Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA.
Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
Science. 2024 Nov 15;386(6723):802-810. doi: 10.1126/science.adl0666. Epub 2024 Nov 14.
Psychedelics hold promise as alternate treatments for neuropsychiatric disorders. However, the neural mechanisms by which they drive adaptive behavioral effects remain unclear. We isolated the specific neurons modulated by a psychedelic to determine their role in driving behavior. Using a light- and calcium-dependent activity integrator, we genetically tagged psychedelic-responsive neurons in the medial prefrontal cortex (mPFC) of mice. Single-nucleus RNA sequencing revealed that the psychedelic drove network-level activation of multiple cell types beyond just those expressing 5-hydroxytryptamine 2A receptors. We labeled psychedelic-responsive mPFC neurons with an excitatory channelrhodopsin to enable their targeted manipulation. We found that reactivation of these cells recapitulated the anxiolytic effects of the psychedelic without driving its hallucinogenic-like effects. These findings reveal essential insight into the cell-type-specific mechanisms underlying psychedelic-induced behavioral states.
迷幻剂有望成为神经精神疾病的替代疗法。然而，它们驱动适应性行为效果的神经机制仍不清楚。我们分离了被迷幻剂调节的特定神经元，以确定它们在驱动行为中的作用。我们使用光和钙依赖性活性整合器，在小鼠的内侧前额叶皮层 (mPFC) 中对迷幻剂反应神经元进行了基因标记。单细胞 RNA 测序显示，迷幻剂不仅驱动了表达 5-羟色胺 2A 受体的细胞类型，还驱动了多个细胞类型的网络级激活。我们使用兴奋性通道视紫红质标记迷幻剂反应性 mPFC 神经元，以实现对其的靶向操作。我们发现，这些细胞的再激活再现了迷幻剂的抗焦虑作用，而没有驱动其致幻样作用。这些发现揭示了迷幻剂诱导的行为状态的细胞类型特异性机制的重要见解。
