Relative to many mammalian species, the brains of humans and other primates are immature at birth and undergo extensive postnatal changes. These include gray matter changes in neurotransmitter receptor levels and extensive white matter changes in myelination, which continue even into adulthood. Different brain regions mature at different rates, so a complete characterization of postnatal development requires an anatomic context, ideally at high spatial resolution. Regional differences in maturational processes are thought to play a major role in the timing of normal developmental milestones and are also hypothesized to define critical temporal periods of vulnerability during which brain injury may lead to specific patterns of deficits. Critical periods in postnatal brain development has been identified in an NIMH National Advisory Mental Health Council Workgroup report as a high priority area for accelerating translational research in mental illness. Human developmental studies of neurotransmitter receptors are limited in terms of time points and regions sampled and in terms of the number of receptor types characterized, a situation unlikely to change given the difficulties of obtaining suitable post-mortem postnatal human tissues and the radiation exposures required for in vivo measurements. Post-mortem human studies of myelination are available, but provide only broad anatomic generalizations. Likewise, in vivo human myelination studies using magnetic resonance (MR) imaging have limited resolution, are typically based on fast acquisitions that potentially confound myelin with other signals and are complicated by the fact that the positions of individual tracts within white matter change as a result of myelination. Though not subject to the same fundamental limitations, available non-human primate studies of postnatal brain development are nonetheless undersampled both temporally and spatially, and comprehensive studies of multiple neurotransmitter receptors are not available. We propose here in a model system to characterize, at microscopic resolution and at six different postnatal developmental time points, myelination of white matter and the concentrations of 19 different major neurotransmitter receptor subtypes in gray matter. These will be placed in the context of micro-anatomic features (cytoarchitectonics in gray matter and tracts defined at ultrahigh (60-100 5m) resolution in white matter using 3D polarized light imaging). These microscopic studies will be supplemented by antecedent in vivo imaging of the same specimens, including structural, high angular resolution diffusion (HARDI), and resting state functional magnetic resonance (MR) imaging at 3 Tesla. Post-mortem MR scanning of 90 banked hemispheres at fifteen developmental time points at 7 Tesla will provide finer temporal sampling and allow more detailed characterization of individual variability of myelination (evaluated using quantitative MR T2 relaxometry) and white matter tract localization (evaluated using HARDI). All results will be integrated into a user-friendly, atlas- based on-line resource with links to other on-line human and non-human primate developmental resources.
This project will study important changes that take place in the brain between birth and adulthood. The changes to be studied are thought to play an important role in brain function during normal development. Better characterization of these changes and their timing will help to identify critical times during which developmental problems might lead to neurological or psychiatric disorders.
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