PROJECT SUMMARY Sleep is essential to our well-being, yet sleep problems are pervasive across mental health disorders and are heightened during adolescence – a developmental window of notable biological and social changes coinciding with escalations of anxiety disorders and depression. Consistent with the NIMH strategic plan, we aim to map the longitudinal course of sleep neurophysiology, brain maturation, emotion reactivity, and memory generalization and their relation to emotional health from the onset of adolescence through mid-late adolescence to inform novel treatments and minimize emotional health risks during this critical developmental window. In our ongoing R01, we have focused on mechanisms related to negative overgeneralization – a core dimension of anxiety that is poorly understood. We have found that sleep fails to depotentiate the response of the amygdala to negative stimuli in participants with elevated anxiety and negative overgeneralization emerges from an interplay between the amygdala at encoding and pattern completion supported by activity in the CA1 subfield of the hippocampus during retrieval. This proposal builds on and extends our ongoing R01 by longitudinally following the same individuals to investigate our hypothesis that altered emotional reactivity, sleep neurophysiology, and overgeneralization of negative memories arise from an imbalance between the amygdala and the hippocampus. Further, we posit that the amygdalo-hippocampal imbalance, exacerbated by the emotional and social changes prevalent during adolescence, contributes to the escalation of internalizing symptom severity often noted during this developmental window. The current renewal proposal tests this model using an accelerated longitudinal approach combining multiple methods – detailed clinical assessment, neuroimaging, polysomnography, and emotional memory task – across three time points, collected every ~18 months, in each participant to examine longitudinal maturation from peri-adolescence through mid-late adolescence. Youth (retained: n=140; newly recruited: n=80; total: N=220) across a continuum of anxiety symptoms, assigned to one of four cohorts based on their age at baseline will be enrolled in the proposed renewal study. Aim 1 will utilize the nocturnal polysomnography and structural and functional neuroimaging data collected at baseline and the two follow-up sessions to evaluate the longitudinal relation between amygdalo-hippocampal function and changes in sleep. Aim 2 will focus on behavior from the emotional memory task and functional neuroimaging data collected across waves to evaluate the longitudinal relation between amygdalo-hippocampal function and changes in negative overgeneralization. Aim 3 will incorporate the detailed clinical assessments collected across waves to investigate the longitudinal relation between amygdalo-hippocampal function, sleep neurophysiology, negative overgeneralization, and internalizing symptom severity. This project will provide critically needed data to advance mechanistic understanding of how sleep and neuromaturation influence emotional health in this sensitive period.

PROJECT NARRATIVE The current proposal focuses on the escalation of anxiety severity across adolescence and aims to elucidate a developmental mechanism rooted in the functional balance between the amygdala and hippocampus. We propose a developmental model for how altered amygdalo-hippocampal function in early adolescence contributes to heightened emotional reactivity, disturbed sleep neurophysiology, and the overgeneralization of negative memories, which in turn leads to the rise of internalizing symptom severity in mid-late adolescence. Support for our model would suggest that the functional balance between key brain structures in sensitive developmental periods are central to the course and severity of anxiety and related disorders and may point to novel biomarkers and interventions.