Psilocybin rewires brain circuits to boost fear extinction and behavioral flexibility in mice

Psilocybin, a psychedelic compound contained in some varieties of mushrooms, has recently been found to be promising for the treatment of some neuropsychiatric disorders, including depression, some anxiety disorders and post-traumatic stress disorder(PTSD). Some studies suggest that the consumption of this compound may be particularly advantageous for individuals who struggle to adapt their behavior in helpful ways when facing unexpected events or changes in their environment.

While a growing pool of research has been assessing the therapeutic benefits of psilocybin, the neural mechanisms through which it promotes long-lasting psychological changes remain poorly understood. If it does prompt greater behavioral flexibility in individuals diagnosed with some psychiatric disorders, the processes through which it does so are not yet clear.

Researchers at the University of Pennsylvania recently carried out a new study on mice, which was aimed at better understanding how psilocybin could increase adaptability and potentially ease symptoms of anxiety disorders or PTSD. Their findings, published in Nature Neuroscience, suggest that the compound prompts the reorganization of neural circuits in the retrosplenial cortex, a part of the brain located in the posterior region of the cerebral cortex (i.e., the outermost layer of the mammalian brain).

“The psychedelic drug psilocybin demonstrates rapid and long-lasting efficacy across neuropsychiatric disorders that are characterized by behavioral inflexibility,” Sophie A. Rogers, Elizabeth A. Heller and Gregory Corder wrote in their paper.

“However, its impact on the neural activity underlying sustained changes in behavioral flexibility has not been characterized. To test whether psilocybin enhances behavioral flexibility by altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the mouse retrosplenial cortex across a 5-day trace fear learning and extinction assay.”

As part of their study, the researchers trained the mice to associate a neutral stimulus with an unpleasant experience, such as a mild shock to their feet. Subsequently, they repeatedly presented the mice with the neural stimulus without shocking their feet, so that they could “unlearn” the fear response they had acquired earlier.

While they performed this experiment, the researchers tracked the activity of individual neurons in the mice’s retrosplenial cortex, using an experimental technique known as single-cell calcium imaging. This technique works by measuring calcium levels, which are known to rise when neurons are firing (i.e., when they are active).

After the mice had learned fear-based associations, the researchers administered a single dose of psilocybin to explore its impact on their neural activity and on their ability to unlearn the associations they had made. Ultimately, they used computational tools to model the neural mechanisms they had observed during their experiments.

“We found that a single dose of psilocybin altered cortical ensemble turnover and oppositely modulated fear- and extinction-active neurons. Suppression of fear-active neurons and recruitment of extinction-active neurons predicted psilocybin-enhanced fear extinction,” wrote Rogers, Heller and Corder.

“In a computational model of this microcircuit, inhibition of simulated fear-active units modulated recruitment of extinction-active units and behavioral variability in freezing, aligning with experimental results. These results suggest that psilocybin enhances behavioral flexibility by recruiting new neuronal populations and suppressing fear-active populations in the retrosplenial cortex.”

Overall, the findings of this recent study suggest that psilocybin promotes fear extinction (i.e., the unlearning of fearful responses to neutral stimuli previously associated with threats) via the reorganization of neural circuits in the retrosplenial cortex. Specifically, the team found that the compound suppressed the activity of fear-related neurons, while recruiting other neurons that become active as fears become extinct.

These results could prompt more research exploring the therapeutic benefits of psilocybin and how it could foster adaptive behavior. In addition, future work could examine the neural mechanisms identified by Rogers, Heller and Corder in greater depth to shed more light on their contribution to fear extinction and behavioral flexibility.

© 2025 Science X Network

Psilocybin, a psychedelic compound contained in some varieties of mushrooms, has recently been found to be promising for the treatment of some neuropsychiatric disorders, including depression, some anxiety disorders and post-traumatic stress disorder(PTSD). Some studies suggest that the consumption of this compound may be particularly advantageous for individuals who struggle to adapt their behavior in helpful ways when facing unexpected events or changes in their environment.

While a growing pool of research has been assessing the therapeutic benefits of psilocybin, the neural mechanisms through which it promotes long-lasting psychological changes remain poorly understood. If it does prompt greater behavioral flexibility in individuals diagnosed with some psychiatric disorders, the processes through which it does so are not yet clear.

Researchers at the University of Pennsylvania recently carried out a new study on mice, which was aimed at better understanding how psilocybin could increase adaptability and potentially ease symptoms of anxiety disorders or PTSD. Their findings, published in Nature Neuroscience, suggest that the compound prompts the reorganization of neural circuits in the retrosplenial cortex, a part of the brain located in the posterior region of the cerebral cortex (i.e., the outermost layer of the mammalian brain).

“The psychedelic drug psilocybin demonstrates rapid and long-lasting efficacy across neuropsychiatric disorders that are characterized by behavioral inflexibility,” Sophie A. Rogers, Elizabeth A. Heller and Gregory Corder wrote in their paper.

“However, its impact on the neural activity underlying sustained changes in behavioral flexibility has not been characterized. To test whether psilocybin enhances behavioral flexibility by altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the mouse retrosplenial cortex across a 5-day trace fear learning and extinction assay.”

As part of their study, the researchers trained the mice to associate a neutral stimulus with an unpleasant experience, such as a mild shock to their feet. Subsequently, they repeatedly presented the mice with the neural stimulus without shocking their feet, so that they could “unlearn” the fear response they had acquired earlier.

While they performed this experiment, the researchers tracked the activity of individual neurons in the mice’s retrosplenial cortex, using an experimental technique known as single-cell calcium imaging. This technique works by measuring calcium levels, which are known to rise when neurons are firing (i.e., when they are active).

After the mice had learned fear-based associations, the researchers administered a single dose of psilocybin to explore its impact on their neural activity and on their ability to unlearn the associations they had made. Ultimately, they used computational tools to model the neural mechanisms they had observed during their experiments.

“We found that a single dose of psilocybin altered cortical ensemble turnover and oppositely modulated fear- and extinction-active neurons. Suppression of fear-active neurons and recruitment of extinction-active neurons predicted psilocybin-enhanced fear extinction,” wrote Rogers, Heller and Corder.

“In a computational model of this microcircuit, inhibition of simulated fear-active units modulated recruitment of extinction-active units and behavioral variability in freezing, aligning with experimental results. These results suggest that psilocybin enhances behavioral flexibility by recruiting new neuronal populations and suppressing fear-active populations in the retrosplenial cortex.”

Overall, the findings of this recent study suggest that psilocybin promotes fear extinction (i.e., the unlearning of fearful responses to neutral stimuli previously associated with threats) via the reorganization of neural circuits in the retrosplenial cortex. Specifically, the team found that the compound suppressed the activity of fear-related neurons, while recruiting other neurons that become active as fears become extinct.

These results could prompt more research exploring the therapeutic benefits of psilocybin and how it could foster adaptive behavior. In addition, future work could examine the neural mechanisms identified by Rogers, Heller and Corder in greater depth to shed more light on their contribution to fear extinction and behavioral flexibility.

© 2025 Science X Network