The Clinical and Translational Neuroscience Branch continues to make advances on several fronts 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. Recent progress 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. In large collaborative publications, we and colleagues performed the largest genome-wide association study (GWAS) to date of general cognitive ability, which was able to identify numerous loci with statistically reliable associations to cognitive performance. By implicating important biological pathways for cognition and establishing a basis for quantification of cumulative polygenic cognitive scoring that may further drive discovery in independent cohorts, this work has been an important step for the field (Davies et al, 2018; Lam et al, 2018; Savage et al, 2018). Building on this discovery, we have now also reported in pleiotropic analyses on divergent sets of schizophrenia risk loci: those that show expected directions of effect in educational attainment GWAS and those that show reverse associations. The results identified distinct and coherent molecular networks that may be meaningful sources of heterogeneity in patients. 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. 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, Wei et al, 2019). Remarkably, in parallel investigations of ovarian hormone-related changes in gene expression of BDNF transgenic mice models, estrogen add-back treatment is differentially associated with behavioral anxiety depending on BDNF genotype, providing a translational path to better understanding these complex gene-hormone interactions in a manner that may elucidate mechanisms in hormone-related psychiatric disorders. (Marrocco et al, 2018)
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