ICF Sleep as a therapeutic target for enhancing resilience to traumatic experience

Most of us experience serious trauma during our lifetime. This trauma leads to post-traumatic stress disorder (PTSD) in approximately 10% of cases, though this can rise to 40% following major events such as terrorist attacks and wars. PTSD is disabling, involving distressing flashbacks, avoidance, hyperarousal, sleep disruption and co-morbid reduction of general health and productivity. Unfortunately, current pharmacological and psychological therapies fail to deliver long-term control of symptoms in ~50% of sufferers. Understanding what makes someone more vulnerable to PTSD and designing novel, biologically informed prevention and treatment strategies is essential, not least in the face of the global trauma of COVID-19.

Sleep plays a major role in shaping what and how we remember and understand from our daily experiences, filing and interpreting memories so that only those of most importance are stored. An increasing body of work suggests that sleep after a traumatic event plays a crucial role in the appropriate processing of that memory. Inadequate processing of traumatic experiences during sleep may therefore in part explain why PTSD develops. However, exactly how the brain processes emotional memories while we sleep is not well understood. For example, how is the brain able to reorganise and store traumatic memories, yet at the same time reduce their emotional tone to prevent distressing re-experiences? The classification of sleep into non-rapid eye movement (NREM) and REM may reflect differential roles in emotional memory, but there is currently limited direct evidence to support this.

This proposal integrates extensive clinical evidence for sleep's contributions to PTSD vulnerability, severity and therapy, the neuroscience of sleep-dependent memory consolidation, and my expertise in monitoring and manipulating network activity in the brain. My overarching objective is to validate sleep neurophysiology not only as a translatable metric of traumatic memory processing and vulnerability, but also as a potential therapeutic target. To do this I will record electrical activity patterns from large numbers of brain cells of freely behaving rats as they are exposed to a predatory threat, modelling traumatic experience. By measuring cellular activity during subsequent sleep, I will unravel the roles of NREM and REM sleep to establish how and when this traumatic experience is processed. I then aim to identify physiological markers of maladaptive processing of this experience, allowing me to predict which individual rats are more likely to develop PTSD-like symptoms. This essential knowledge will allow me to test the effectiveness of an emerging methodology, known as targeted memory reactivation, to modulate this memory processing and reduce the development of PTSD-like symptoms. For the final part of this project I will test this approach in healthy human participants after exposure to an experimental trauma-like paradigm. This will establish a proof-of-concept for developing a novel therapy for PTSD treatment and prevention.

Mapping the neurobiological bases of diverse responses to trauma is a prerequisite to precision-based prevention and treatment of PTSD. This project is designed to achieve this mapping with cellular resolution in a refined preclinical model, resolving longstanding uncertainties about the contributions of REM and non-REM sleep to emotional memory, enabling drug development, informing psychological therapies and public health interventions, and potentially extending the impact of sleep therapeutics to other psychiatric disorders.