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.
bioRxiv. 2024 May 15:2024.02.04.578811. doi: 10.1101/2024.02.04.578811.
The serotonin 2 receptor (5HT2R) agonist psilocybin displays rapid and persistent therapeutic efficacy across neuropsychiatric disorders characterized by cognitive inflexibility. However, the impact of psilocybin on patterns of neural activity underlying sustained changes in behavioral flexibility has not been characterized. To test the hypothesis that psilocybin enhances behavioral flexibility by altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the retrosplenial cortex across a five-day trace fear learning and extinction assay. A single dose of psilocybin induced ensemble turnover between fear learning and extinction days while oppositely modulating activity in fear- and extinction- active neurons. The acute suppression of fear-active neurons and delayed recruitment of extinction-active neurons were predictive of psilocybin-enhanced fear extinction. A computational model revealed that acute inhibition of fear-active neurons by psilocybin is sufficient to explain its neural and behavioral effects days later. These results align with our hypothesis and introduce a new mechanism involving the suppression of fear-active populations in the retrosplenial cortex.
5-羟色胺2受体（5HT2R）激动剂裸盖菇素在以认知灵活性不足为特征的神经精神疾病中显示出快速且持久的治疗效果。然而，裸盖菇素对行为灵活性持续变化背后的神经活动模式的影响尚未得到明确。为了验证裸盖菇素通过改变皮质神经集群的活动来增强行为灵活性这一假设，我们在为期五天的痕迹恐惧学习和消退试验中，对脾后皮质进行了纵向单细胞钙成像。单剂量的裸盖菇素在恐惧学习和消退日之间诱导了集群更替，同时对恐惧活跃神经元和消退活跃神经元的活动进行了相反的调节。恐惧活跃神经元的急性抑制和消退活跃神经元的延迟募集预示着裸盖菇素增强的恐惧消退。一个计算模型表明，裸盖菇素对恐惧活跃神经元的急性抑制足以解释其数天后的神经和行为效应。这些结果与我们的假设一致，并引入了一种涉及抑制脾后皮质中恐惧活跃群体的新机制。
