Isolation of psychedelic responsive neurons underlying anxiolytic behavioral states

Psychedelics hold promising potential 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 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. Prefrontal cortex of C57BL/6J male and female mice expressing scFLARE2 was miscodissected following24 hours after a psychedelic (DOI) or saline injection.