Brain without Rictor: mTORC2 Signaling Regulates Central Dopamine Homeostasis
Dadalko, Olga Igorevna
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.