Genetic Determinants of Local Circuit Organization

局部电路组织的遗传决定因素

• 批准号: 8072672
• 负责人: Charles A Greer
• 金额: $ 33.7万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-12-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072672
• 关键词: Address; Afferent Neurons; Apical; Apoptosis; Apoptotic; Autistic Disorder; Axon; Brain; Brain-Derived Neurotrophic Factor; Categories; Cell Death; Cells; Code; Conflict (Psychology); Cortical Dysplasia; Data; Date of birth; Deafferentation procedure; Dendrites; Dendritic Cells; Dendrodendritic Synapse; Development; Disease; Drosophila genus; Embryo; Employee Strikes; Event; Foundations; Fragile X Syndrome; Genetic Determinism; Goals; Health; Heterogeneity; Image; Individual; Interneurons; Intervention; Lobe; Location; Mediating; Modeling; Nervous system structure; Neuraxis; Neurons; Odors; Olfactory Pathways; Perinatal; Positioning Attribute; Process; Property; Radial; Reporting; Resolution; Role; Seminal; Sensory; Series; Specificity; Synapses; Syndrome; System; Testing; Visual Pathways; Work; developmental disease; granule cell; insight; migration; molecular marker; molecular phenotype; nerve supply; neural circuit; neurogenesis; olfactory bulb; receptive field; receptor; synaptogenesis

Description (provided by applicant): Throughout the CNS diversity in the location and laminar organization of subpopulations of neurons and their synaptic circuits underlies functional specificity, as is evident in the visual pathways mediating low versus high resolution images. The degree of circuit specification in the olfactory bulb remains controversial. Functional analyses suggest a topography of odor-induced activity, but this has focused on the glomeruli where sensory neuron axons expressing the same odor receptor converge and terminate; conflicting data has been reported on the odor-specificity of mitral cells and the deeper radial and horizontal circuits in the bulb. Our proposal has two primary goals. First, there is little information on the innervation of individual glomeruli by subsets of mitral cells. Estimates suggest that each glomerulus is innervated by a subset of 25 mitral cells, but given the heterogeneity in the volume of individual glomeruli, this is likely a misleading generalization. Whether the mitral cells innervating single glomeruli share a common birth date, migratory timeframe or molecular phenotype are also not known. Second, while several studies have examined deafferentation in the bulb, we know comparatively little about trophic mechanisms influencing the fine structural organization of dendrites and their synaptic organization. In brief, our overarching goal is a better understanding of the embryonic and perinatal events underlying the primary cellular organization in the olfactory bulb. To achieve this goal our specific aims are summarized as: 1) Determine the principles underlying targeting of glomeruli by subsets of mitral cells; 2) Establish the relationship between birth date, apoptotic cell death, and topography of olfactory bulb mitral cells; and 3) Test the hypothesis that trophic mechanisms, in particular BDNF, contribute to the differentiation and maturation of mitral cells. This work provides insight into determinants of early development relevant to diseases such as Kallman's syndrome and autism; the principles derived are also likely relevant to broad categories of anomalous cortical development and syndromes such as Fragile-X. PUBLIC HEALTH RELEVANCE: the mechanisms that regulate the development of organization and functional properties of the nervous system remain largely unknown. Developmental disorders such as Kallmans syndrome, autism and cortical dysplasia all represent likely aberrations in the development and differentiation of the central nervous system. The studies proposed here address questions related to the genesis of new neurons and the mechanisms that may influence their distribution, organization and connections in the brain. As such, these new studies are likely to be important in understanding and developing interventional strategies for syndromes such as those noted above, among others.

描述（由申请人提供）：在整个中枢神经系统中，神经元亚群的位置和层流组织的多样性及其突触回路是功能特异性的基础，这在调节低分辨率和高分辨率图像的视觉通路中是显而易见的。嗅觉球的电路规格程度仍有争议。功能分析表明了气味诱导活动的地形，但这主要集中在肾小球上，在肾小球上，表达相同气味受体的感觉神经元轴突聚集并终止；关于二尖瓣细胞的气味特异性和球茎中更深的径向和水平回路的矛盾数据已被报道。我们的建议有两个主要目标。首先，关于二尖瓣细胞亚群对单个肾小球的神经支配的信息很少。估计表明每个肾小球由25个二尖瓣细胞亚群支配，但考虑到单个肾小球体积的异质性，这可能是一种误导性的概括。支配单个肾小球的二尖瓣细胞是否具有相同的出生日期、迁移时间或分子表型尚不清楚。其次，虽然有几项研究已经检查了球茎中的神经分化，但我们对影响树突精细结构组织及其突触组织的营养机制知之甚少。简而言之，我们的首要目标是更好地了解嗅球初级细胞组织的胚胎和围产期事件。为了实现这一目标，我们的具体目标总结为：1)确定二尖瓣细胞亚群靶向肾小球的基本原则；2)建立出生日期、凋亡细胞死亡与嗅球二尖瓣细胞形态的关系；3)验证营养机制，特别是BDNF，促进二尖瓣细胞分化和成熟的假设。这项工作为卡尔曼综合征和自闭症等疾病的早期发育决定因素提供了深入的见解；所衍生的原理也可能与皮层异常发育和脆性x综合征等广泛类别有关。公共卫生相关性：调节神经系统组织发育和功能特性的机制在很大程度上仍然未知。发育障碍如卡尔曼斯综合征、自闭症和皮质发育不良都可能代表中枢神经系统发育和分化的异常。这里提出的研究解决了与新神经元的起源以及可能影响它们在大脑中的分布、组织和连接的机制有关的问题。因此，这些新的研究可能对理解和制定上述综合征的介入策略非常重要。