Due to the escalating obesity epidemic in the United States, an important public health concern is the comorbidity of metabolic disorders and mental illness. Mounting clinical evidence supports the comorbid nature of mental illness with metabolic disorders such as diabetes and obesity. Human epidemiologic data as well as studies in animal models showed that aberrant metabolic mTORC2/Akt signaling is linked to monoamine related neuropsychiatric disorders, particularly DA-associated brain dysfunctions, which manifest in many mental diseases including schizophrenia. Of utmost interest and relevance to this thesis was to elucidate how fine-tuning of Akt activity, particularly its upstream mTORC2/rictor signaling, regulates striatal DA homeostasis and subcortical DA-dependent behaviors.
Collectively, our studies reveal that disrupted central mTORC2/Akt signaling results in aberrant subcortical DA neurotransmission and disrupted DA-dependent behaviors. We utilized transgenic mouse models and viral intervention techniques to induce whole brain or region-specific deletion of protein rictor, an essential mTORC2 component. Here, we demonstrate how disruption of mTORC2/Akt signaling in brain-region specific manner results in altered subcortical DA neurotransmission. Importantly, we show that these genetic alterations manifest in neurochemical and biochemical changes in the brain that influence neurophysiological behaviors as well as peripheral metabolic phenotype.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11162015-144711 |
| Date | 19 November 2015 |
| Creators | Dadalko, Olga Igorevna |
| Contributors | Todd Graham, Ariel Deutch, Danny Winder, Eugenia Gurevich, Aurelio Galli |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11162015-144711/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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