Imaging reveals psilocybin's neurological mechanisms in the brain that enable the psychedelic compound’s long-lasting effects

Good news! When will we finally be able to separate pain killing and other beneficial effects from becoming addicted and/or to hallucinate!

"... researchers have identified a pair of key neurological mechanisms in the brain – a cell type and receptor – that enable the psychedelic compound’s long-lasting effects.

Targeting the pyramidal tract neurons and their specific serotonin 5-HT2A receptor in the medial frontal cortex could enable pharmaceuticals to deliver psilocybin’s mood-altering benefits while suppressing the perceptual hallucinatory trip. ...

Using two-photon microscopy on transgenic mice, the researchers targeted the two largest populations of primary cells in the brain: 

pyramidal tract (PT) neurons and 

intratelencephalic (IT) neurons.

Inactivating the IT neurons, which are responsible for high-order cortical-cortical communication, did not change the behavioral effects of the psilocybin. ...

silenced the PT neurons, the drug was essentially ineffective – proof that this cell type and its pathway, which extends from the frontal cortex down into the midbrain and brainstem – is essential to psilocybin’s effects.

Equally important is the PT neurons’ 5-HT2A receptor, which has previously been shown to play an important role in humans experiencing acute, short-term hallucinatory trips. When the researchers knocked out the receptors, psilocybin’s positive behavioral effects disappeared. None of their manipulations affected the acute effects. ..."

From the abstract:

"Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses. At the cellular level, psychedelics induce structural neural plasticity, exemplified by the drug-evoked growth and remodeling of dendritic spines in cortical pyramidal cells.

A key question is how these cellular modifications map onto cell-type-specific circuits to produce the psychedelics’ behavioral actions.

Here we use in vivo optical imaging, chemogenetic perturbation and cell-type-specific electrophysiology to investigate the impact of psilocybin on the two main types of pyramidal cells in the mouse medial frontal cortex.

We find that a single dose of psilocybin increases the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types.

Behaviorally, silencing the PT neurons eliminates psilocybin’s ability to ameliorate stress-related phenotypes, whereas silencing IT neurons has no detectable effect. In PT neurons only, psilocybin boosts synaptic calcium transients and elevates firing rates acutely after administration.

Targeted knockout of 5-HT2A receptors abolishes psilocybin’s effects on stress-related behaviour and structural plasticity. Collectively, these results identify that a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex have essential roles in psilocybin’s long-term drug action."

Hitting the target: Imaging reveals psilocybin’s neural odyssey | Cornell Chronicle

The neurons that mediate a psychedelic’s long-term antidepressive effects (research briefing; no public access) "Psilocybin, a classic psychedelic, has therapeutic potential for psychiatric disorders. A specific brain circuit and receptor have now been found to be required for psilocybin’s long-term effects on neural plasticity and depression-related behaviour."

Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors (no public access)

Pyramidal cell types and 5-HT2A receptors are essential for psilocybin’s lasting drug action (preprint, open access)

Fig. 1 Psilocybin induces structural plasticity in both PT and IT types of frontal cortical pyramidal neurons