Multiscale Genetic Connectivity of Primate Social Circuits

描述(申请人提供)：建立灵长类动物大脑与社会障碍相关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，这一需求最为明显，在那里，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程轴突投影的连续切片中生成多基因特异性的3D重建，包括下丘脑、床核和终纹、基底前脑核、杏仁核和基底节，并与MRI相结合。这将解决理解灵长类大脑和人类社会行为的两个障碍：缺乏内生电路的知识，以及缺乏大规模多色轴突连续配准和处理TB数据集的计算系统。我们已经生成了一个新的多色共焦图像采集流水线，并集成了一套用于重建和可视化结核图像集的计算算法。我们已经应用这些方法在轴突水平上生成了45,295,200张图像(1,620 mm)的3D重建，涉及催产素(OT)和加压素(AVP)的社会回路以及威廉姆斯综合征基因GTF2IRD1，所有这些都与社会行为有关。我们已经确定了新的OT和AVP结构和稀疏区域，可以填补关键的空白，作为人类行为的底物和生物标记物。此外，我们还开发了轴突水平图像到MRI图像的分层3D整合的方法。该提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*)方面的专家；灵长类大脑电路和神经解剖学(Angelucci、Hof*、Dong*、Korenberg)；动物和人类MRI(Hsu、Joshi)；以及遗传学和轴突投影的多色荧光成像(Korenberg、Angelucci)方面的专家。我们将：1)建立短尾猴OT、AVP和GTF2IRD1轴突投射的遗传网络图。我们将生成、验证和成像超过667个猕猴脑连续冠状切片(21,100 mm)，使用共聚焦显微镜和轨迹跟踪技术进行配体及其受体的多色荧光免疫组织化学。将采集死前/死后MRI(150-200 mm分辨率)和块状面部图像。新的电路将在人脑的相关区域得到验证。2)建立一个神经信息系统，集成和可视化社会神经肽的灵长类遗传连接性的多尺度体积性TB数据集，使用自动切片到切片图像配准来对齐轴突投影到MRI，并注释神经解剖学。这一结果将确定与OT/AVP相关的新的社会回路，并建立一条连接(宏观)连接体和(微观)轴组以及两者与精神疾病遗传学的集成技术管道。这些将为疾病特征和受体靶点提供新的生物标记物，并加速将神经肽对社会行为的不协调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.