Multiscale Genetic Connectivity of Primate Social Circuits

灵长类动物社会回路的多尺度遗传连接

• 批准号: 8632821
• 负责人: SARANG JOSHI
• 金额: $ 73.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-21 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632821
• 关键词: Address; Adult; Affect; Algorithms; Amygdaloid structure; Animal Model; Animals; Anxiety; Architecture; Argipressin; Attention; Autistic Disorder; Axon; Basal Ganglia; Beds; Behavior; Biological Markers; Brain; Cell Nucleus; Child; Color; Confocal Microscopy; Data Set; Disease; Dreams; Drug Targeting; Emotional; Emotions; Engineering; Equilibrium; Face; Family; Fluorescence; Foundations; Gene Expression; Genes; Genetic; Goals; Hereditary Disease; Human; Human Genetics; Hypothalamic structure; Image; Imagery; Immunohistochemistry; Information Systems; Knowledge; Label; Life; Ligands; Link; Macaca; Macaca fascicularis; Magnetic Resonance Imaging; Maps; Medicine; Mental Depression; Mental disorders; Microscopy; Molecular; Neuroanatomy; Neurobiology; Neurons; Neuropeptide Gene; Neuropeptides; Neurotransmitters; Oxytocin; Phenotype; Post-Traumatic Stress Disorders; Primates; Proteins; Resolution; Rodent; Role; Schizophrenia; Science; Slice; Social Behavior; Social Behavior Disorders; Social Network; Solutions; Speed; Stimulus; Structure; Structure of terminal stria nuclei of preoptic region; Synapses; System; Technology; Therapeutic; Time; Translating; United States National Institutes of Health; Vasopressins; Vision; Williams Syndrome; addiction; autism spectrum disorder; basal forebrain; brain behavior; cost; fluorescence imaging; forging; image reconstruction; image registration; in vivo; innovation; insight; multidisciplinary; neural circuit; nonhuman primate; novel; novel strategies; novel therapeutics; prevent; public health relevance; receptor; reconstruction; relating to nervous system; response; social; therapeutic target; tool; wasting

DESCRIPTION (provided by applicant): Establishing a genetic network diagram of the primate brain linked to social disorders is one of the major challenges of modern neurobiology and medicine. Nowhere is this need clearer than in social-emotional systems, where dysregulation of circuitry is implicated in mental illnesses: autism, depression and anxiety. We will generate multiple-gene-specific 3D reconstructions from serial sections of long range axon projections of social circuitry in primate, including hypothalamus, bed nucleus and stria terminalis, basal forebrain nuclei, amygdala and basal ganglia, and integrate with MRI. This will address two barriers to understanding primate brain and human social behavior; lack of knowledge of endogenous circuitry, and lack of computational systems for large scale multicolor axon projections in serial registration and for handling the terabyte datasets. We have generated a novel pipeline of multicolor confocal image acquisition integrated with a computational suite of algorithms for reconstructing and visualizing TB image sets. We have applied these to generate a 3D reconstruction of 45,295,200 images (1,620mm) at the axon level for social circuitry involving oxytocin (OT) and vasopressin (AVP) and the Williams syndrome gene, GTF2IRD1, all implicated in social behavior. We have identified novel OT and AVP structures and sparse tracts that may fill critical gaps as substrates and biomarkers for human behavior. Moreover, we have developed approaches for hierarchical 3D integration of axon-level images to MRI images. The proposal emerges from a unique multidimensional team and advisors*; experts in segmentation, large scale image reconstruction and 3D visualization (Tasdizen, Joshi, Pascucci, Roysam*), in primate brain circuitry and neuroanatomy (Angelucci, Hof*, Dong*, Korenberg), in animal and human MRI (Hsu, Joshi), and in genetics and multicolor fluorescence imaging of axon projections (Korenberg, Angelucci). We will: 1) Establish a genetic wiring diagram of axonal projections for OT, AVP and GTF2IRD1 in macaque. We will generate, validate and image more than 667 serial coronal sections (21,100mm) of macaque brains multicolor fluorescence immunohistochemistry of ligands and their receptors, using confocal microscopy and tract tracing. Pre-/post-mortem MRI(150-200mm resolution) and block-faces images will be acquired. Novel circuitry will be validated in cognate regions of human brain. 2) Build a Neural Information System that integrates and visualizes a multiscale volumetric TB dataset of primate genetic connectivity for social neuropeptides, aligned using automated slice-to-slice image registration at the resolution of axonal projections to MRI, and annotated neuroanatomy. The results will identify novel OT/AVP related social circuitry and establish a pipeline of integrated technologies for bridging (macro)connectome with (micro)axome and both with genetics of mental illness. These will provide novel biomarkers for disease features and receptor targets, and accelerate translating the dissonant orchestration of social behavior by neuropeptides to therapeutic harmony in humans.

描述（由申请人提供）：建立与社会疾病有关的灵长类动物大脑的遗传网络图是现代神经生物学和医学的主要挑战之一。在社会情感系统中，这无处不在，在社会情感系统中，电路失调与精神疾病有关：自闭症，抑郁和焦虑。我们将从灵长类动物中社会电路的远距离轴突投影（包括下丘脑，床核，床核和质谱末端），基础前脑核，杏仁核，杏仁核和基础神经节中产生多个基因特异性的3D重建。这将解决了解灵长类动物大脑和人类社会行为的两个障碍。缺乏内源性电路的知识，以及缺乏用于串行注册和处理Terabyte数据集的大型多色轴突投影的计算系统。我们已经生成了一条新型的多色共聚焦图像采集管道，该管道与用于重建和可视化结核图像集的算法计算套件集成在一起。我们已将其应用于轴突级别的45,295,200张图像（1,620mm）的3D重建，以用于涉及催产素（OT）（OT）和加压素（AVP）和Williams综合征基因GTF2IRD的社交电路，均与社会行为有关。我们已经确定了新型的OT和AVP结构以及稀疏的区域，这些结构可能填补了关键的空白，作为人类行为的底物和生物标志物。此外，我们已经开发了将轴突级图像与MRI图像整合的分层3D整合的方法。该提议来自独特的多维团队和顾问*；细分，大规模图像重建和3D可视化的专家（Tasdizen，Joshi，Pascucci，Roysam*），灵长类动物的脑电路和神经解剖学（Angelucci，Hof*，Dong*，korenberg，korenberg） Angelucci）。我们将：1）在猕猴中为OT，AVP和GTF2IRD1建立轴突投影的遗传接线图。我们将使用共聚焦显微镜和图形跟踪生成，验证和图像超过667个串联冠状动脉切片（21,100mm）的猕猴多色荧光免疫组织化学及其受体。将获取前/验尸MRI（150-200mm分辨率）和块面图像。新型电路将在人脑的同源区域进行验证。 2）建立一个神经信息系统，该系统可以整合和可视化灵长类动物遗传连通性的多尺度体积结核病数据集，以使社会神经肽的遗传连通性使用自动化的切片式图像图像注册，并在将轴突预测分解为MRI上，并注释神经术。结果将确定新颖的OT/AVP相关的社会电路，并建立与（微型）Axome和精神疾病遗传学的桥接（宏）连接组的集成技术管道。这些将为疾病特征和受体靶标提供新颖的生物标志物，并加快将神经肽对社会行为的不和谐编排转化为人类治疗和谐。