IGF-1 in neocortical development and plasticity

IGF-1 在新皮质发育和可塑性中的作用

• 批准号: 7022223
• 负责人: DAVID RAY RIDDLE
• 金额: $ 26.62万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022223
• 关键词: autocrine; cell growth regulation; cerebral cortex; dendrites; dosage; genetically modified animals; insulinlike growth factor; laboratory mouse; laboratory rat; neural plasticity; neurogenesis; neuropil; paracrine; tissue /cell culture

DESCRIPTION (provided by applicant): Understanding the regulation of dendritic growth is essential to understanding how neural circuits form and function. Dendrites are the targets of 90% of all synapses, and both the extent and pattern of dendritic branching critically influence the integration of synaptic inputs. The cognitive impairments that accompany many developmental disorders are likely to result in part from inappropriate regulation of dendritic growth and plasticity in the developing CNS. One significant challenge currently is elucidating the molecular mediators that control of how much and where dendrites elaborate during development. Recent evidence suggests that neural activity influences dendritic growth through the actions of trophic factors, which focally promote formation and elaboration of new branches. It is likely, however, that one or more factors promote dendritic elaboration more generally and thereby prime neurons for the focal regulation of development and plasticity that is mediated by factors with more restricted actions. With respect to agents that might provide a broad but critical stimulus for dendritic elaboration, insulin-like growth factor 1 (IGF-1) is of particular interest. IGF receptors are widely expressed in the developing brain. IGF-1 can cross from the plasma into the brain as an endocrine factor, and also may act in a paracrine and/or autocrine fashion following production by cells of the cerebral vasculature and by neurons and glia within the brain. Several laboratories have reported that IGF-1 promotes dendritic elaboration by neurons in vitro. Moreover, the growth of neuropil in the cerebral cortex appears to be increased in transgenic mice in which IGF-1 is overexpressed and decreased in mice in which IGF-1 activity is decreased. Significantly, human studies and clinical cases indicate that abnormal IGF-1 signaling during development can result in intellectual impairment, which may arise in part from dysregulation of dendritic development. Building upon such studies, the experiments proposed will test key predictions of the hypothesis that IGF-1 modulates the growth of neuropil and provides a critical stimulus for dendritic elaboration in the developing cerebral cortex. IGF-1-dependent regulation of dendritic development will be tested in vitro, using organotypic slices of the developing cerebral cortex, and also in vivo, using transgenic mice in which IGF-1 signaling is increased or decreased specifically within the brain.

描述（由申请人提供）：了解树突生长的调节对于了解神经回路如何形成和发挥作用至关重要。树突是 90% 的突触的目标，树突分支的范围和模式都严重影响突触输入的整合。许多发育障碍伴随的认知障碍可能部分是由于中枢神经系统发育中树突生长和可塑性的不当调节造成的。目前的一项重大挑战是阐明控制树突在发育过程中发育的程度和位置的分子介体。 最近的证据表明，神经活动通过营养因子的作用影响树突生长，营养因子集中促进新分支的形成和形成。然而，一种或多种因素可能更普遍地促进树突的精细化，从而为神经元进行由作用更受限的因素介导的发育和可塑性的局部调节做好准备。对于可能为树突形成提供广泛但关键刺激的药物而言，胰岛素样生长因子 1 (IGF-1) 特别令人感兴趣。 IGF 受体在发育中的大脑中广泛表达。 IGF-1 可以作为内分泌因子从血浆进入大脑，并且还可以在由脑脉管系统细胞以及大脑内的神经元和神经胶质细胞产生后以旁分泌和/或自分泌方式发挥作用。一些实验室报告称，IGF-1 在体外可促进神经元的树突形成。 此外，在IGF-1过度表达的转基因小鼠中，大脑皮层中神经纤维的生长似乎增加，而在IGF-1活性降低的小鼠中，神经纤维的生长则减少。值得注意的是，人类研究和临床案例表明，发育过程中异常的 IGF-1 信号传导可能导致智力障碍，部分原因可能是树突发育失调所致。在这些研究的基础上，提出的实验将测试以下假设的关键预测：IGF-1 调节神经纤维的生长，并为发育中的大脑皮层中的树突细化提供关键刺激。树突发育的 IGF-1 依赖性调节将在体外使用发育中的大脑皮层的器官切片进行测试，并在体内使用转基因小鼠进行测试，其中 IGF-1 信号在大脑内特异性增加或减少。