantoin on NADPH oxidase-1 immunoreactivity (NOX-1ir). Allantoin treatment decreased the number of NOX-1ir cells in the SN and the central gray. The current results demonstrate allantoin’s potential to be a systemically administered, non-invasive therapy for PD. The effect of allantoin on NOX-1ir cells suggests that allantoin may reduce oxidative stress and be able to modify the underlying disease process of PD.
Advisors/Committee Members: Collier, Timothy.
Subjects: Neurology
Keywords: Parkinson's Disease; Inosine; Allantoin; Uric Acid; Oxidative Stress
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18.
Wilson-Pérez, Hilary E.
Effects and Mechanisms of Bariatric Surgery: Altered Food Choice and the Role of Glucagon-Like Peptide-1.
Degree: PhD, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary, 2012, University of Cincinnati
► With obesity now reaching epidemic proportions, and the associated health risks and…
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▼ With obesity now reaching epidemic proportions, and the associated health risks and economic burden, effective weight loss strategies are critical. Currently, the only highly-effective, long-term treatment for obesity is weight-reduction bariatric surgery. Roux-en-Y Gastric Bypass (RYGB), the most commonly-performed bariatric surgery, decreases stomach capacity and bypasses part of the small intestine, re-routing the flow of nutrients. Vertical Sleeve Gastrectomy (VSG), a newer and lesser-known procedure, involves removal of approximately 80 percent of the stomach, and does not manipulate the intestine. VSG is rapidly gaining in popularity due to its safety and positive outcomes regarding weight loss, glycemic control, and other metabolic endpoints. Despite the broad success of bariatric surgery, we understand remarkably little about how these procedures actually produce their potent effects. One thing we know is that patients who undergo bariatric surgery frequently change their eating behavior after surgery. In particular, after RYGB, humans and rodents select or prefer foods which are lower in fat content. We investigated whether a bariatric surgical procedure limited to the stomach, VSG, causes a similar reduction of fat intake/preference. We found that VSG-operated rats decreased their intake of fat in several diet choice paradigms, and that this change in food choice is comparable to the changes induced by RYGB. One candidate to mediate the effects of VSG on food choice and other metabolic outcomes is the peptide hormone Glucagon-Like Peptide-1 (GLP-1). GLP-1 is secreted from the intestine in response to nutrient ingestion, and has potent effects to improve glycemic control and reduce food intake. Furthermore, GLP-1 secretion is greatly enhanced following VSG and RYGB, and has been widely hypothesized to be at least partially responsible for the metabolic benefits of those surgeries. To test this hypothesis, we performed VSG in mice with genetic deficiency for the GLP-1 receptor. Contrary to our hypothesis, GLP-1 receptor-deficient mice responded normally to VSG in all examined aspects, including weight loss, glycemic control, and altered food choice. These studies demonstrate for the first time the potent effect of VSG surgery to alter food choice, particularly by decreasing fat intake. These data provide another parallel between the effects of VSG and RYGB, suggesting that these two anatomically-distinct surgeries may share a common mechanism to induce their powerful effects. Regarding the nature of that mechanism, we demonstrated that GLP-1 receptor activity is not necessary for those effects to manifest in VSG-operated mice. Instead, enhanced GLP-1 secretion and changes in food choice may be downstream of more global adaptations of the digestive system in response to the surgical manipulations.
Advisors/Committee Members: Seeley, Randy.
Subjects: Biology
Keywords: bariatric surgery; vertical sleeve gastrectomy; food choice; macronutrient; GLP-1; gastric bypass
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