Neuroimaging of Brain Circuits and Molecular Mechanisms in Normal Cognition

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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 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. Building on this discovery, we have now also reported on analyses distinguishing divergent sets of schizophrenia risk loci: those that show expected associations with poor educational attainment and those that show reverse associations (i.e., greater educational attainment). The results identified distinct and coherent molecular networks that may be meaningful sources of heterogeneity in patients (Lam et al., 2019). Cognition and susceptibility to mental health conditions is dynamic over the lifespan, and characterization of underlying maturational, hormonal, and molecular forces will necessarily improve understanding of neuropsychiatric illness risk. Much of our efforts in the past year has focused on the pubertal transition, as this is a period of vulnerability for schizophrenia, and on sex differences in brain developmental processes, which may help elucidate mechanisms underlying demographic trends in schizophrenia. We are currently testing hypotheses related to sex differences prior to the onset of puberty, and thus prior to a rise in gonadal hormones, in the functional connections of networks that show alterations in psychopathology. Additional experimentation is examining sex differences in trajectories of gray matter development across the pubertal transition in brain regions associated with executive function and reward processing. We continue 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, 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, 2020)