The Role of GSK3B in Progressive Alcohol Consumption

项目摘要 酒精使用障碍(AUD)是美国境内的一个主要公共卫生问题。酒精排在第三位 全国可预防死亡的主要原因，近6%的成年人口符合 澳元。不幸的是，由于遗传和环境之间的复杂关系导致了 虽然AUD的发生、发展及其发病机制尚不清楚。本项目旨在阐明 糖原合成酶激酶3β(GSK3B)在调节酒精行为中的作用。之前的研究已经 Gsk3b基因是小鼠内侧前额叶酒精高度调控网络中的一个中枢基因 皮质(MPFC)。作为对急性乙醇的反应，GSK3B在两个mPFC中都经历了抑制性的磷酸化 伏隔核(NAC)。此外，对啮齿动物饮酒行为的研究表明 GSK3B的药理抑制作用可减少乙醇的消耗。基因打靶研究有了进一步的 GSK3B与乙醇反应途径有关，显示敲除基因可减少乙醇消耗，而 过度表达会导致增加。这种反应背后的确切细胞类型特异性尚不清楚， 然而，有证据表明，整个前脑CamKIIa+细胞中GSK3B的缺失能够 减少饮酒行为。这项建议旨在增加我们对关键细胞类型背后的知识 这种反应更具体地针对mPFC内的CamKIIa+细胞。此外，它是我们的 假设GSK3B对乙醇的反应发生在NAC和PFC之间的回路中以调节 乙醇行为。最后，我们试图研究GSK3B在该回路中的适应反应 在从急性酒精暴露到长期饮酒的转变过程中，可能有助于 渐进式乙醇消费。

Project Summary Alcohol Use Disorder (AUD) is a major public health problem within the United States. Alcohol is the third leading cause of preventable death in the country and nearly 6% of the adult population meets criteria for an AUD. Unfortunately, due to the complex relationship between genetics and environment which contribute to the development of AUD, the mechanisms behind its etiology remain unclear. This project aims to elucidate the role of glycogen synthase kinase 3 beta (GSK3B) in modulating ethanol behaviors. Previous research has revealed Gsk3b to be a hub gene in a network highly regulated by ethanol in the mouse medial prefrontal cortex (mPFC). In response to acute ethanol, GSK3B undergoes inhibitory phosphorylation in both the mPFC and nucleus accumbens (NAc). Additionally, studies on rodent drinking behavior have demonstrated pharmacological inhibition of GSK3B decreases ethanol consumption. Gene targeting studies have further implicated GSK3B in an ethanol-response pathway, showing knock-out decreases ethanol consumption while overexpression produces an increase. The exact cell type specificity behind this response is yet unknown, however evidence suggests deletion of GSK3B within CamKIIa+ cells of the entire forebrain is capable of decreasing drinking behavior. This proposal seeks to increase our knowledge on the critical cell type behind this response by more specifically targeting CamKIIa+ cells exclusively within the mPFC. Additionally, it is our hypothesis that GSK3B’s response to ethanol occurs within a circuit between the NAc and PFC to regulate ethanol behaviors. Finally, we seek to investigate how adaptations of the GSK3B response within this circuit during the shift from acute ethanol exposure to chronic drinking may be contributing to the development of progressive ethanol consumption.