Cellular basis of psilocybin actions in frontal cortex

项目概要 迷幻药是产生非典型意识状态的化合物，其特征是改变 感知、认知和情绪。在迷幻药中，裸盖菇素最近引起了人们的关注，因为早期 临床试验显示出潜在的抗抑郁作用，从而获得了“突破性疗法”称号 FDA 将测试裸盖菇素治疗重度抑郁症的效果。然而，尽管有这样的希望，生物学机制 人们对裸盖菇素潜在治疗作用的基础知之甚少。我们的实验室采用亚细胞- 分辨率双光子显微镜可观察头部固定小鼠的树突结构和功能。目标是 该项目旨在表征单剂量裸盖菇素如何改变内侧树突结构 小鼠额叶皮层和相关的细胞机制。假设裸盖菇素 通过激活特定的血清素受体亚型来促进脊柱形成，并对 锥体神经元的不同亚型。为了检验这个假设，我们提出了一系列实验 将亚细胞分辨率光学成像、条件敲除和小鼠因果扰动结合起来。的 结果将回答有关裸盖菇素促进体内结构可塑性的能力的关键问题，以及 描述了促进可塑性作用的受体和细胞因子。我们期望 当该领域评估致幻剂作为潜在的治疗选择时，机制见解将非常重要 神经精神疾病和寻找新型抗抑郁药。

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.