Neuroimaging of Brain Circuits and Molecular Mechanisms in Normal Cognition

临床和翻译神经科学分部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。 在合作出版物中，我们和同事进行了迄今为止规模最大的全基因组关联研究(GWAS)，该研究能够识别出许多与认知能力具有统计上可靠的关联的基因座。通过揭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，这项工作可能进一步推动独立队列中的发现，这是该领域的重要一步。在这一发现的基础上，我们现在还报告了区分不同组精神分裂症风险基因座的分析：那些显示与低教育程度预期关联的分析，以及那些显示相反关联(即较高教育程度)的分析。结果确定了不同的和连贯的分子网络，这可能是患者异质性的有意义的来源(Lam等人，2019年)。 对心理健康状况的认知和易感性在一生中是动态的，表征潜在的成熟、激素和分子作用力必然会提高对神经精神疾病风险的理解。在过去的一年里，我们的大部分工作都集中在青春期的过渡上，因为这是精神分裂症的易感时期，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统计学趋势的潜在机制。我们目前正在测试与青春期开始之前的性别差异有关的假说，从而在性腺激素上升之前，在显示精神病理学变化的网络的功能连接中进行测试。此外，还有一项实验正在检验青春期过渡期间大脑中与执行功能和奖励处理相关的区域中灰质发育轨迹的性别差异。我们还在继续努力了解荷尔蒙对认知操作的贡献，已经完成了一系列研究，证明了脑源性神经营养因子(BDNF)和卵巢类固醇激素之间的新的相互作用符合小鼠模型。这些研究采用了严格的激素操作方案，涉及醋酸亮丙瑞林诱导的卵巢抑制和雌激素和孕激素的添加条件，并揭示了PET和fMRI测量的工作记忆期间的海马区活动仅在雌二醇条件下显示出与基因型相关的差异(魏等人，2019)。值得注意的是，在对BDNF转基因小鼠模型中卵巢激素相关基因表达变化的平行研究中，雌激素加回治疗与行为焦虑之间的关系取决于BDNF基因的不同，提供了一条翻译途径，以更好地理解这些复杂的基因-激素相互作用，从而可能阐明激素相关精神障碍的机制。(Marrocco等人，2020)

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)