Psilocybin helps the brain unlearn fear by silencing specific neural pathways

A new study published in Nature Neuroscience provides a detailed look at how the psychedelic drug psilocybin facilitates the unlearning of fear in the brain. The research reveals that the drug does not simply boost learning capabilities but specifically coordinates the suppression of neurons holding traumatic memories while recruiting new cells to encode safety. These changes in neural activity patterns were found to predict how successfully an individual could overcome a conditioned fear response.

Neuropsychiatric conditions often trap patients in rigid patterns of thought and behavior. Disorders such as post-traumatic stress disorder (PTSD), depression, and anxiety affect over a billion people globally. A defining feature of these conditions is behavioral inflexibility. This is the inability to adapt to new information, such as realizing a previously dangerous trigger is now safe.

Psilocybin is a compound naturally found in certain species of mushrooms. It has emerged as a potential treatment for these stubborn disorders. Clinical trials have shown that even a single dose can produce lasting improvements in mental health. Patients often report increased feelings of well-being and a greater ability to break out of negative thought loops.

Despite these promising clinical results, the biological changes driving this flexibility remain partially understood. Researchers know that psilocybin activates specific serotonin receptors in the brain. This activation initiates a cascade of molecular events that promote neural plasticity, which is the brain’s ability to rewire itself. However, it has been unclear how these molecular changes translate into the editing of specific memories within neural circuits.

A team of researchers sought to bridge the gap between molecular signaling and behavioral change. The study was authored by Sophie A. Rogers, Elizabeth A. Heller, and Gregory Corder from the Perelman School of Medicine at the University of Pennsylvania. They focused their investigation on the retrosplenial cortex.

The retrosplenial cortex is a brain region essential for memory and navigation. It helps the brain link past events with current contexts to guide future behavior. This area is particularly active when the brain must associate two events that are separated by a span of time. This function makes it a prime candidate for storing the types of complex fear memories that characterize human trauma.

To understand how psilocybin affects this region, the researchers employed a mouse model of fear learning. They used a technique called trace fear conditioning. In this protocol, mice hear a tone, followed by a twenty-second silence, and then receive a mild electric shock.

The silence, or “trace period,” forces the brain to maintain a memory of the tone to associate it with the impending shock. This requires the active participation of the cortex. Once the mice learned this association, they displayed fear by freezing in place when they heard the tone.

The researchers then put the mice through an extinction process. This is similar to exposure therapy in humans. The mice were exposed to the tone and the waiting period repeatedly, but the shock was omitted. Over time, animals typically learn that the tone no longer signals danger.

Thirty minutes before the first extinction session, the researchers administered either a saline solution or a dose of psilocybin to the mice. They monitored the animals’ behavior over several days to see how well they retained the safety memory. To observe the brain during this process, the team used miniature microscopes implanted in the mice.

These devices allowed the scientists to perform longitudinal single-cell calcium imaging. This technology visualizes the activity of hundreds of individual neurons in the living brain. When a neuron fires, calcium floods the cell, which the microscope records as a flash of light.

By tracking the same neurons over five days, the team could identify which cells were involved in different stages of the experiment. They used a computational analysis to group these neurons into “ensembles.” An ensemble is a team of neurons that fire together to represent a specific piece of information, such as the fear memory or the new safety memory.

The behavioral results showed significant variability among the subjects. Psilocybin did not universally cure fear in every animal. Instead, the population split into “responders” and “non-responders.” The researchers classified these as low-freezing and high-freezing groups based on their behavior days after the drug was administered.

In the low-freezing group, the mice that received psilocybin extinguished their fear more effectively than the control group. They learned that the tone was safe and stopped freezing. This allowed the researchers to compare the brain activity of animals that successfully adapted with those that did not.

The imaging data uncovered a distinct neural signature in the successful mice. During the initial formation of the fear memory, a specific group of neurons in the retrosplenial cortex became highly active. In mice that failed to overcome their fear, this “fear ensemble” remained active throughout the extinction sessions. The old memory trace persisted, drowning out new information.

A different pattern emerged in the mice that responded well to psilocybin. In these animals, the drug appeared to cause a rapid and lasting suppression of the fear ensemble. The neurons associated with the traumatic event were silenced. This suppression was much stronger in the psilocybin group than in the saline control group.

Simultaneously, a new group of neurons began to fire. The researchers identified this as the “extinction ensemble.” These cells encoded the new information that the context was safe. The study found that the inhibition of the fear neurons was linked to the successful recruitment of these safety neurons.

This phenomenon is described as bidirectional modulation. The drug did not simply excite the entire brain region. Instead, it turned down the volume on the maladaptive memory while turning up the volume on the adaptive one. The balance between these two populations of neurons predicted the animal’s behavior.

The researchers observed that this remodeling happened rapidly. The suppression of the fear-active neurons occurred during the session when the drug was active. This suggests that the psychedelic state creates an opportunity for the brain to overwrite established patterns.

To verify their interpretation, the team built a computational model of this neural circuit. They simulated two populations of neurons that inhibited each other. One represented the fear memory, and the other represented the extinction memory.

The model showed that simply boosting the safety neurons was insufficient to explain the behavioral results. To replicate the rapid learning seen in the mice, the model required the active inhibition of the fear neurons. When the fear neurons were suppressed, the safety neurons were able to emerge and stabilize.

This computational finding aligns with the experimental data. It supports the idea that psilocybin facilitates flexibility by disrupting the dominance of entrenched neural patterns. This allows weaker, alternative pathways to gain strength.

The study also noted acute effects on behavior during the drug experience itself. Mice under the influence of psilocybin showed disrupted freezing patterns during the first extinction session. Their freezing bouts were shorter and more frequent. This suggests that the drug acutely interferes with the retrieval or expression of the fear memory.

The researchers analyzed how the neurons encoded the act of freezing. In control mice, distinct patterns of neural activity separated moments of motion from moments of freezing. In psilocybin-treated mice, this distinction blurred. The neural representation of the behavior became less precise while the drug was active.

However, this acute disruption was temporary. Two days later, the neural encoding of freezing returned and was even stronger in the animals that had learned effectively. This indicates that the temporary dismantling of neural structure may be a necessary step in rebuilding a more adaptive one.

There are limitations to this research. The study relied on freezing behavior as the primary metric for fear. It is possible that mice experience or express fear in ways that this specific measurement does not capture. Additionally, the variability in response suggests that biological differences between individuals influence the drug’s efficacy.

The distinction between responders and non-responders is significant. It indicates that psilocybin is not a magic bullet that works automatically for every subject. Understanding why some brains are primed to respond while others remain rigid is a necessary next step.

Future research will need to investigate the molecular identity of the neurons involved. Identifying the specific markers on the fear-active neurons could help explain why they are susceptible to psilocybin-induced suppression. This could lead to more targeted pharmaceutical interventions.

The authors also suggest that these findings might apply to other forms of rigid behavior. The mechanism of suppressing a dominant, maladaptive ensemble to allow a new behavior to emerge could be relevant for addiction or obsessive-compulsive disorders. The retrosplenial cortex is just one node in a larger network, and similar dynamics may play out elsewhere in the brain.

This study provides a concrete neural mechanism for the therapeutic effects of psychedelics. It moves beyond general statements about plasticity to identify specific circuit-level changes. By dampening the noise of past trauma, psilocybin appears to open a window for the brain to learn that the world is safe again.

The study, “Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles,” was authored by Sophie A. Rogers, Elizabeth A. Heller & Gregory Corder.