International Business Department           Liu Bojia           December 04, 2024

  Facing stress is something unavoidable in daily life. The right amount of stress can help the body to produce a positive attitude and enhance action; however, when the stress is too much, the brain may produce a lot of negative memories of the stressful scenario, which can destroy how an individual feels when faced with a similar scenario.

  Imagine when you are not good at or very afraid of going on stage to make a public speech, and when you face the gazes of many people on the stage, you will talk and tremble and feel dizzy. This immense stress will stick in your brain and may even make you feel nervous and tongue-tied when you encounter any scenario that requires you to interact with more than one person. While more serious symptoms may be seen in patients with Post Traumatic Stress Disorder (PTSD), many individuals who have suffered from disasters and serious accidents may be stimulated by normal life scenarios such as fireworks and engine rattles that can cause intense mental stimulation and heightened alertness, leading to excessive anxiety and distress.

  From a neuroscience perspective, PTSD patients experience a stress-induced generalisation of aversive memories, which means that the memory is no longer specific and any event can trigger this negative memory. Recently, researchers from the Toronto Children's Hospital and the University of Toronto in Canada collaborated to decipher the cause of the formation of this aversive memory generalisation, and they found that endogenous cannabinoids play a key role in the formation of such memories. By inhibiting cannabinoid-binding receptors in specific neurons, it was possible to restore the specificity of dangerous memories in mice, which opens up entirely new therapeutic ideas for PTSD treatment.

  According to the team's paper, published in Cell, the formation of specific memories is often associated with a class of ‘engram’ neurons. These memory-related neurons are active when memories are formed and recalled. When the authors analysed the brains of mice that had been subjected to stressful conditions, they found that these mice had more extensive imprinting, which is the underlying cause of post-stress disorders.

  For the study, the authors designed a special series of experiments in which groups of mice were first subjected to either corticosterone injections or restraint conditions to trigger a state of stress. The mice were then placed in a special space and a medium-pitched sound was played. After they rested for a while, the mice were then moved on to another space where they heard a high-pitched sound and received electric shocks to their feet. The control mice were subjected to the same process as the experimental group except that the stress was not triggered.

  At the end of the experiment, all the mice were placed in a completely new environment and the authors replayed the two different pitched sounds in turn. The results showed that the control mice only froze when they heard the high pitch, while the experimental mice froze no matter which sound they heard, suggesting that their memories were unable to distinguish between neutral and fearful events.

  The authors analysed the imprinted neurons of two batches of mice, and they found that the control mice had a smaller and restricted population of imprinted neurons, while the experimental mice had not only a larger number of imprinted neurons, but also a wider range of imprinted neurons. Among the neurons, there is a class of inhibitory neurons that are specifically involved in controlling the extent of imprinting, but the stressed mice seemed to have some problems.

  Normally, these inhibitory neurons release γ-aminobutyric acid (GABA) to tightly control the population of imprinted neurons; however, in response to a stressful stimulus, the brains of the mice released large amounts of endogenous cannabinoids, which bind to glucocorticoid receptors in the inhibitory neurons and prevent the release of GABA. The authors found that the higher the levels of endogenous cannabinoids, the less GABA was released from the inhibitory neurons, which represented a rapid weakening of their control, resulting in expanded imprinting and non-specificity of memory.

  In addition to finding this new mechanism, the authors found that there may already be means to restore this imprinting abnormality. A drug used to target the glucocorticoid receptor, mifepristone, can also play a role in reducing endogenous cannabinoid levels. After the use of such drugs, the mice did not develop PTSD-like symptoms even when they experienced stress. ‘With the study's deeper understanding of the mechanisms of memory formation, it may lead to new treatments in the future for people with psychiatric disorders who are plagued by memory.’ Paul W. Frankland, PhD, co-corresponding author of the study, said.