HALLUCINOGENS IN SPECIFIC SIGNALING AND CIRCUITRY

为什么像LSD这样的5-羟色胺能致幻剂具有独特的神经心理效应 与药物滥用、精神病学和神经药理学有关的神经生物学的基本问题。这个 致幻剂的主要靶点是5-羟色胺5-HT2A受体(5HT2AR)。神经元信号事件 与密切相关的非迷幻剂相比，负责其独特效果的电路有 没有得到解决。在体外，迷幻剂和其他5HT2AR激动剂显示激动剂导向的信号 贩运，即它们不同地激活5HT2AR信号通路。我们开发了一种高吞吐量的 一种基于定量基因组学的方法，称为转录组指纹分析(TFP)，它反映了复杂性 信号反应，我们的研究与迷幻剂在体内和初级体内的信号传递一致 培养的神经元。与小鼠行为反应相关的TFP图谱与切割- 温斯坦和金里奇实验室开发的边缘计算和遗传方法提供了 基因调控的分子靶点、信号机制和神经元的研究基础 迷幻剂。为了阐明致幻剂的细胞和分子机制 信号的特殊性，我们将追求两个目标。我们将使用体外研究来研究血管紧张素转换酶 神经元中的致幻剂特异性信号，5HT2AR结构在致幻剂特异性信号中的作用 以及5HT2AR-mGlu2受体复合体的存在和功能作用。在小鼠中，我们将研究 致幻剂反应神经元的解剖学特征及其将与多种小鼠合作研究 在活体内检验有关致幻剂靶标和作用机制的假说的模型。这些研究将使用 这种PPG独特的协同作用，可以测试和完善对PPG作用机制的具体假设 迷幻剂。

Why serotonergic hallucinogens such as LSD have unique neuropsychological effects remains a fundamental question for neurobiology relevant to drug abuse, psychiatry and neuropharmacology. The primary target for hallucinogens is the serotonin 5HT2A receptor (5HT2AR). The neuronal signaling events and circuitry responsible for their unique effects in comparison with closely related non-hallucinogens have not been resolved. In vitro, hallucinogens and other 5HT2AR agonists show agonist-directed signal trafficking, i.e.they differentially activate 5HT2AR signaling pathways. We developed a high-throughput quantitative genomics-based approach called transcriptome fingerprinting (TFP) that reflects complex signaling responses, and our studies are consistent with hallucinogen signal trafficking in vivo and in primary cultured neurons. TFP profiles that correlate with behavioral responses in mice in conjunction with cutting- edge computational and genetic approaches developed by the Weinstein and Gingrich laboratories provide the basis to investigate the molecular target, signaling mechanisms and neurons modulated by hallucinogens. In order to elucidate the cellular and molecular mechanisms underlying hallucinogen signaling specificity, we will pursue two aims. We will use in vitro studies to investigate the mediators of hallucinogen-specific signaling in neurons, the role of 5HT2AR structure on hallucinogen-specific signaling and the presence and functional role of 5HT2AR-mGlu2 receptor complexes. In mouse, we will study the identity of hallucinogen-responsive neurons anatomically and will collaboratively study a variety of mouse models to test hypotheses about the target and mechanism of hallucinogens in vivo. These studies will use the unique synergy of this PPG to test and refine specific hypotheses for the mechanism of action of hallucinogens.