How psychedelics remap the brain to help overcome traumatic fear

Sophie A. Rogers was the lead author on this study. Sophie is a sixth-year PhD candidate investigating the impact of psychedelics on cortical computations underlying persistent fear and pain in Dr. Gregory Corder's laboratory at the University of Pennsylvania. Sophie's thesis work has been published in Nature Neuroscience, accepted in Nature, and was awarded an F31 training grant from the National Institute of Neurological Disorders and Stroke. In 2020, Sophie graduated from the University of Chicago with an Honors B.S. in Neuroscience, after completing an undergraduate thesis in the laboratory of Dr. Ming Xu. In 2026, she will join the laboratory of Dr. Maria Geffen at UPenn as a postdoctoral fellow studying the effect of psilocybin on auditory predictive processing in mouse models of autism spectrum disorder. In the future, Sophie hopes to become an independent academic researcher using large-scale neural recordings and computational techniques to understand how psychedelics alter mood, motivation, and decision-making across disease models.

or technically,

Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles

[See Original Abstract on Pubmed]

Authors of the study: Sophie A. Rogers, Elizabeth A. Heller & Gregory Corder

According to the World Health Organization, approximately 70% of people worldwide will experience a potentially traumatic event in their lifetime. Of these people, 5.6% will go on to develop post-traumatic stress disorder (PTSD), which is a condition where individuals have persistent, frightening thoughts and memories of the traumatic event. Often, individuals with PTSD experience sleep problems, feel detached or numb, or may be easily startled. Psychedelic drugs are being increasingly researched as a tool to help people overcome mental health conditions like PTSD. One of the most commonly studied drugs, and the focus of today's post, is called psilocybin. Although no large-scale clinical study has investigated psilocybin as a treatment for PTSD, scientists have found that even a single dose of psilocybin can have lasting impact on patients suffering from other neuropsychiatric disorders such as depression, substance use disorder and anxiety. In order to explore the effects of psilocybin on trauma, Sophie Rogers, a former NGG graduate student in Greg Corder’s lab, carried out experiments in mice to identify how psilocybin affects the brain after a traumatic events.

            To begin exploring the question of how psilocybin produces its therapeutic effects on the brain, Sophie first needed to choose a way to model a traumatic event in mice. She used a very common experimental approach called trace fear conditioning (TFC). Under this approach, mice undergo a 5-day long experiment (Figure 1). On the first day, called habituation, mice are placed in a box (Box A) and a sound is played. The mice explore the environment and become familiar and comfortable with the box and the sound that is played. On the second day, mice are placed in a new box (Box B) and now, 20 seconds after the sound is played (the same sound from day 1), the mice receive a ~2 second electric shock, which is considered a traumatic event for the mice. On this day of the experiment, called acquisition, the mice learn to associate the sound played and the box environment with a painful memory. On the third, fourth and fifth days, the mice are returned to the original box (Box A) and the same sound is again played but without any shocks delivered. These final three days are called extinction, where the mice slowly learn that the sound no longer predicts the shock.

Figure 1. Illustration of the experimental approach used to investigate the effect of psilocybin on traumatic fear memories. The graphs below each box represent the relative amount of freezing that mice, on average, exhibited on a given day of the protocol.

Throughout the experiment, scientists can measure how afraid of the sound the mice are by measuring the amount of time that the mice spend freezing, defined as the complete absence of movement except for breathing. In this experiment, freezing levels are very low or zero on day 1 (habitation) but after the shock is delivered on day 2 (acquisition), the mice start to freeze for as high as 50% of the time. On day 3, the mice show a very high freezing response to the sound despite being in Box A, rather than Box B, where the shock took place. This demonstrates the fear memory of the mice is generalized to different contexts, which occurs similarly in PTSD patients. Throughout extinction (days 3-5), most mice show a decline in freezing behavior, suggesting that they are beginning to loosen the association between the sound and the shock. However, their overall freezing levels are still way higher than during the habitation day (before the shock was introduced at all), suggesting that the fear memory is still present.

Sophie next wanted to test whether giving mice the psilocybin drug directly after acquisition (day 2) affected how they responded during the extinction (days 3-5). If psilocybin helps in overcoming the traumatic memory, we would expect that psilocybin-treated mice would show even lower freezing on the extinction days than those that were not given psilocybin (control). Interestingly, Sophie found some mice were greatly benefited by the psilocybin, showing a large reduction in freezing compared to the control mice, but not all the mice that received psilocybin after acquisition responded this way. This suggests that there is significant individual variability when it comes to  psilocybin’s effect on treating traumatic events. Nevertheless, Sopie wanted to take a closer look at the brains of the mice to determine if something was different between the group of mice that were benefitted by psilocybin versus the group that was not benefitted, along with the control group.

In order to determine how the psilocybin affected the brains of these mice after trace fear conditioning (TFC), Sophie measured the “activity” of single brain cells, or neurons, in an area called the retrosplenial cortex (RSC). Some neurons become active in response to things in our environment that they represent, for example a “sound neuron” might be activated by a sound being played. Other neurons become active in response to more internal things, like fear and memories. Sophie chose to focus on RSC because the neurons in the area are involved in storing and retrieving memories of lived experiences and because these neurons are involved in extinguishing fear memories. Sophie measured the activity of individual neurons in this brain area across the 5 days of trace fear conditioning (TFC). She found that in control mice, there was a group of neurons in the RSC that were strongly activated after the acquisition of the fear memory (day 2). During extinction (days 3-5) and while the control mice were freezing, this group of ‘fear neurons’ was highly active and did not vary much. This suggests that the fear neurons in RSC were inflexible while the mice remained focused on the strong association formed between the sound and the shock, even in the absence of the shock. When Sophie looked at the RSC neurons of mice that were given psilocybin and showed reduced freezing, she found that the group of fear neurons were less active during freezing and instead became more active in response to other things, like walking around. In other words, the neurons in the psilocybin mice were more flexible and able to dissociate from the original fear response. So Sophie found that psilocybin helps overcome traumatic experiences like TFC by allowing the brain to be more flexible, which enables therapeutic-like responses.

Taken together, Sophie’s results offer strong motivation for future studies of psilocybin on the treatment of neuropsychiatric disorders, like PTSD. Her work in mice shows us that psilocybin has a powerful effect on the brain’s ability to process and overcome traumatic events by changing how our brain responds to things associated with bad experiences. Furthermore, her finding that the effects of psilocybin can vary between individual mice leaves open the question of why some people respond differently to the same treatment. One possibility is that the mice that weren’t helped by psilocybin were already “behaviorally rigid” meaning that they were already prone to repetitive, inflexible behaviors. This may correspond to a person who suffers from PTSD, in addition to other neuropsychiatric disorders, like obsessive compulsive disorder, for example. It may be the case, therefore, that patients with multiple or overlapping disorders would not benefit from psilocybin treatment. Nevertheless, Sophie’s work provides invaluable insight into how psilocybin could be used as a therapeutic drug for the treatment of neuropsychiatric disorders, like PTSD.

About the brief writer: Jafar Bhatti

Jafar Bhatti is a PhD Candidate in the lab of Dr. Long Ding / Dr. Josh Gold. He is broadly interested in brain systems involved in sensory decision-making.

Want to dive deeper into how psilocybin affects the brain after trauma?
Check out Sophie’s full research paper here.