A single dose of psilocybin increases dendritic spine density in two types of pyramidal cells in the mouse medial frontal cortex: subcortical-projecting pyramidal tract (PT) and intratelencephalic (IT) neurons. Silencing PT neurons eliminates psilocybin's ability to reduce stress-related behaviors, while silencing IT neurons has no effect. Psilocybin boosts synaptic calcium transients and firing rates specifically in PT neurons shortly after administration. Knocking out the 5-HT2A receptor blocks psilocybin's effects on both stress-related behavior and structural plasticity. These findings identify PT neurons and the 5-HT2A receptor as essential for psilocybin's long-term actions.
A single dose of psilocybin causes structural remodeling of dendritic spines in the medial frontal cortex of mice. Using monosynaptic rabies tracing, the researchers mapped brain-wide inputs to frontal cortical pyramidal neurons and found that psilocybin's effect on connectivity is network specific: it strengthens routing of inputs from perceptual and medial regions (homolog of the default mode network) to subcortical targets while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on drug-evoked spiking activity, as silencing a presynaptic region during psilocybin administration disrupts the rewiring. These results reveal how psilocybin impacts large-scale cortical network connectivity and show that neural activity modulation can sculpt psychedelic-evoked plasticity.
Psilocybin transiently increases calcium event rates in apical dendritic tufts of pyramidal tract neurons in the mouse medial frontal cortex, an effect that parallels the drug's brain pharmacokinetics. This acute effect occurs selectively during quiet wakefulness and depends on the 5-HT2A receptor. Under normal conditions, dendritic calcium signaling predicts subsequent spine formation, but psilocybin disrupts this relationship. The findings suggest that the mechanisms linking acute dendritic activity to long-term structural plasticity differ between physiological and psychedelic-induced plasticity.
Psilocybin, a classic psychedelic, alters the activity of specific inhibitory neurons in the mouse medial frontal cortex. It reduces firing of somatostatin-expressing interneurons while increasing activity of parvalbumin-expressing interneurons. This cell type-specific response depends on the 5-HT1A receptor on somatostatin interneurons, and contributes to the drug's long-term behavioral effects. The findings reveal that psilocybin changes cortical inhibition in a targeted manner, highlighting a mechanism beyond the commonly studied pyramidal cells.
A single dose of psilocybin increased the density of dendritic spines in both subcortical-projecting pyramidal tract (PT) and intratelencephalic (IT) cell types in the mouse medial frontal cortex. Silencing PT neurons eliminated psilocybin's ability to ameliorate stress-related phenotypes, whereas silencing IT neurons had no detectable effect. In PT neurons only, psilocybin boosted synaptic calcium transients and elevated firing rates acutely after administration. Targeted knockout of 5-HT2A receptors abolished psilocybin's effects on stress-related behavior and structural plasticity. These results identify a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex as essential for psilocybin's long-term drug action.