Neuroimaging of Brain Circuits and Molecular Mechanisms in Normal Cognition

正常认知中脑回路和分子机制的神经影像

• 批准号: 10266583
• 负责人: Karen FAITH Berman
• 金额: $ 116.35万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10266583
• 关键词: 8 year old; Adolescent; Adult; Anxiety; Back; Base of the Brain; Behavior Disorders; Behavioral; Biological; Brain; Brain imaging; Brain region; Brain-Derived Neurotrophic Factor; Child; Clinical; Cognition; Cognition Disorders; Cognitive; Collaborations; Complex; Data; Data Collection; Data Set; Development; Developmental Process; Endocrinology; Environmental Risk Factor; Epidemiology; Estradiol; Estrogens; Functional Magnetic Resonance Imaging; Functional disorder; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genotype; Gonadal Hormones; Health; Heterogeneity; Hippocampus (Brain); Hormonal; Hormonal Change; Hormones; Individual; Investigation; Knowledge; Leuprolide Acetate; Light; Link; Longevity; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; Mental Health; Mental disorders; Molecular; Multimodal Imaging; Nature; Neurobiology; Neuropsychological Tests; Neuropsychology; Onset of illness; Ovarian Ablation; Ovarian Steroid Hormone; Ovarian hormone; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Positron-Emission Tomography; Postpartum Period; Predisposition; Progesterone; Protocols documentation; Psychopathology; Psychotic Disorders; Puberty; Publications; Reporting; Resources; Risk; Schizophrenia; Series; Sex Differences; Short-Term Memory; Source; Structure; System; Testing; Time; Transgenic Mice; Translating; Variant; Woman; Work; brain circuitry; cognitive ability; cognitive function; cognitive performance; cohort; comorbidity; course development; data acquisition; developmental disease; executive function; gene interaction; genome wide association study; gray matter; imaging modality; imaging study; improved; indexing; insight; longitudinal design; mouse model; multimodality; neurochemistry; neurodevelopment; neurogenetics; neuroimaging; neuropsychiatry; novel; operation; premenstrual dysphoric disorder; puberty transition; relating to nervous system; repository; reward processing; risk variant; severe mental illness; therapeutic target; translational neuroscience; trend

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)

临床和转化神经科学分支继续在几个方面取得进展，以描绘神经化学，神经遗传学和神经心理学对与精神疾病相关的神经系统功能和发育的贡献。我们为两个前所未有的科学资源投入了大量的努力来收集数据：首先，一个独特的成人多模态神经成像数据集，包括神经心理测试，广泛的多巴胺能PET成像以及功能和结构MRI；第二，纵向的神经发育数据集，包括基于结构和功能磁共振的脑成像，神经心理学测量，以及与行为内分泌学部分结合，精确的，最先进的青春期状态内分泌测量。这些全面的、持续的数据采集工作已经形成了一个不断增长的关于大脑的综合、多模式信息库，这将允许对神经化学功能的不同但相互关联的指标进行新的分析，并发现指导神经发育的关键遗传和内分泌因素。最近的进展集中在解剖遗传、神经化学和激素对认知功能的贡献，包括总体一般能力和执行/工作记忆能力，这是神经精神疾病的关键治疗目标，但也显示出在生命周期和个体之间甚至在健康状况下的巨大差异。