Intense stress can cloud memories, increasing generalized fear responses. A new study published in *Cell* sheds light on this phenomenon, potentially revolutionizing the treatment of PTSD and anxiety disorders. Researchers discovered that stress hormones dramatically alter how memories are recorded in the brain, leading to imprecise recollections and a heightened susceptibility to misinterpreting safe stimuli as threats.
The research, conducted on mice, reveals the intricate mechanisms behind this process. Lead author Sheena Josselyn, a memory researcher at The Hospital for Sick Children and the University of Toronto, explains that acute stress fundamentally changes memory encoding. For instance, someone exposed to gunfire might later experience intense fear upon hearing a loud noise – an inappropriate, overgeneralized fear response. This phenomenon, known as fear overgeneralization, is a hallmark of anxiety disorders.
To understand the underlying brain mechanisms, Josselyn and her team subjected lab mice to 30 minutes of restricted movement, a significant stressor for rodents. These mice were then trained to associate two distinct sounds: one paired with an unpleasant electric shock, and one that was neutral. Predictably, the stressed mice exhibited impaired memory of the sounds, exhibiting fear responses to a wide range of sounds, not just the one associated with the shock.
Delving deeper into the brains of these stressed mice, the researchers examined the ‘engram’ – the physical trace of a memory represented by altered neuronal activity. Normally, engrams are ‘sparse,’ involving a relatively small number of neurons, preventing memories from becoming muddled. However, under stress, the engrams became significantly larger. This was attributed to the disruption of inhibitory interneurons – the ‘bouncers’ of the brain, which regulate neuronal activity and prevent an excessive number of neurons from being recruited into a memory trace.
Stress, through the release of corticosterone (the rodent equivalent of cortisol), triggered the release of endocannabinoids. These neurotransmitters then inhibited the inhibitory interneurons, leading to the expanded engrams and the resulting memory distortions. This explains the characteristic haziness of traumatic memories and the tendency towards fear overgeneralization, as more neurons are involved in encoding the experience.
Crucially, the researchers demonstrated that administering metyrapone, a drug that blocks corticosterone synthesis, before stress exposure, reversed these effects without impairing the memory of the original stressful event. This suggests a potential therapeutic target for future treatments.
While this research utilized mice, the implications for understanding human PTSD and generalized anxiety disorders are profound. Denise Cai, an associate professor of neuroscience at Mount Sinai, highlights the study’s translational relevance for developing targeted therapies that counteract the negative effects of stress on memory without compromising other memories. The findings hold significant promise for the development of new treatments for PTSD and anxiety disorders.
However, the study also raises important questions surrounding the use of cannabis in treating PTSD. While some clinical trials explore the potential benefits of cannabinoids, the field remains in its early stages, and the US Department of Veterans Affairs currently advises against using cannabis products for PTSD. The potential impacts of cannabinoids on memory and anxiety need further investigation.
This research underscores the critical link between stress, memory distortion, and anxiety disorders, opening exciting new avenues for therapeutic intervention and highlighting the urgent need for further research, particularly into the effects of cannabinoids on PTSD treatment. The findings offer a crucial step toward more effective and targeted therapies to alleviate the suffering of those affected by these debilitating conditions.
