Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states

• 成果类型: Article
• 署名作者: Muir, J.; Lin, S.; Aarrestad, I. K.; Daniels, H. R.; Ma, J.; Tian, L.; Olson, D. E.; Kim, C. K.
• 署名单位: University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California Davis; Max Planck Society
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9360
• DOI: 10.1126/science.adl0666
• 发表日期: 2024-11-15
• 页码: 802-810
• 关键词: prefrontal cortex; receptor; psilocybin; DYNAMICS; 5-ht2a; hallucinogens; activation; DISCOVERY

摘要

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.