Serotonin modulated mitochondrial dysfunction in Depression Diabetes and Dementia (3Ds)

项目摘要 我们的研究旨在了解5-羟色胺调节的线粒体生物发生在糖尿病中的作用， 抑郁症和痴呆症（阿尔茨海默病，AD）。糖尿病和抑郁症是糖尿病的独立危险因素 痴呆和恶化痴呆病理和治疗反应。抑郁共病损害 代谢功能如高血糖症、胰岛素抵抗、炎症和氧化应激导致 身体抑郁和认知障碍。血清素是一种重要的神经递质， 衰老和痴呆中的突触传递、可塑性、能量稳态。长期以来，人们都知道， 脑干含有独特的神经元，可以合成血清素并将其投射到整个中枢神经系统。 然而，血清素水平与线粒体生物发生、线粒体动力学、 痴呆症、糖尿病和抑郁症中的线粒体自噬/自噬还没有完全了解。经确定 中缝背核5-羟色胺合成对细胞稳态和能量代谢具有保护作用和必要性。它 已经假设低血清素水平诱导线粒体生物合成缺陷， 线粒体动力学、线粒体功能障碍和抑郁症中的线粒体自噬/自噬缺陷， 选择性5-羟色胺再摄取抑制剂，如西酞普兰治疗逆转 缺陷的线粒体生物发生和所有线粒体缺陷方面。我们已经将研究概念化， 在啮齿类动物中，聚焦于3D聚焦海马的转基因模型（APP、Tau、HT 22细胞）， 下丘脑（DbDb，mHypo细胞）和中缝（TPH 2/ko，RN 46 A-B 14细胞）。因此，目前的研究 建议了解西酞普兰（SSRI）的病理和保护作用， 线粒体生物发生、受损的线粒体动力学和有缺陷的线粒体自噬/自噬。成果 我们提出的实验将为5-羟色胺在抑郁症、糖尿病和糖尿病中的作用提供新的见解。 涉及线粒体生物发生、线粒体动力学、线粒体功能和 线粒体自噬结果还将提供西酞普兰对常见的 降钙素诱导的线粒体动力学、线粒体功能和线粒体自噬/自噬缺陷。

Project Summary Our research aims to understand the role of serotonin modulated mitochondrial biogenesis in diabetes, depression, and dementia (Alzheimer's disease, AD). Diabetes and depression are independent risk factors for dementia and worsen the dementia pathology and therapeutic response. Depression comorbidity impaired metabolic function such as hyperglycemia, insulin resistance, inflammation, and oxidative stress results in physical depression and cognitive impairment. Serotonin is an essential neurotransmitter that performs synaptic transmission, plasticity, energy homeostasis in aging and dementia. For a long time, it is known that the brainstem harbors unique neurons to synthesize and project serotonin to the entire central nervous system. However, molecular links between serotonin levels and mitochondrial biogenesis, mitochondrial dynamics, mitophagy/autophagy in dementia, diabetes, and depression are not entirely understood. It is established that serotonin synthesis in dorsal raphe is protective and essential for cell homeostasis and energy metabolism. It has been hypothesized that low serotonin levels induce defective mitochondrial biogenesis, impaired mitochondrial dynamics, mitochondrial dysfunction and defective mitophagy/autophagy in depression, diabetes, and dementia, and selective serotonin reuptake inhibitors, such as citalopram treatment reverses defective mitochondrial biogenesis and all mitochondrial defective aspects. We have conceptualized the study in rodents focusing on the transgenic models of 3Ds focusing hippocampus (APP, Tau, HT22 cells), hypothalamus (DbDb, mHypo cells), and raphe (TPH2/ko, RN46A-B14 cells). Therefore, the current study proposes to understand the pathologies and the protective effects of citalopram (SSRI) against defective mitochondrial biogenesis, impaired mitochondrial dynamics, and defective mitophagy/autophagy. The outcome of our proposed experiments will provide new insights into the role of serotonin in depression, diabetes, and dementia concerning mitochondrial biogenesis, mitochondrial dynamics, mitochondrial function, and mitophagy/autophagy. The outcome will also provide beneficial effects of citalopram against common serotonin-induced defects of mitochondrial dynamics, mitochondrial function, and mitophagy/autophagy.