Rogers Sophie A, Heller Elizabeth A, Corder Gregory
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nat Neurosci. 2025 May 26. doi: 10.1038/s41593-025-01964-9.
The psychedelic drug psilocybin demonstrates rapid and long-lasting efficacy across neuropsychiatric disorders that are characterized by behavioral inflexibility. However, its impact on the neural activity underlying sustained changes in behavioral flexibility has not been characterized. To test whether psilocybin enhances behavioral flexibility by altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the mouse retrosplenial cortex across a 5-day trace fear learning and extinction assay. We found that a single dose of psilocybin altered cortical ensemble turnover and oppositely modulated fear- and extinction-active neurons. Suppression of fear-active neurons and recruitment of extinction-active neurons predicted psilocybin-enhanced fear extinction. In a computational model of this microcircuit, inhibition of simulated fear-active units modulated recruitment of extinction-active units and behavioral variability in freezing, aligning with experimental results. These results suggest that psilocybin enhances behavioral flexibility by recruiting new neuronal populations and suppressing fear-active populations in the retrosplenial cortex.
致幻药物裸盖菇素在以行为僵化特征的神经精神疾病中显示出快速且持久的疗效。然而，其对行为灵活性持续变化背后的神经活动的影响尚未得到描述。为了测试裸盖菇素是否通过改变皮质神经集群的活动来增强行为灵活性，我们在一项为期5天的痕迹恐惧学习和消退试验中，对小鼠 retrosplenial 皮质进行了纵向单细胞钙成像。我们发现，单剂量的裸盖菇素改变了皮质集群更替，并对恐惧激活神经元和消退激活神经元产生相反的调节作用。抑制恐惧激活神经元和招募消退激活神经元预示着裸盖菇素增强的恐惧消退。在这个微电路的计算模型中，对模拟恐惧激活单元的抑制调节了消退激活单元的招募和冻结行为的变异性，与实验结果一致。这些结果表明，裸盖菇素通过在 retrosplenial 皮质中招募新的神经元群体并抑制恐惧激活群体来增强行为灵活性。
