The Role of GSK3B in Progressive Alcohol Consumption

项目摘要 酒精使用障碍（AUD）是美国的一个主要公共卫生问题。酒精是第三种 是该国可预防死亡的主要原因，近6%的成年人口符合死亡标准 澳元。不幸的是，由于遗传和环境之间的复杂关系， 尽管AUD的发展，其病因学背后的机制仍不清楚。本项目旨在阐明 糖原合成酶激酶3 β（GSK3B）在调节乙醇行为中的作用。先前的研究 揭示了Gsk3b是小鼠内侧前额叶中受乙醇高度调控的网络中的枢纽基因 皮质（mPFC）。在对急性乙醇的反应中，GSK3B在mPFC和mPFC中经历抑制性磷酸化， 和神经核（NAc）。此外，对啮齿动物饮酒行为的研究表明， GSK3B的药理学抑制降低了乙醇消耗。基因靶向研究进一步 在乙醇反应途径中涉及GSK3B，显示敲除降低乙醇消耗， 过表达产生增加。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，在整个前脑的CamKIIa+细胞内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的知识， 这种反应通过更特异性地靶向mPFC内的CamKIIa+细胞来实现。此外，这是我们的 假设GSK3B对乙醇的反应发生在NAc和PFC之间的回路中， 乙醇行为最后，我们试图研究如何适应GSK 3B的反应，在这个电路 在从急性乙醇暴露到慢性饮酒的转变过程中， 乙醇消费的进步。

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.