Deciphering Inhibition of Visual Plasticity by NgR1

描述(申请人提供)：初级视觉皮质内的功能连接在发育后期表现出对视觉体验的高度敏感性，称为关键期。弱视是一种常见的儿童视力障碍，在关键时期的异常视觉体验是弱视的原因。在关键时期结束之前，治疗对儿童最有效。随后，可塑性减弱，有效的治疗方法更多 很难。在弱视小鼠模型中，单眼剥夺在关键期，但不是 此后，两者都改变了视皮层神经元的相对反应性，并降低了视觉敏锐度。与临床发现类似，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(NgR1)是关闭关键期所必需的。在缺乏NgR1的小鼠中，关键期的可塑性是正常的，但这种可塑性持续到成年小鼠表现出与关键期相同的可塑性。这项建议调查了NgR1如何结束关键期。具体目标1结合小鼠遗传学和电生理记录，剖析了NgR1表达需要与皮质回路一起关闭临界期并限制进一步的外径可塑性。特定目的2利用NgR1突变小鼠独特的可塑性表型，通过体内重复双光子成像研究结构突触可塑性对外径可塑性的影响。特定的 目的3探讨阻断NgR1功能关键期后是否能恢复弱视小鼠的OD可塑性和提高视力。这项建议的目标是提高对大脑皮质可塑性如何在发育和成熟的视觉系统中进行管理的理解。 与公共健康相关：儿童时期处于敏感或关键时期的视力异常是弱视的原因，弱视也被称为懒眼。弱视的治疗在关键时期最有效。这项研究调查了关键期是如何关闭和 探索如何“重新开启”成人的关键时期。

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.