The Clinical and Translational Neuroscience Branch continues to make advances on several fronts in order to delineate the neurochemical, neurogenetic, and neuropsychological contributions to neural systems function and development relevant to mental illness. We have devoted extensive efforts toward data collection for two unprecedented scientific resources: first, a unique multimodal neuroimaging dataset in adults that includes neuropsychological testing, extensive dopaminergic PET imaging as well as functional and structural MRI; and, second, a longitudinal, neurodevelopmental dataset that incorporates structural and functional magnetic resonance-based brain imaging, neuropsychological measures, and, in conjunction with the Section on Behavioral Endocrinology, precise, state-of-the-art endocrinological measurements of pubertal status. These comprehensive ongoing data acquisition efforts have resulted in a growing repository of integrated, multimodal information about the brain, which will permit both novel analyses synthesizing disparate but interrelated indices of neurochemical functioning and discovery of critical genetic and endocrinological factors guiding neurodevelopment. Further progress this year has focused on dissecting genetic, neurochemical and hormonal contributions to cognitive functions, both overall general ability and executive/working memory capacity, which are crucial therapeutic targets in neuropsychiatric illness but also show substantial variation over the lifespan and across individuals even in health. For instance, in two large collaborative publications, we and colleagues report on genome-wide association studies of general cognitive ability in the largest samples that have yet been assembled for this important phenotype. These studies were able to identify numerous loci with statistically reliable associations to cognitive performance. The work paves the way for fine mapping at significant loci aimed at identifying functional variants and important biological pathways for cognition and provides the foundation for quantification of cumulative polygenic cognitive scoring that may further drive discovery in independent cohorts (Davies et al, 2018; Lam et al, 2018; Savage et al, 2018). Cognition is dynamic over the lifespan, as our work in neurodevelopmental and aging cohorts has particularly highlighted. For instance, even within early and middle adulthood among healthy individuals, we have found declining acuity in select cognitive measures, consistent with prior studies; however, biological mechanisms underlying the aging process in the brain remain obscure. To address this gap in knowledge, we employed magnetic resonance spectroscopy to assay GABA concentrations in the anterior cingulate. In pursuing this line of inquiry, we have made a number of technological advances, including corrections for frequency drift, which improve signal-to-noise ratios (van der Veen et al, 2017). We found that age-related declines in executive function test performance were mediated by measures of GABA, a result that was not explained by structural atrophic effects. These data suggest that in line with preclinical work, GABA-related mechanisms may be an important aspect of age-related cognitive deficits (Marenco et al, 2018). We have continued to further our efforts toward understanding hormonal contributions to cognitive operations as well, having completed a series of studies demonstrating novel interactions between a well-established functional polymorphism in brain-derived neurotrophic factor (BDNF) and ovarian steroid hormones consistent with murine models. These studies employed a rigorous hormone manipulation protocol involving leuprolide acetate induced ovarian suppression and add-back conditions with estrogen and progesterone, and revealed that hippocampal activity during working memory as measured with PET and fMRI showed genotype-related differences only under the estradiol condition (Wei et al, 2018).
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