Multiscale Genetic Connectivity of Primate Social Circuits

灵长类动物社会回路的多尺度遗传连接

基本信息

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
项目类别：
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

项目摘要

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）：建立与社会障碍相关的灵长类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。这种需求在社会情感系统中表现得最为明显，其中回路失调与精神疾病有关：自闭症、抑郁症和焦虑症。我们将从灵长类动物社会回路的长距离轴突投影的连续切片中生成多基因特异性 3D 重建，包括下丘脑、床核和终纹、基底前脑核、杏仁核和基底神经节，并与 MRI 集成。这将解决理解灵长类动物大脑和人类社会行为的两个障碍；缺乏对内源电路的了解，并且缺乏用于串行配准中大规模多色轴突投影和处理太字节数据集的计算系统。我们已经生成了一种新颖的多色共焦图像采集流程，与用于重建和可视化 TB 图像集的计算算法套件集成。我们应用这些技术在轴突水平上生成了 45,295,200 个图像 (1,620mm) 的 3D 重建，用于涉及催产素 (OT) 和加压素 (AVP) 以及威廉姆斯综合征基因 GTF2IRD1 的社交回路，所有这些都与社交行为有关。我们已经确定了新的 OT 和 AVP 结构以及稀疏束，它们可能填补作为人类行为底物和生物标志物的关键空白。此外，我们还开发了将轴突级图像分层 3D 集成到 MRI 图像的方法。该提案由独特的多维团队和顾问提出*；分割、大规模图像重建和 3D 可视化专家 (Tasdizen、Joshi、Pascucci、Roysam*)、灵长类脑电路和神经解剖学专家 (Angelucci、Hof*、Dong*、Korenberg)、动物和人类 MRI (Hsu、Joshi) ，以及轴突投影的遗传学和多色荧光成像（Korenberg，Angelucci）。我们将： 1) 建立猕猴 OT、AVP 和 GTF2IRD1 轴突投影的遗传接线图。我们将使用共聚焦显微镜和束追踪来生成、验证和成像超过 667 个猕猴大脑的连续冠状切片 (21,100mm)，对配体及其受体进行多色荧光免疫组织化学分析。将采集死前/死后 MRI（150-200mm 分辨率）和块面图像。新型电路将在人脑的同源区域得到验证。 2) 构建一个神经信息系统，集成并可视化灵长类社交神经肽遗传连接的多尺度体积 TB 数据集，使用自动切片到切片图像配准以轴突投影到 MRI 的分辨率进行对齐，并注释神经解剖学。研究结果将确定与 OT/AVP 相关的新型社会回路，并建立一系列集成技术，用于桥接（宏）连接组与（微）轴组以及两者与精神疾病遗传学。这些将为疾病特征和受体靶点提供新的生物标志物，并加速将神经肽对社会行为的不和谐协调转化为人类的治疗和谐。