EARLY LIFE STRESS FACILITATION OF FEAR MEMORY ASSOCIATED WITH CELLULAR ENGRAM DYNAMICS IN THE DORSAL DENTATE GYRUS

Early life adversity (ELA) is a leading risk factor for the development of stress- and anxiety disorders, such as post-traumatic stress disorder (PTSD). However, the biological basis of the stress enhancing ELA effect towards adult trauma experience has not been sufficiently clarified. This can be studied by addressing contextual fear memory encoding and retrieval, the disturbance of which represents a hallmark of PTSD. Therefore, using an established rodent model of ELA, we applied a variable three-day stress paradigm to pre-pubertal male mice (postnatal days 24 to 26), which corresponds to mid-childhood in humans, and tested their contextual fear memory during adulthood. Strikingly, ELA animals displayed significantly enhanced fear memory 7 days, but not 1 day after contextual fear conditioning, in line with the delayed development of PTSD pathology after trauma. Immunohistochemical analysis revealed hyperactivity in the right amygdala of ELA groups at both retrieval time points, but an increased reactivation of engram cells in the dorsal dentate gyrus at the 7-day time point, as determined with the viral Robust Activity Marking system. Behavioral profiling is used to further categorize the individual outcomes of stress, anxiety and engram reactivation in affected and unaffected individuals. Our findings highlight the association of cellular memory engram dynamics with the development of ELA-induced excessive fear memory.