Brainwide circuitry mapping reveals how psilocybin drives therapeutic neural rewiring

An international collaboration led by Cornell University researchers used a combination of psilocybin and the rabies virus to map how – and where – the psychedelic compound rewires the connections in the brain.

Specifically, they showed psilocybin weakens the cortico-cortical feedback loops that can lock people into negative thinking. Psilocybin also strengthens pathways to subcortical regions that turn sensory perceptions into action, essentially enhancing sensory-motor responses.

The findings published Dec. 5 in Cell.

The project is the latest by Alex Kwan, professor of biomedical engineering and the paper's senior author. Kwan's lab studies the ways psychiatric drugs such as psilocybin, ketamine and 5-MeO-DMT rewire the brain's neurological circuitry, with the goal of developing therapeutic treatments for depression.

Psilocybin, which is the active ingredient in magic mushrooms, is a promising candidate for pharmaceutical development because the clinical trials has shown that the psychedelic drug can reduce symptoms in people with depression – for weeks and perhaps even months after a single treatment.

With psilocybin, it's like we're adding all these roads to the brain, but we don't know where the roads go. Here we use the rabies virus to read out the connectivity in the brain, because these viruses are engineered in nature to transmit between neurons. That's how they're so deadly. It jumps a synapse and goes from one neuron to another."

 Alex Kwan, professor of biomedical engineering and the paper's senior author

The researchers saw that the sensory area of the brain becomes more strongly wired to the subcortical region, strengthening the link between perception and action.

Initially Kwan expected to find connections between one or two regions of the brain, but he was surprised to discover psilocybin's rewiring involved the whole brain. 

"This is really looking at brain-wide changes," he said. "That's a scale that we have not worked at before. A lot of times, we're focusing on a small part of the neural circuit."

The extensive pathway mapping also showed that the amount of firing activity in the brain may determine what gets rewired by the drug. That inspired the researchers to demonstrate that by perturbing and manipulating the neural activity of one brain region, they could actually change the way psilocybin rewires the circuitry.

"That opens up many possibilities for therapeutics, how you maybe avoid some of the plasticity that's negative and then enhance specifically those that are positive," Kwan said.

The research was supported by One Mind and the National Institutes of Health.