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

基本信息

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
项目类别：
财政年份：
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

项目摘要

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步，以描述对与精神疾病有关的神经系统功能和发展的神经化学，神经遗传学和神经心理学的贡献。我们已经为两种前所未有的科学资源致力于数据收集的广泛努力：首先，是成年人中独特的多模式神经影像学数据集，其中包括神经心理学测试，广泛的多巴胺能宠物成像以及功能和结构性MRI；其次，是一个纵向的神经发育数据集，结合了基于结构性和功能性磁共振的脑成像，神经心理学测量，以及与行为内分泌学的一部分，精确，最先进的，最先进的前分泌学测量值。这些全面的数据获取工作导致了越来越多的有关大脑的综合多模式信息的存储库，这将允许新颖的分析神经化学功能的不同但相互关联的索引神经化学功能和发现关键遗传学和内分泌因子指导神经发育的指标。最近的进步集中在剖析对认知功能的遗传，神经化学和荷尔蒙的贡献，包括整体能力和执行/工作记忆能力，这些能力是神经精神疾病的关键治疗靶标，但即使在健康方面，也会显示出生命周期的实质性差异。在合作出版物中，我们和同事们在一般认知能力的迄今为止进行了最大的全基因组协会研究（GWAS），该研究能够识别出许多与认知绩效统计上可靠的关联的基因座。通过暗示认知的重要生物学途径并建立量化累积多基因认知评分的基础，这可能会进一步推动独立人群中的发现，这项工作一直是该领域的重要一步。在这一发现的基础上，我们现在还报告了分析区分分歧的精神分裂症风险基因座：那些表现出与教育程度差的预期关联的人以及表现出反向关联的人（即更大的教育程度）。结果确定了明显的和相干的分子网络，这些网络可能是患者中异质性的有意义来源（Lam等，2019）。在整个生命周期中，认知和对心理健康状况的敏感性是动态的，而基本的成熟，荷尔蒙和分子力的表征将一定会改善对神经精神疾病风险的理解。在过去的一年中，我们的大部分努力都集中在青春期过渡上，因为这是精神分裂症的脆弱时期，以及大脑发育过程中的性别差异，这可能有助于阐明精神分裂症人口趋势的基础机制。我们目前正在青春期开始之前测试与性别差异有关的假设，因此在促性腺激素升高之前，在显示精神病理学发生变化的网络的功能连接中。其他实验正在研究与执行功能和奖励处理相关的大脑区域中灰质发展轨迹的性别差异。我们继续为了解认知操作的荷尔蒙贡献而努力，完成了一系列研究，这些研究表明了脑衍生的神经营养因子（BDNF）（BDNF）和卵巢固醇激素与鼠模型一致的脑部功能多态性之间的新型相互作用。这些研究采用了一种严格的激素操纵方案，涉及乙酸苯二酚诱导的卵巢抑制和带有雌激素和孕激素的添加条件，并揭示了使用PET和FMRI测量的工作记忆过程中的海马活性在雌二醇条件下仅显示基因型相关的差异（WEI等，2019年）。值得注意的是，在对BDNF转基因小鼠模型基因表达的卵巢激素相关变化的平行研究中，雌激素添加后补充治疗与行为焦虑差异不同于行为焦虑，具体取决于BDNF基因型，从而提供了一种转化途径，可以更好地理解这些复杂的基因基因相互作用，以使这些复杂的基因相互作用以一种可以在激素机制中使用激素的精神分裂药，使其更加了解。（Marrocco等，2020）