Psychedelics Recruit Multiple Cellular Types and Produce Complex Transcriptional Responses Within the Brain

Psychedelics directly activate a small subset of serotonin 5-HT2A receptor-expressing excitatory neurons in the cortex, which then recruit inhibitory somatostatin and parvalbumin GABAergic interneurons, as well as astrocytes, producing distinct regional responses. This finding clarifies the cellular mechanisms underlying psychedelics' effects on perception and cognition, and their therapeutic potential for anxiety, depression, and addiction. The study also introduces a fluorescence-activated cell sorting (FACS) method for isolating specific brain cell subtypes based on cytoplasmic epitopes, enabling downstream nucleic acid analysis and expanding FACS applications in neuroscience.

Study at a glance

Abstract

There has recently been a resurgence of interest in psychedelics, substances that profoundly alter perception and cognition and have recently demonstrated therapeutic efficacy to treat anxiety, depression, and addiction in the clinic. The receptor mechanisms that drive their molecular and behavioral effects involve activation of cortical serotonin 5-HT 2A receptors, but the responses of specific cellular populations remain unknown. Here, we provide evidence that a small subset of 5-HT 2A -expressing excitatory neurons is directly activated by psychedelics and subsequently recruits other select cell types including subpopulations of inhibitory somatostatin and parvalbumin GABAergic interneurons, as well as astrocytes, to produce distinct and regional responses. To gather data regarding the response of specific neuronal populations, we developed methodology for fluorescence-activated cell sorting (FACS) to segregate and enrich specific cellular subtypes in the brain. These methods allow for robust neuronal sorting based on cytoplasmic epitopes followed by downstream nucleic acid analysis, expanding the utility of FACS in neuroscience research.