Genetic Determinants of Local Circuit Organization

局部电路组织的遗传决定因素

• 批准号: 8367833
• 负责人: Charles A Greer
• 金额: $ 9.27万
• 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/8367833
• 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CNS中，神经元亚群及其突触回路的位置和层状组织的多样性是功能特异性的基础，这在介导低分辨率与高分辨率图像的视觉通路中是显而易见的。嗅球中的电路规格的程度仍然存在争议。功能分析表明，地形的气味诱导的活动，但这集中在肾小球的感觉神经元轴突表达相同的气味受体的收敛和终止;矛盾的数据已报告的气味特异性的二尖瓣细胞和更深的径向和水平电路的灯泡。我们的建议有两个主要目标。首先，很少有关于二尖瓣细胞亚群对单个肾小球的神经支配的信息。估计表明，每个肾小球由25个二尖瓣细胞的子集支配，但考虑到个体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不清楚。第二，虽然有几项研究已经检查了在球的传入神经阻滞，我们知道相对较少的营养机制影响树突的精细结构组织和突触组织。简而言之，我们的首要目标是更好地了解胚胎和围产期事件的基础上的初级细胞组织在嗅球。为了实现这一目标，我们的具体目标概括为：1）确定的原则，通过二尖瓣细胞亚群的肾小球靶向; 2）建立出生日期之间的关系，凋亡细胞死亡，嗅球二尖瓣细胞的地形;和3）测试的假设，营养机制，特别是BDNF，有助于分化和成熟的二尖瓣细胞。这项工作提供了深入了解早期发展相关的疾病，如卡尔曼综合征和自闭症的决定因素;所得出的原则也可能与广泛类别的异常皮质发育和综合征，如脆性X。公共卫生关系：调节神经系统的组织和功能特性的发育的机制在很大程度上仍然是未知的。发育障碍如卡尔曼综合征、自闭症和皮质发育不良都代表中枢神经系统发育和分化中的可能畸变。这里提出的研究解决了与新神经元的发生有关的问题，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，这些新的研究可能对理解和制定上述综合征的干预策略非常重要。