Cellular basis of psilocybin actions in frontal cortex

项目摘要 迷幻药是一种化合物，它能产生一种非典型的意识状态， 感知认知和情绪在致幻剂中，裸盖菇素最近引起了人们的关注，因为它在早期 临床试验显示了潜在的抗抑郁作用，导致了“突破性疗法”的命名。 FDA将测试裸盖菇素治疗重度抑郁症。然而，尽管有这样的希望， 对裸盖菇素潜在治疗作用的基础了解甚少。我们的实验室使用亚细胞- 分辨率双光子显微镜观察头部固定小鼠的树突结构和功能。的目标 这个项目是为了描述单剂量的裸盖菇素如何改变中膜树突的结构。 小鼠的额叶皮层和相关的细胞机制。假设裸盖菇素 通过激活特定的5-羟色胺受体亚型促进脊柱形成， 锥体神经元的不同亚型。为了验证这一假设，我们提出了一系列实验， 联合收割机结合亚细胞分辨率光学成像，条件性基因敲除，和因果扰动小鼠。的 结果将回答关于裸盖菇素促进体内结构可塑性的能力的关键问题， 描绘了促进可塑性作用的受体和细胞因子。我们预计 机械的见解将是重要的，因为该领域评估迷幻剂作为一种潜在的治疗选择， 神经精神疾病和寻找新的抗抑郁药。

PROJECT SUMMARY Psychedelics are compounds that produce an atypical state of consciousness characterized by altered perception, cognition, and mood. Among psychedelics, psilocybin has gained attention recently because early clinical trials indicated potential antidepressant effects, leading to a ‘breakthrough therapy’ designation from the FDA to test psilocybin for major depressive disorder. However, despite the promise, the biological mechanisms underpinning psilocybin’s potential therapeutic action are poorly understood. Our lab employs subcellular- resolution two-photon microscopy to visualize dendritic structure and function in head-fixed mice. The goal of this project is to characterize how a single dose of psilocybin may alter dendritic architecture in the medial frontal cortex of the mouse and the associated cellular mechanisms. The hypothesis is that psilocybin promotes spine formation by activating specific serotonin receptor subtypes and exerts differential effects on distinct subtypes of pyramidal neurons. To test the hypothesis, we propose a series of experiments that combine subcellular-resolution optical imaging, conditional knockouts, and causal perturbations in mice. The results will answer crucial questions regarding psilocybin’s ability to promote structural plasticity in vivo and delineate receptors and cellular factors that underlie the plasticity-promoting actions. We expect the mechanistic insights will be important as the field evaluates psychedelics as a potential treatment option for neuropsychiatric disorders and searches for novel antidepressants.