Neuroimaging of Brain Circuits and Molecular Mechanisms in Normal Cognition

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

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 building 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 in children 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. In addition, we have engaged in novel imaging experiments assessing the neural effects of ovarian steroid hormones in women with and without premenstrual dysphoric disorder. Recent progress has focused on dissecting genetic, neurochemical and hormonal contributions to cognitive functions and neural circuits that are implicated in neuropsychiatric illness and also show substantial variation over the lifespan and across individuals even in health. In our adult studies, we and collaborators meta-analyzed results from two recent genome-wide association studies, which identified numerous locations in the genome that have 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 employed several complementary transcriptomic methods to identify genes in these locations that are credibly associated with cognition and further annotate the resulting genes using multiple databases to identify druggable targets. Using a meta-analytic data set (N=373,617), we identified 241 independent cognition-associated locations (29 novel), and 76 genes were identified by two or more methods of gene identification. Several novel pathways were recognized that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing. Additionally, we have found that cumulative effects of certain ancient DNA variants that an individual harbors relates to skull shape, brain structure, and functional connectivity in a manner that may have relevance for neuropsychiatric illness (Gregory et al., 2022). In our longitudinal neurodevelopmental neuroimaging and endocrinological studies of children from age eight to 18, much of our focus in the past year has been on data collection, which has been intensive. In this project, our extensive battery of imaging, cognitive, and hormonal measurements allows us to investigate endocrine-driven trajectories of neurobiological development in a comprehensive manner that will permit not only a more integrated view of puberty in the human brain than is currently available, but also will provide an unprecedented opportunity to trace the natural course and endocrinological dependence of key neuroimaging phenotypes established (by us and others) to be perturbed in neuropsychiatric illness. We have recently initiated work focused on understanding the neurobiological correlates of the onset of adrenarche, the activation of the adrenal androgen secretion, a uniquely human phenomenon that plays an important role in puberty. The impact of adrenal androgens, including dehydroepiandrosterone sulfate (DHEAS), on neurodevelopment has been difficult to disambiguate from that of gonadal hormones. To investigate adrenarche-specific changes in prepubertal brain function, we have launched a focused investigation of typically-developing children who were carefully documented to be prepubertal as ascertained by clinicians, and thus had no puberty-related increases in gonadal hormones. In this study, we are examining the impact of DHEAS on brain activations associated with inhibitory control, reward and face processing, with a focus on testing associations between plasma DHEAS and core neural circuitry subserving these functions. Observations of adrenarchy-linked neural phenotypes in typically developing children who are otherwise at similar stages pre-puberty (i.e., pre-gonadarche) would raise the possibility that the onset of adrenarche and adrenal androgen secretion can significantly impact brain development, opening new avenues of scientific inquiry. This work provides a rare and exciting opportunity to capture the onset of this pubertal event and isolate the effects of adrenal hormones from those of other puberty-related hormones typically associated with puberty such as estradiol and testosterone. Our interest in better delineating neuroendocrinological effects on brain development has driven collaborative work in conjunction with our Branch's Williams syndrome project to evaluate whether 7q11.23 copy-number (CNV) is significantly associated with key pubertal milestones, such as age at menarche (AAM) and pituitary gland growth. This work additionally leverages prior GWAS data and using RNAseq to look for dose-dependent differences in gene expression in peripheral lymphocytes of individuals with 7q11.23 CNVs. Collectively, these studies are aimed at better clarifying if and by what molecular mechanisms 7q11.23 CNVs play a meaningful role in pubertal neuroendocrine development, offering a platform upon which to isolate well-defined molecular contributions to these complex phenomena.