Project Summary/Abstract This is the third renewal in a line of inquiry characterizing the neural basis of cognitive maturation through the adolescent period, a time of critical vulnerability to the emergence of major psychopathology (e.g., schizophrenia, mood disorders). We will build on findings from the first three grants using a comprehensive cognitive battery and multimodal neuroimaging, more recently including high field (7T) Magnetic Resonance Spectroscopic Imaging (MRSI), Tissue Iron, and Magnetization Transfer, indicating important specialization in cognitive brain systems during adolescence underlied by changes in neurotransmitters and myelination. We now propose to investigate the contributions of mechanisms of synaptic plasticity by leveraging advances in high field 7T MRI to characterize developmental changes in markers of synaptic pruning as well as braking factors of plasticity and their contributions to the transition from variable executive function in adolescence to stable and reliable cognition in adulthood. Our Central Hypothesis is that the transition in neurocognition from adolescence to adulthood is underlied by synaptic pruning in the PFC, triggered by the completion of puberty, establishment of DA availability and formation of peri- neuronal nets (PNNs), which support the stabilization of cognitive processes and associated brain systems func- tion. In Aim 1, we will leverage brain phosphorus (31P) Magnetic Resonance Spectroscopy, to characterize in vivo in humans phospholipid indices of the developmental trajectory of normative loss of synapses, complemented by 1H MRSI measures of age-related decreases in excitatory glutamate function, which we identified in the last grant; advanced approaches using DWI to assess neural complexity (NODDI); and microRNA markers of mechanisms of synaptic plasticity. We hypothesize that PME/PDE (from 31P-MRSI), miRs involved in synaptic pruning, NODDI, and glutamate (from 1H-MRSI) will show associated changes through adolescence stabilizing in the second decade of life. In Aim 2, we will characterize associations between synaptic pruning and neurocognitive development. We hypothesize that from adolescence to adulthood, stabilization of executive function (EF), variability in brain activa- tion, and frontostriatal connectivity will be associated with, and mediated by, synaptic pruning, stabilizing to optimal processing in adulthood. Finally in Aim 3, we will characterize the role of critical period closing factors into adult- hood. We hypothesize that stability will coincide with growth plate fusion evidence of the completion of puberty and will be associated with the stabilization of striatal tissue iron indices of DA availability, peripheral levels of miRs implicated in PNN formation, and increased myelination, which act as closing factors for this window of plasticity. We will study 192 10-26 year olds who do not have an Axis 1 diagnosis in themselves of a first degree relative and will be tested in an accelerated cohort design with three time points at 18-month intervals. Together these findings will provide innovative evidence for neural mechanisms underlying synaptic plasticity underlying the unique transi- tion from adolescence to adult stabilization of neurocognitive processes informing a normative trajectory of matu- ration, a critical step for discerning vulnerabilities for abnormal development that can lead to psychopathology.

Project Narrative Understanding changes in the brain that occur during the transition from adolescence to adulthood is critical for informing how major mental illness such as schizophrenia, mood disorders, substance use disorders, and others emerge at this time. Past studies, primarily in animals and in postmortem human brains, indicate a normative decrease of neural connections that is critical for refining brain communication and determining adult trajectories. We propose to use state of the art brain imaging and genetic approaches to delineate how the brain refines from adolescence to adulthood to support maturation of cognition, a critical first step for discerning what goes awry in psychopathology.