美国康奈尔大学Alex C. Kwan小组的一项最新研究探明了裸盖菇素的持久作用需要锥体细胞类型和5-HT2A受体。2025年4月2日出版的《自然》发表了这项成果。

在这里，研究小组通过体内光学成像、化学发生扰动和细胞类型特异性电生理学来研究裸盖菇素对无主题内侧额叶皮层两种主要类型锥体细胞的影响。课题组发现单剂量裸盖菇素增加了皮层下突起、锥体束（PT）和脑外（IT）细胞类型的树突棘密度。从行为上讲，沉默PT神经元消除了裸盖菇素改善压力相关表型的能力，而沉默IT神经元没有可检测到的效果。仅在PT神经元中，裸盖菇素增加突触钙瞬态并在给药后急剧升高放电率。靶向敲除5-HT2A受体可消除裸盖菇素对应激相关行为和结构可塑性的影响。总的来说，这些结果表明，内侧额叶皮层的锥体细胞类型和5-HT2A受体在裸盖菇素的长期药物作用中起重要作用。

据介绍，裸盖菇素是一种血清素能致幻剂，具有治疗精神疾病的潜力。在细胞水平上，致幻剂诱导神经结构可塑性，例如药物引起的皮质锥体细胞树突棘的生长和重塑。一个关键的问题是，这些细胞修饰是如何映射到特定类型的细胞回路上，从而产生致幻剂的行为行为的。

附：英文原文

Title: Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors

Author: Shao, Ling-Xiao, Liao, Clara, Davoudian, Pasha A., Savalia, Neil K., Jiang, Quan, Wojtasiewicz, Cassandra, Tan, Diran, Nothnagel, Jack D., Liu, Rong-Jian, Woodburn, Samuel C., Bilash, Olesia M., Kim, Hail, Che, Alicia, Kwan, Alex C.

Issue&Volume: 2025-04-02

Abstract: Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses1,2,3,4. At the cellular level, psychedelics induce structural neural plasticity5,6, exemplified by the drug-evoked growth and remodelling of dendritic spines in cortical pyramidal cells7,8,9. A key question is how these cellular modifications map onto cell-type-specific circuits to produce the psychedelics’ behavioural actions10. Here we use in vivo optical imaging, chemogenetic perturbation and cell-type-specific electrophysiology to investigate the impact of psilocybin on the two main types of pyramidal cells in the mouse medial frontal cortex. We find that a single dose of psilocybin increases the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types. Behaviourally, silencing the PT neurons eliminates psilocybin’s ability to ameliorate stress-related phenotypes, whereas silencing IT neurons has no detectable effect. In PT neurons only, psilocybin boosts synaptic calcium transients and elevates firing rates acutely after administration. Targeted knockout of 5-HT2A receptors abolishes psilocybin’s effects on stress-related behaviour and structural plasticity. Collectively, these results identify that a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex have essential roles in psilocybin’s long-term drug action.

DOI: 10.1038/s41586-025-08813-6

Source: https://www.nature.com/articles/s41586-025-08813-6