Psilocybin Promotes Cell-Type-Specific Changes in the Orbitofrontal Cortex Revealed by Single-Nucleus RNA-seq
OpenAlex – January 07, 2024
Source: OpenAlex
Summary
A single dose of the hallucinogen Psilocybin profoundly impacts brain function, a key finding in Neuroscience. This psychedelic, explored in Psychedelics and Drug Studies, induces long-term genetic and functional changes in neurons within the orbitofrontal cortex, a region crucial for Psychology and vulnerable in brain disorders. These changes, affecting excitatory and inhibitory neurons, collectively reduce circuit activity. Blocking the 5-HT 2A receptor, central to Neurotransmitter Receptor Influence on Behavior, in specific neurons reversed these effects, highlighting psilocybin's precise mechanisms.
Abstract
Abstract Recent clinical breakthroughs hold great promise for the application of psilocybin in the treatments of psychological disorders, such as depression, addiction, and obsessive-compulsive disorder. Psilocybin is a psychedelic whose metabolite, psilocin, is a 5-HT 2A receptor agonist. Nevertheless, the underlying mechanisms for the effects of psilocybin on the brain are not fully illustrated, and cell type-specific and circuit effects of psilocybin are not fully understood. Here, we combined single-nucleus RNA-seq with functional assays to study the long-term effects of psilocybin on the orbitofrontal cortex (OFC), a brain region vulnerable to psychological disorders such as depression. We showed that a single dose of psilocybin induced long-term genetic and functional changes in neurons of the OFC, and excitatory and inhibitory neurons collectively reduced circuit activity of the brain region. Knockdown of 5-HT 2A receptor in deep layer excitatory neurons abated psilocybin-induced functional changes and the anti-depressant effect. Together, these results showed the cell type-specific mechanisms of psilocybin and shed light on the brain region difference in the effect of psychedelics.