Psilocybin, Rabies, and the Brain: How Scientists Are Mapping Depression’s Escape Routes
Psychedelic research is entering a new phase — one where scientists are no longer just asking whether compounds like psilocybin work, but how they fundamentally reshape the brain. In a striking new study published December 5th in Cell, researchers revealed how psilocybin rewires neural circuits involved in depression — with help from an unlikely biological tool: the rabies virus.
The international research effort was led by Cornell University, with collaborators spanning institutions in the U.S. and Asia. Their goal was ambitious: to map, in detail, how psilocybin alters brain connectivity at a circuit-wide level — something that has remained elusive despite growing clinical evidence of the drug’s antidepressant effects.
What they found offers one of the clearest mechanistic explanations yet for why a single psychedelic experience can lead to lasting relief from depression.
Why Brain Wiring Matters in Depression
Depression is not simply a chemical imbalance. It is increasingly understood as a disorder of rigid neural circuitry, where the brain becomes trapped in repetitive patterns of thought and behavior.
One of the most damaging features of depression is rumination — the tendency to cycle endlessly through negative thoughts. These loops are believed to be reinforced by recurrent cortico-cortical connections, especially in frontal brain regions involved in self-referential thinking.
Psilocybin, the active compound in magic mushrooms, has shown remarkable promise in clinical trials, with patients often experiencing relief for weeks or months after a single dose. But until now, scientists lacked a detailed map of which brain connections change — and how those changes might break depressive cycles.
From Dendrites to Entire Circuits
This new study builds on earlier work from Alex Kwan, Ph.D., professor of biomedical engineering at Cornell and senior author on the paper. In 2021, Kwan’s lab demonstrated that a single dose of psilocybin rapidly increases structural plasticity, causing neurons to grow new dendritic spines — the physical structures that form synapses.
That finding helped explain why psilocybin’s effects last. But a key question remained unanswered.
“A lot of people were excited about the earlier study, because psychedelics are promising therapeutics but we don’t know why they work,” Kwan said. “Our study showed that the rewiring in the brain lasts a long time. One of the key questions was that, even though we show that new connections are being made, we don’t know where they connect. The goal of this study is to figure out: what exactly are the parts of the circuit that get rewired?”
Answering that required a radically different approach.
Enter the Rabies Virus
To map brain-wide connectivity, Kwan’s team partnered with researchers at the Allen Institute for Brain Science in Seattle. Instead of relying solely on optical imaging, they turned to a genetically engineered version of the rabies virus — a pathogen uniquely suited for tracing neural connections.
Rabies naturally spreads from neuron to neuron by jumping across synapses. Scientists have learned how to harness this property safely, modifying the virus so it labels connected neurons with fluorescent proteins instead of causing disease.
“With psilocybin, it’s like we’re adding all these roads to the brain, but we don’t know where the roads go,” Kwan explained. “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.”
In essence, the virus functions like Google Maps for the brain, revealing where newly formed connections actually lead.
The Experiment: Tracking Psilocybin’s Pathways
The researchers administered a single dose of psilocybin to mice, targeting frontal cortical pyramidal neurons, which play a central role in cognition and mood regulation. One day later, they introduced the modified rabies virus, allowing it to spread across synapses and label connected neurons.
After a week of incubation, the team imaged the brains and compared them with control mice that received the virus but not psilocybin.
What emerged was a detailed, brain-wide map of how psilocybin reshapes connectivity.
Breaking the Loop of Negative Thought
One of the most significant findings was that psilocybin weakens recurrent connections within the cortex — precisely the feedback loops thought to sustain 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,” Kwan said. “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.”
In other words, psilocybin appears to loosen the grip of the mind on itself, making it harder for negative thoughts to reinforce one another endlessly.
Strengthening the Link Between Perception and Action
At the same time, the study revealed a complementary effect: psilocybin strengthens connections between sensory regions of the cortex and subcortical brain areas.
These subcortical regions are responsible for turning perception into action — helping organisms respond to the world rather than becoming stuck in internal narratives. Strengthening these pathways may explain why many people report feeling more present, embodied, and responsive after psychedelic experiences.
Rather than overthinking, the brain becomes more oriented toward doing.
A Whole-Brain Phenomenon
Initially, the researchers expected to see changes in only a handful of circuits. Instead, psilocybin’s effects turned out to be global.
“This is really looking at brain-wide changes,” Kwan 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.”
This finding aligns with subjective psychedelic reports, which often describe a sense of whole-system reset rather than localized change.
Guiding Plasticity for Better Therapies
Another key insight from the study is that neural activity itself influences what gets rewired. Regions that were more active during psilocybin exposure showed greater changes in connectivity.
Crucially, the team demonstrated that by manipulating activity in specific brain regions, they could influence how psilocybin reshaped circuits.
“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.
This raises the possibility of combining psychedelics with targeted therapies — such as psychotherapy, brain stimulation, or behavioral interventions — to guide plasticity in beneficial directions.
What This Means for Psychedelic Medicine
This study represents a major step forward in understanding how psilocybin treats depression at a circuit level. Rather than simply boosting mood, the compound appears to reorganize the brain’s wiring, weakening rigid feedback loops while strengthening pathways that support engagement with the world.
It also highlights why set, setting, and context matter so much. If neural activity shapes plasticity, then what happens during a psychedelic experience may directly influence long-term outcomes.
As psychedelic therapies move closer to mainstream medicine, research like this provides a crucial foundation — showing not just that these compounds work, but how they open new routes out of depression, one neural pathway at a time.
