TaggingMemory · Understanding whole-brain circuits mediating fear memory attenuation

Understanding whole-brain circuits mediating fear memory attenuation

Post-traumatic Stress Disorder (PTSD) is a severe mental health condition that affects millions of people worldwide and represents a major societal and clinical challenge in Europe and beyond. A defining feature of PTSD is the persistence and maladaptive generalisation of fear, whereby individuals experience fear responses even in situations that should be perceived as safe. Although current treatments can reduce symptoms, the brain-wide mechanisms that drive fear extinction and fear discrimination are still poorly understood, limiting the development of more precise and effective interventions. This project addresses this gap by investigating how fear memories are formed, modified, and disrupted across whole-brain neural circuits. By combining behavioural paradigms with brain-wide cellular mapping, the project aims to identify the networks that support adaptive fear regulation and those that underlie pathological fear generalisation. Importantly, the project moves beyond extinction alone by explicitly including fear discrimination, a process that is often impaired in PTSD and closely linked to fear generalisation. To achieve these goals, the project developed an innovative multiple Arc (mArc) tagging system that enables simultaneous tracking of different memory-related neuronal ensembles within the same brain. This approach allows researchers to follow how fear memories evolve across learning, recall, discrimination, and extinction within individual subjects. When combined with whole-brain imaging and computational analysis, this strategy generates detailed, single-cell-resolution maps of memory-related brain activity. In parallel, the project examined how psychedelic and psychedelic-like compounds influence fear regulation. By testing pharmacological interventions in preclinical models, the project explored how these compounds affect brain-wide fear networks and whether they can reduce maladaptive fear generalisation. The identification of circuit-level changes linked to improved fear discrimination provides a mechanistic basis that may guide future PTSD therapies. Overall, the project advances understanding of how fear memories become dysregulated in pathological states and identifies the brain networks involved in PTSD-like behaviours, with long-term relevance for mental health research and European innovation priorities.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз