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.
Establishing a network diagram of the brain is one of the major challenges of modern neurobiology and medicine, particularly a diagram of genetic connectivity. No where is this need clearer than for the brain systems controlling social behavior and emotion, where dysregulation of circuitry has been implicated in the most devastating mental illnesses. Animal models have been important in beginning to understand these diseases but it is now clear that the field must pay serious attention to Humans-First. Using an entirely new approach, highly multidisciplinary partnerships between neuroscientists and engineers and information theorists, we have found a powerful way to provide these. This dream is the vision and reality of this proposal. Autism spectrum disorder (ASD), anxiety, depression, addiction and schizophrenia alone affect the lives of more than 70 million children and adults in the USA at a cost of more than $300 billion per year and incalculable human suffering. State-of-the-art superb NIH and foundation consortia have expressed dire need for biomarkers for ASD and the crushing effects of anxiety, depression. There is no time to be wasted and no way to replace the years lost for our nation's families. It is the goal of this proposal to accelerate greatly the pace of developing novel therapeutics and deep understanding of these mental illnesses through bridging the current chasm between finding a gene and understanding its role in determining human social behavior, and to speed the transformation of these insights to understand the causes and best treatments for mental illnesses that all take their toll on the sensitive balance of brain circuitry essential for a productive life. This knowledge of brain and behaviors that are very close to humans will provide insights into new drug targets to prevent, treat, and ultimately cure mental illness.
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