Deciphering Inhibition of Visual Plasticity by NgR1

解读 NgR1 对视觉可塑性的抑制

• 批准号: 8295849
• 负责人: Aaron W McGee
• 金额: $ 40.5万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295849
• 关键词: Address; Adult; Alleles; Amblyopia; Behavioral; Calcium-Binding Proteins; Child; Childhood; Chronic; Clinical; Dendritic Spines; Development; Electrophysiology (science); Exhibits; Genes; Genetic; Goals; Image; Interneurons; Knock-out; Lazy Eyes; Measures; Modification; Mus; Mutant Strains Mice; Neurons; Neuropeptides; Ocular Dominance; Parvalbumins; Phenotype; Population; Recovery; Relative (related person); Research; Role; Signal Transduction; Somatostatin; Strabismus; Structure; Synapses; Synaptic plasticity; Tamoxifen; Testing; Therapeutic; Vision; Vision Disorders; Visual; Visual Acuity; Visual Cortex; Visual system structure; Water; Wild Type Mouse; area striata; calretinin; critical developmental period; critical period; effective therapy; experience; improved; in vivo; insight; monocular deprivation; mouse model; mutant; neural circuit; optical imaging; programs; promoter; receptor; recombinase; research study; two-photon; visual process; visual processing

DESCRIPTION (provided by applicant): The functional connectivity within primary visual cortex exhibits heightened sensitivity to visual experience during an interval late in development termed the critical period. Abnormal visual experience during the critical period is the cause of amblyopia, a prevalent childhood visual disorder. Treatment is most effective in children before the close of the critical period. Subsequently, plasticity diminishes and effective therapy is more difficult. In a mouse model of amblyopia, monocular deprivation during the critical period, but not thereafter, both shifts the relative responsiveness of neurons in visual cortex and decreases visual acuity. Analogous to clinical findings, these deficits persist if normal vision is restored after the close of the critical period. The nogo-66 receptor (NgR1) is required to close the critical period. In mice lacking NgR1, plasticity during the critical period is normal, but it continues such that adult mice display the same plasticity as during the critical period. This proposal investigates how NgR1 closes the critical period. Specific Aim 1 dissects where NgR1 expression is required with cortical circuitry to close the critical period and limit further OD plasticity with a combination of mouse genetics and electrophysiological recordings. Specific Aim 2 exploits the unique plasticity phenotype of NgR1 mutant mice to study how structural synaptic plasticity contributes to OD plasticity with repeated two-photon in vivo imaging. Specific Aim 3 explores whether blocking NgR1 function after the critical period will reactivate OD plasticity and improve visual acuity in amblyopic mice. The goal of this proposal is to improve understanding of how cortical plasticity is governed in the developing and mature visual system. PUBLIC HEALTH RELEVANCE: Abnormal vision during a sensitive or 'critical' period in childhood is the cause of amblyopia, also known as lazy eye. Treatment for amblyopia is most effective during the critical period. This research investigates how the critical period closes and explores how to 'reopen' the critical period in adults.

描述（由申请人提供）：初级视觉皮层内的功能连接在发育后期的关键期对视觉体验表现出高度的敏感性。弱视是一种常见的儿童期视觉障碍，其发生的原因是儿童在弱视发生的关键期出现异常的视觉体验。在关键期结束之前，治疗对儿童最有效。随后，可塑性减弱，有效的治疗更多 难在弱视小鼠模型中，单眼剥夺在关键期，但不是 此后，两者均使视皮层神经元的相对反应性发生偏移，并降低视敏度。与临床结果类似，如果在关键期结束后恢复正常视力，这些缺陷仍然存在。 Nogo-66受体（NgR 1）是关闭关键期所必需的。在缺乏NgR 1的小鼠中，在关键期的可塑性是正常的，但它继续这样，成年小鼠显示出与关键期相同的可塑性。该提案研究NgR 1如何关闭关键期。具体目标1解剖NgR 1表达所需的皮质电路关闭的关键期，并限制进一步OD可塑性与小鼠遗传学和电生理记录的组合。具体目标2利用NgR 1突变小鼠的独特可塑性表型，通过重复的双光子体内成像研究结构突触可塑性如何有助于OD可塑性。具体 目的3探讨在弱视小鼠的关键期后阻断NgR 1的功能是否会重新激活OD可塑性并改善视力。这个建议的目的是提高对皮层可塑性在发育和成熟的视觉系统中是如何控制的理解。 公共卫生相关性：在儿童敏感或“关键”时期的异常视力是弱视的原因，也被称为弱视。弱视的治疗最有效的是在关键时期。本研究探讨了关键期是如何结束的， 探索如何“重新打开”成年人的关键期。