Researchers have paired the active ingredient in magic mushrooms with the rabies virus to create a wiring diagram showing precisely how psychedelics physically alter the brain to treat depression.
An international collaboration led by Cornell University used the virus to chart the brain’s “very complex wiring diagram,” revealing that psilocybin weakens the neural feedback loops that lock patients into negative thinking cycles while strengthening connections to areas governing action.
The study, published in Cell, solves a critical mystery in psychedelic science: whilst clinical trials have shown the drug can reduce depression symptoms for weeks or months, scientists previously did not know exactly which circuits were being rewired.
“With psilocybin, it’s like we’re adding all these roads to the brain, but we don’t know where the roads go,” said Alex Kwan, professor of biomedical engineering at Cornell Engineering and the paper’s senior author. “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.”
Jumping rabies virus
The research team employed a novel approach to map these connections. They first injected a single dose of psilocybin into a mouse’s frontal cortical pyramidal neurons. One day later, they introduced a variant of the rabies virus engineered to jump across synapses and label connected neurons with fluorescent proteins.
After incubating for a week, the team imaged the brain, using the virus like “Google’s mapping cars roaming all the streets in a neighbourhood” to visualise the changes.
The fluorescent tagging revealed that psilocybin had weakened recurrent connections within the cortex — specifically, the “cortico-cortical” feedback loops associated with rumination.
“Rumination is one of the main points for depression, where people have this unhealthy focus and they keep dwelling on the same negative thoughts,” said Kwan. “By reducing some of these feedback loops, our findings are consistent with the interpretation that psilocybin may rewire the brain to break, or at least weaken, that cycle.”
The mapping also revealed that the drug strengthens links to the subcortical region, potentially enhancing the brain’s ability to turn sensory perception into action. Surprisingly, the rewiring was not limited to specific areas but involved the entire brain.
“This is really looking at brain-wide changes,” said Kwan. “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.”
Crucially, the researchers discovered that neural firing activity determines which connections get rewired. By manipulating activity in specific brain regions, they could alter how the drug reshaped circuitry, suggesting future therapies could be targeted to avoid negative plasticity.
“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,” said Kwan.
