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Browsing by Subject "Glutamate"

Now showing 1 - 3 of 3
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    AMPA Glutamate Receptor Trafficking in Models of Disease
    (2013-08) Miller, Eric
    The signaling between neurons in the brain underlies many crucial processes - from the beating of the heart to remembering that you have a meeting at noon. Indeed, it is proposed that changes in the way neurons communicate with each other form the basis of learning and memory. In this dissertation I will explore the ways in which neurological diseases can affect these integral neuronal functions and explain the changes on a cellular and molecular level. Deficits in AMPAR signaling are found in numerous diseases. I will explore the mechanisms of these deficits using in vitro models of three diseases: opioid-related cognitive deficits and addiction, Alzheimer's disease, and Parkinson's disease-related dementia. Background information is presented in the first chapter. In the second chapter the signaling pathways underlying morphine-induced synaptic deficits are delineated. I found that calcineurin is necessary for both functional and structural deficits in AMPAR signaling, while CaMKII is necessary for only the structural deficits. The role of tau in synaptic deficits cause by soluble Abeta; oligomers, which are found at elevated levels in Alzheimer's disease patients, are probed in the third chapter. I found that treatment with soluble Abeta; oligomers leads to phosphorylation- dependent mislocalization of tau to dendritic spines. Furthermore, treatment with soluble Abeta; oligomers leads to decreases in AMPAR signaling that require calcineurin activity and GluR1 residue S845, much like the mechanisms of AMPAR internalization in neurons treated with morphine. The fourth chapter unveils a novel role of tau and GSK3 in synaptic deficits found in neurons expressing A53T alpha-synuclein. In fact, I discovered that tau is involved in AMPAR signaling deficits found in neurons expressing A53T alpha- synuclein. Furthermore, both mislocalization of tau and synaptic deficits require phosphorylation of tau by GSK3. This dissertation shows that divergent pathways mediate structural and functional plasticity found in neurons exposed to morphine. Also, I show that deficits in AMPAR signaling in both Alzheimer's disease and Parkinson's disease involve tau mislocalization. These findings shed new light on the signaling pathways involved in AMPAR signaling deficits found in neurological diseases and provide new therapeutic targets for pharmacological interventions.
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    Investigation of Glutamatergic Circuitry Underlying Copulatory Reward in Female Syrian Hamsters
    (2019-01) Moore, Kelsey
    Sex behavior in female mammals is known to involve rewarding consequences that increase the motivation to copulate. I have utilized female hamsters as a model to examine the underlying circuitry and mechanisms of this natural reward. Despite a wealth of information detailing dopaminergic neurotransmission in this region during sexual behavior, the role of glutamate, although the major excitatory neurotransmitter in the brain, has been disproportionately understudied. The goal of this dissertation work was to help close this gap in knowledge to further develop an understanding of the complex underpinnings of female sexual reward and motivation. This understanding is vital in the effort towards evidence-based therapeutic targets in the treatment of disorders of sexual desire in women. In order to determine the role of glutamate in signaling the rewarding properties of sex, I utilized a multi-faceted approach. First, through establishing the use of enzymatic biosensing in the lab, I evaluated glutamate release patterning in key reward regions during sexual behavior in the female hamster. I discovered time-locked glutamate transients specifically in the core of the nucleus accumbens (NAc) in response to penile intromission from the male. Next, I sought to uncover the potential source of this glutamate innervation of the NAc. Immunohistochemical and retrograde tracing analyses determined the involvement of excitatory glutamatergic efferents from the medial prefrontal cortex (mPFC) to the NAc. Then, to determine if mPFC activity was driving the activation of the NAc during female sexual behavior, I employed designer receptors exclusively activated by designer drugs (DREADDs) to selectively inhibit these excitatory mPFC efferents. I demonstrated that this selective inhibition decreases sex-induced activation of the NAc, confirming the importance of the mPFC in driving increased glutamatergic activity in the NAc in response to sexual behavior in the female. The novel findings reported in this body of work demonstrate the involvement of glutamatergic neurotransmission in sexual reward through a prefrontal-accumbal circuit. These are not only exciting additions to the development of a comprehensive model of female sexual reward, but also provide potential targets for therapeutic intervention. Currently there are no effective treatment options for disorders of sexual desire in women and these results provide attractive avenues for pursuing target-specific and clinically-relevant therapies.
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    Spinal regulation of sympathetic nerve activity and arterial pressure under conditions of increased plasma osmolality
    (2012-09) Veitenheimer Rupp, Britta J.
    Hypertension, or chronic high blood pressure, is a major health concern worldwide. Increased dietary salt may contribute to high blood pressure through the activation of the sympathetic nervous system. Indeed, more than half of the cases of human hypertension show evidence of elevated sympathetic nerve activity. Key brain regions that activate sympathetic activity in response to increased osmolality have been identified, but regulation at the level of the spinal cord - the final point of sympathetic outflow from the central nervous system - is much less understood. The experiments in this thesis were designed to examine the spinal neurotransmitters and sympathetic nerves that may increase arterial pressure in response to elevated plasma osmolality. The first major finding of this thesis suggests that the arterial pressure response to increased osmolality relies on spinal glutamate, not vasopressin as previously hypothesized. The second major finding suggests that elevated arterial pressure during water deprivation - a condition of chronic hyperosmolality - is sympathetically mediated and may be dependent on the adrenal cortex, but is not due to increased sympathetic activity to a specific vascular bed. The discoveries described in this thesis contribute to the overall knowledge of spinal regulation of osmotically driven sympathoexcitation and suggest new areas of focus for future studies. Moreover, these findings may lead to a better understanding of the etiology of salt-sensitive hypertension and development of novel antihypertensive therapies.