Multiscale Genetic Connectivity of Primate Social Circuits

描述（由申请人提供）：建立与社会障碍相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，这种需求最为明显，在这些系统中，神经回路的失调与自闭症、抑郁症和焦虑症等精神疾病有关。我们将从灵长类动物社会回路的长距离轴突投射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相结合。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;缺乏内源性电路的知识，以及缺乏用于序列登记中的大规模轴突投影和处理TB数据集的计算系统。我们已经生成了一个新的管道的共焦图像采集集成了一套算法的计算重建和可视化TB图像集。我们应用这些方法在轴突水平生成了45，295，200张图像（1，620 mm）的3D重建，用于涉及催产素（OT）和血管加压素（AVP）以及威廉姆斯综合征基因GTF 2 IRD 1的社会回路，所有这些都与社会行为有关。我们已经确定了新的OT和AVP结构和稀疏的管道，可能会填补关键的空白，为人类行为的基板和生物标志物。此外，我们已经开发出的方法，层次的三维整合轴突水平的图像，MRI图像。该建议来自一个独特的多维团队和顾问 *;分割，大规模图像重建和3D可视化（Tasdizen，Joshi，Pascucci，Roysam*），灵长类动物脑回路和神经解剖学（Angelucci，霍夫 *，Dong*，Korenberg），动物和人类MRI（Hsu，Joshi）以及轴突投影的遗传学和荧光成像（Korenberg，Angelucci）。我们将：1）建立猕猴OT、AVP和GTF 2 IRD 1轴突投射的遗传布线图。我们将使用共聚焦显微镜和束追踪，生成、验证和成像超过667个猕猴脑的连续冠状切片（21，100 mm），用于配体及其受体的荧光免疫组织化学。将采集尸检前/尸检后MRI（150- 200 mm分辨率）和块面图像。新的电路将在人类大脑的同源区域中得到验证。2)构建一个神经信息系统，该系统集成并可视化灵长类动物社会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。研究结果将确定新的OT/AVP相关的社会电路，并建立一个集成技术的管道，用于桥接（宏观）连接体与（微观）轴突体以及两者与精神疾病的遗传学。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。

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.