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
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, USA.
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, 06511, USA.
bioRxiv. 2024 Nov 3:2024.11.02.621692. doi: 10.1101/2024.11.02.621692.
Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses. At the cellular level, psychedelics induce structural neural plasticity, exemplified by the drug-evoked growth and remodeling of dendritic spines in cortical pyramidal cells. A key question is how these cellular modifications map onto cell type-specific circuits to produce psychedelics' behavioral actions. Here, we use 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 increased the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types. Behaviorally, 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-HT receptors abolishes psilocybin's effects on stress-related behavior and structural plasticity. Collectively these results identify a pyramidal cell type and the 5-HT receptor in the medial frontal cortex as playing essential roles for psilocybin's long-term drug action.
裸盖菇素是一种血清素能致幻剂，对治疗精神疾病具有潜在的治疗作用。在细胞水平上，致幻剂会诱导结构性神经可塑性，其例证是药物诱发的皮质锥体细胞中树突棘的生长和重塑。一个关键问题是这些细胞修饰如何映射到细胞类型特异性回路，以产生致幻剂的行为效应。在这里，我们使用光学成像、化学遗传学扰动和细胞类型特异性电生理学来研究裸盖菇素对小鼠内侧前额叶皮质中两种主要类型锥体细胞的影响。我们发现，单剂量的裸盖菇素增加了皮质下投射的锥体束（PT）和脑内（IT）细胞类型中树突棘的密度。在行为上，沉默PT神经元会消除裸盖菇素改善应激相关表型的能力，而沉默IT神经元则没有可检测到的影响。仅在PT神经元中，裸盖菇素在给药后会急性增强突触钙瞬变并提高放电率。靶向敲除5-羟色胺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。这些结果共同表明，内侧前额叶皮质中的一种锥体细胞类型和5-羟色胺受体在裸盖菇素的长期药物作用中起着至关重要的作用。
