Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states.

Psychedelics may offer new treatments for neuropsychiatric disorders, but how they produce adaptive behavioral changes is not well understood. By using a light- and calcium-dependent activity integrator in mice, researchers tagged neurons in the medial prefrontal cortex that respond to a psychedelic. Single-nucleus RNA sequencing showed the drug activates many cell types, not just those with 5-HT2A receptors. When these tagged neurons were reactivated with an excitatory channelrhodopsin, the mice showed reduced anxiety without hallucinogenic-like effects. This points to specific cell-type mechanisms behind psychedelic-induced behavioral states.

Study at a glance

Abstract

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.