Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states.
Science (New York, N.Y.) – November 15, 2024
Source: PubMed
Summary
Psychedelics may offer a new avenue for treating neuropsychiatric disorders by targeting specific neurons. In a study involving genetically modified mice, researchers identified psychedelic-responsive neurons in the medial prefrontal cortex (mPFC) and discovered that these neurons activated diverse cell types, not just those with 5-HT2A receptors. By manipulating these tagged neurons, they replicated the anxiety-reducing effects of psychedelics without producing hallucinations. This work highlights crucial insights into how psychedelics can influence behavior through distinct neural pathways.
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.