Influence of early developmental ethanol exposure on genes, the mTOR signaling pathway and behavior

项目摘要/摘要 精神疾病源于基因和环境之间错综复杂的相互作用。产前酒精暴露 是最常见的导致大脑和行为紊乱的环境输入。胎儿酒精谱 精神障碍(FASD)统称为产前酒精暴露造成的所有缺陷。在美国 据估计，每100名儿童中就有1名患有FASD。社交行为受损是一种常见的、令人衰弱的症状。 FASD的。FASD的风险受个体基因的影响，一些缺陷与损伤有关 神经递质系统，如多巴胺。然而，FASD社会缺陷的确切机制是 未知。 我的东道主实验室已经证明，上调mTORC1信号可以修复由乙醇引起的斑马鱼面部缺陷。 使用斑马鱼，我已经证明了发育过程中暴露在1%乙醇中两个小时(导致组织水平 约27 mM乙醇)，这与已建立的啮齿动物FASD暴露相当，会导致永久性 社会缺陷和多巴胺功能紊乱。因此，我加入了我的宿主实验室来表征基因 易受酒精诱导的社会行为缺陷。我要测试一下乙醇会减弱 机制靶向雷帕霉素(MTOR)通路信号的总体水平，它调节 多巴胺能系统以及随后的社会行为。 总而言之，我的结果将为我们提供对人类最具破坏性的疾病之一的机械洞察， 会对大脑和行为产生终生影响。

Project Summary / Abstract Mental illness stems from intricate interactions between genes and the environment. Prenatal alcohol exposure is most common environmental input that leads to disorders of the brain and behavior. Fetal Alcohol Spectrum Disorder (FASD) collectively describes all the defects caused by prenatal alcohol exposure. In the United States it is estimated that 1 in 100 children have FASD. Impaired social behavior is a frequent and debilitating symptom of FASD. The risk of FASD is modified by an individual's genetics, with some deficits being linked to impairments of neurotransmitter systems such as dopamine. However, the exact mechanisms for FASD social deficits are unknown. My host lab has shown that elevating mTORC1 signaling rescues ethanol-induced facial defects in zebrafish. Using zebrafish, I have shown that a two-hour developmental exposure to 1% ethanol (resulting in tissue levels of approximately 27 mM ethanol), which is comparable to established rodent FASD exposure leads to permanent social deficits and disrupted dopamine functioning. Thus, I joined my host lab to characterize the genetic predisposition to ethanol-induced social behavior deficits. I will test the hypothesis that ethanol attenuates the overall level of mechanistic target-of-rapamycin (mTOR) pathway signaling which regulates development of the dopaminergic system and, subsequently social behavior. Collectively my results will provide mechanistic insight into one of the most devastating human disorders which, has a life-long impact on the brain and behavior.