The role of the clustered protocadherins in neural circuit formation and implications for neurodevelopmental disorders

簇状原钙粘蛋白在神经回路形成中的作用及其对神经发育障碍的影响

基本信息

批准号：
10366863
负责人：
THOMAS P MANIATIS
金额：
$ 65.76万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366863
关键词：
Address Axon Behavior Brain Cell membrane Cell surface Cells Data Defect Development Disease Dopamine Ensure Exons Failure Family Fright GTP-Binding Proteins Gene Cluster Gene Deletion Gene Expression Regulation Genes Genetic Transcription Human Immunoglobulin Constant Region Individual Interneurons Label Laboratories Lead Link Logic Major Depressive Disorder Mammals Mediating Mental Depression Methods Midbrain structure Molecular Mus Neurites Neurodevelopmental Disorder Neurons Pattern Phenotype Physiological Process Protein Isoforms Proteins RNA Splicing Regulation Rewards Role Schizophrenia Serotonin Shapes Signal Pathway Signal Transduction Sister Structure Surveys Synapses Work autism spectrum disorder cell type dopaminergic neuron in vivo insight neural circuit neural network neurodevelopment neuromechanism neuropsychiatric disorder neuroregulation novel novel therapeutic intervention olfactory sensory neurons prevent receptive field relating to nervous system response self organization transcriptomics

项目摘要

PROJECT SUMMARY Functional circuits between the approximately 80 billion human neurons connecting trillions of synapses in the human brain must be established during development. Failure to organize proper neural circuits has been linked to neurodevelopmental disorders such as autism and neuropsychiatric diseases. During development, individual neurons extend highly branched neurites that innervate the surrounding territory with minimal overlap. Moreover, some neuronal subtypes, such as serotonergic and dopaminergic neurons, must tile throughout receptive fields in the brain to ensure that their neurites do not cross over or clump with sister or neighboring neurites or other neurons of the same type. Proper wiring of these neuronal cell types is required for the physiological distribution of serotonin and dopamine in the brain. In mammals, a family of highly diverse cell-surface homophilic proteins, the clustered protocadherins (cPcdh), provides each neuron a unique cell-specific identity required for normal neural circuit assembly. The protocadherin gene cluster encompasses three distinct gene clusters, designated ,  and and previous studies from our laboratory demonstrated that a single gene in the Pcdh gene cluster (Pcdhc2) is required for normal serotonergic wiring in mice. Deletion of the entire Pcdh gene cluster or Pcdhc2 alone led to clumping and crossing of serotonergic neurons (a tiling defect), and altered behavior (depression and enhanced fear response). These findings provided significant advances in defining a role for individual cPCDH proteins in specific neuronal subtypes; however, a role for the exclusive expression of specific cPcdh isoforms in other neuronal subtypes and the mechanisms used to execute self-avoidance and tiling remain poorly understood. Here, we propose to address these gaps in understanding by studying the role of the cPcdh gene cluster in the wiring of dopaminergic neurons and behavior in mice. In Aim 1, we will survey the transcriptional landscape of cPcdh isoforms across midbrain dopaminergic neurons in mice. In Aim 2, we will investigate the role of Pcdhβ cluster on dopaminergic wiring, dopamine release and reward prediction and novelty behaviors. In Aim 3, we will examine the mechanism by which PCDHβ proteins, establish proper DAN organization. Together, these new directions should provide novel insights into the molecular logic underlying neural circuit formation and have implications for neurodevelopmental and neuropsychiatric disorders.

项目概要大约 800 亿个人类神经元之间的功能电路连接着数万亿个突触人类大脑必须在发育过程中建立，无法组织适当的神经回路。与自闭症和神经精神疾病等神经发育障碍有关。单个神经元延伸出高度分支的神经突，以最小的方式支配周围区域此外，一些神经元亚型，例如血清素能神经元和多巴胺能神经元，必须平铺。整个大脑的感受野，以确保它们的神经突不会与姐妹或姐妹交叉或聚集这些神经元细胞类型需要邻近的神经突或其他神经元的正确连接。用于大脑中血清素和多巴胺的生理分布。在哺乳动物中，高度多样化的细胞表面同源蛋白家族，簇状原钙粘蛋白（cPcdh），为每个神经元提供正常神经回路组装所需的独特细胞特异性身份。原钙粘蛋白基因簇包含三个不同的基因簇，分别称为 、 和 以及之前的我们实验室的研究表明，需要 Pcdh 基因簇 (Pcdhc2) 中的单个基因删除整个 Pcdh 基因簇或单独删除 Pcdhc2 会导致小鼠正常的血清素连接。血清素能神经元的聚集和交叉（平铺缺陷）以及行为改变（抑郁和（增强恐惧反应）。这些发现为定义单个 cPCDH 蛋白在特定领域中的作用提供了重大进展。神经元亚型；然而，特定 cPcdh 亚型在其他神经元中的独特表达的作用我们对亚型以及用于执行自我回避和平铺的机制仍然知之甚少。建议通过研究 cPcdh 基因簇在连接中的作用来解决这些理解上的差距小鼠的多巴胺能神经元和行为在目标 1 中，我们将调查 cPcdh 的转录景观。在目标 2 中，我们将研究 Pcdhβ 簇的作用。在目标 3 中，我们将研究多巴胺能线路、多巴胺释放和奖励预测以及新奇行为。研究 PCDHβ 蛋白建立适当 DAN 组织的机制。方向应该为神经回路形成的分子逻辑提供新的见解，并且具有对神经发育和神经精神疾病的影响。