Genetic Determinants of Local Circuit Organization

局部电路组织的遗传决定因素

• 批准号: 7727826
• 负责人: Charles A Greer
• 金额: $ 35.17万
• 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/7727826
• 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; 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; public health relevance; 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(申请人提供)：在整个中枢神经系统中，神经元及其突触回路亚群的位置和层状组织的多样性是功能特异性的基础，这在调节低分辨率与高分辨率图像的视觉通路中是明显的。嗅球的电路规范程度仍然存在争议。功能分析表明气味诱导的活动具有地形图，但这主要集中在肾小球，表达相同气味感受器的感觉神经元轴突在那里汇合并终止；关于二尖瓣细胞的气味特异性以及球部更深的放射状和水平状环路，已有相互矛盾的数据报道。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个二尖瓣细胞的子集支配，但考虑到单个肾小球体积的异质性，这可能是一个误导性的概括。支配单个肾小球的二尖瓣细胞是否具有共同的出生日期、迁移时间或分子表型也尚不清楚。其次，虽然一些研究已经研究了球的去传入，但我们对影响树突及其突触组织的精细结构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背后的胚胎和围产期事件。为了实现这一目标，我们的具体目标概括为：1)确定二尖瓣细胞亚群靶向肾小球的基本原理；2)建立出生日期、凋亡细胞死亡和嗅球二尖瓣细胞形态之间的关系；3)检验营养机制，特别是BDNF，有助于二尖瓣细胞分化和成熟的假设。这项工作提供了对与Kallman综合征和自闭症等疾病相关的早期发育决定因素的洞察；推导出的原理也可能与广泛类别的皮质发育异常和综合征相关，如脆性X综合征。与公共健康相关：调节神经系统组织和功能特性发展的机制在很大程度上仍不清楚。发育障碍，如卡尔曼斯综合征、自闭症和皮质发育不良，都可能是中枢神经系统发育和分化的异常。这里提出的研究涉及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。因此，这些新的研究很可能对理解和开发针对上述综合征的干预策略具有重要意义。