MECHANISMS UNDERLYING MONOCULAR DEPRIVATION

单眼剥夺的潜在机制

• 批准号: 2710843
• 负责人: BARBARA GORDON-LICKEY
• 金额: $ 20.42万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-07-01 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2710843
• 关键词: NMDA receptors; binocular vision; brain mapping; developmental neurobiology; digital imaging; immunocytochemistry; in situ hybridization; laboratory rat; messenger RNA; molecular site; neural plasticity; neurotransmitters; polymerase chain reaction; receptor binding; visual cortex; visual deprivation; visual pathways; western blottings

The development of vision in children and other young mammals involves a critical period when synaptic connectivity in the visual cortex can be altered by visual experience. As the brain matures synaptic plasticity diminishes, leaving the visual connections in a more stable state. The loss of plasticity limits the brain's capacity for further adaptation or recovery from injury. The discovery of methods for extending or reinstating synaptic plasticity would have profound therapeutic implications. We and others hypothesize that plasticity is regulated by a type of glutamate receptor called the NMDA receptor. NMDA receptors exist in a number of molecular forms determined by alternative subunit composition and alternative splicing of mRNA. Two recent findings suggest the hypothesis that changes in the composition and resultant physiological properties of NMDA receptors are responsible for developmental changes in plasticity. First, experiments in recombinant systems have shown that physiological responses to glutamate vary with receptor composition. Second, receptor composition changes during cortical development. After testing the relations between receptor composition, physiology and plasticity in visual cortex, we will ask whether these relationships are more than correlative by manipulating the plastic and testing for linked changes in NMDA receptor development. In the first experiments we will examine the development of receptor composition using in situ hybridization and immunohistochemistry. Second we will use whole cell recording, followed by PCR or immunohistochemistry, to ask whether, on a cell by cell basis, the relation between receptor composition and receptor physiology in real neurons is similar to that already known in recombinant systems. Third, having defined correlations between NMDA receptor composition, physiology, and visual plasticity, we will use dark rearing, intraocular tetrodotoxin and drug treatment (MK-801) to perturb the plastic period and/or receptor development. We will then ask whether the changes in development of receptor composition and physiology occur in synchrony with changes in plasticity. Finding that the effects of these perturbation are synchronous will greatly strengthen the hypothesis that synaptic plasticity in the visual cortex is controlled by NMDA receptors.

儿童和其他幼年哺乳动物的视力发育涉及 视觉皮层突触连接的关键时期 因视觉经验而改变。 随着大脑突触可塑性的成熟 减弱，使视觉连接处于更稳定的状态。 这 可塑性的丧失限制了大脑进一步适应的能力或 从受伤中恢复。 发现扩展或 恢复突触可塑性将具有深远的治疗作用 影响。 我们和其他人假设可塑性是由一种类型调节的 谷氨酸受体称为NMDA受体。 NMDA 受体存在于 由替代亚基组成决定的分子形式的数量 以及 mRNA 的选择性剪接。 最近的两项研究结果表明 假设成分和由此产生的生理变化 NMDA 受体的特性导致发育变化 在可塑性方面。 首先，重组系统的实验表明 对谷氨酸的生理反应随受体组成而变化。 其次，受体组成在皮质发育过程中发生变化。 后 测试受体组成、生理学和 视觉皮层的可塑性，我们会问这些关系是否是 通过操纵塑料并测试相关性，不仅具有相关性 NMDA 受体发育的变化。 在第一个实验中，我们将检查受体的发育 使用原位杂交和免疫组织化学的组合物。 其次，我们将使用全细胞记录，然后进行 PCR 或 免疫组织化学，询问是否在逐个细胞的基础上， 受体组成与受体生理学之间的真实关系 神经元与重组系统中已知的神经元相似。 第三， 确定了 NMDA 受体组成之间的相关性， 生理学和视觉可塑性，我们将使用黑暗饲养，眼内 河豚毒素和药物治疗（MK-801）扰乱可塑期 和/或受体发育。 然后我们会询问是否有变化 受体组成和生理学的发展同步发生 随着可塑性的变化。 发现这些影响 扰动是同步的将大大加强假设 视觉皮层的突触可塑性由 NMDA 控制 受体。