PROJECT SUMMARYUp to 50% of peripubertal youth with anxiety have unmet clinical needs, leaving these youth at high risk forsuicide, depression and substance abuse across adolescence. In accord with the NIMH strategic plan, we aimto deepen mechanistic understanding of anxiety during the sensitive period of peripuberty to inform noveltreatments and reduce health risks. This proposal focuses on negative overgeneralization, which is a coredimension of anxiety that is poorly understood, and refers to the tendency to generalize aversive responsesfrom one context (house fire) to other contexts (camp-fire) that share features. Amygdala activity, induced byheightened emotional arousal, enhances plasticity in associative learning mechanisms, facilitating the bindingof contextual features in memory that are only loosely related. We posit that sleep plays a critical role innegative overgeneralization. Specifically, we draw from basic neuroscience to propose a model by whichheightened amygdala reactivity during wakefulness, induced by increased emotional arousal, facilitates replayof negative memories during sleep. This facilitated replay leads to the stabilization and integration(consolidation) of negative memories into long-term memory networks via slow wave oscillatory events duringNREM sleep. We further propose that facilitated replay of negative memories during sleep promotesgeneralization by influencing underlying neurocomputational mechanisms (i.e., pattern completion – acomputational process that makes neural representations similar). Finally, we propose that sleep-dependentconsolidation is malleable, such that Targeted Memory Reactivation (TMR) of positive memories during sleepcan competitively displace consolidation of negative memories, and reduce negative overgeneralization. Thecurrent proposal tests this model using a novel multi-method approach combining neuroimaging,polysomnography, and a memory task that captures behavioral generalization and its underlying neuralmechanisms (i.e. pattern completion). Aim 1 examines 200 peripubertal youth (ages 10-13 years) across a fullcontinuum of anxious symptoms in a randomized sleep (n=140) versus wake (n=60) design to demonstratesleep-dependent effects on behavioral and neural mechanisms of negative overgeneralization. Aim 2 focuseson the 140 youth in the sleep condition to evaluate amygdala reactivity at encoding and sleep neurophysiologyduring post-encoding sleep as mediators between anxiety and negative overgeneralization. Aim 3 uses thesame design as the sleep condition but recruits a new sample of youth with elevated anxiety (n=60) to enroll ina randomized trial in which positive memories are cued during sleep (TMR, n=30), or sham cues are presentedduring sleep (n=30), to examine malleability of sleep-dependent mechanisms of negative overgeneralization.This project will set the stage for the long-term goal of developing novel interventions that manipulate sleep(e.g. via TMR) not only to improve existing symptoms, but also to positively shape neurodevelopment andreduce risk in the sensitive period of peripuberty.
