Reversible activation on critical plasticity in visual cortex

视觉皮层关键可塑性的可逆激活

• 批准号: 9129706
• 负责人: Alfredo Kirkwood
• 金额: $ 35万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129706
• 关键词: Acute; Adult; Affect; Amblyopia; Clinical; Coupled; Development; Excitatory Synapse; Eye; Health; Human; Interneurons; Mediating; Methods; Modeling; Neurons; Ocular Dominance; Output; Pharmacology; Physiological; Population; Property; Recovery; Regulation; Resistance; Rhodopsin; Series; Slice; Synapses; Synaptic plasticity; Testing; Time; Transgenic Organisms; Translating; Viral; Visual; Visual Cortex; Whole-Cell Recordings; Wild Type Mouse; critical period; deprivation; designer receptors exclusively activated by designer drugs; functional loss; genetic manipulation; hippocampal pyramidal neuron; improved; in vivo; method development; monocular; monocular deprivation; multidisciplinary; novel; optogenetics; postnatal; preference; research study; response; success; synaptic function; therapeutic development; visual deprivation

 DESCRIPTION (provided by applicant): During a critical period of early postnatal development, an asymmetry in the quality of visual input to the two eyes shifts ocular preference away from the weaker eye and induces amblyopia, the most common cause of monocular visual deficits in humans. Amblyopia is highly resistant to reversal in adulthood, due in large part to th termination of the critical period of heightened plasticity. Understanding how the enhanced plasticity of the critical period is initiated and terminated over development is fundamental to th development of therapeutic strategies aimed to reactivate plasticity to treat amblyopia in adults, which can be translated to a clinical population and to other critical periods. A popular model for the regulation of the critical period proposes that inhibitory control of plasticity at excitatory synapses is mediated by the maturation of the output of fast-spiking interneurons (FS-INs) that mediate perisomatic inhibition. However, we have shown that ocular dominance plasticity can be induced several months after the maturation of perisomatic inhibition. We propose instead that ocular dominance plasticity is regulated by plasticity "upstream" of inhibitory output, likely affecting the recruitment of inhibition into functional circuits. In addition we propose that the functional connectivity of Pyr->FS synapses must be retained in a permissive range for ocular dominance plasticity to be expressed, as larger reductions in Pyr->FS connectivity induced by genetic manipulations inhibit the expression of ocular dominance plasticity. Our preliminary analysis of the regulation of excitation from pyramidal neurons onto FS-INs (Pyr->FS) reveals that monocular deprivation during the critical period may functionally disconnect FS-INs from the cortical network by significantly reducing the number of excitatory inputs onto these neurons. Therefore we hypothesize that a novel mechanism of plasticity, deprivation-induced loss of functional Pyr->FS connectivity 1) is an early and obligatory step in the shift in ocular dominance induced by MD, and 2) determines the timing of the critical period. We propose a multidisciplinary set of experiments to test these hypotheses that combine: the expertise of the Quinlan lab in the examination of physiological changes in visual cortex in vivo in response to monocular deprivation; the expertise of the Kirkwood lab in the direct assessment of contribution of changes in single synapses to activity-dependent plasticity in the visual cortex; and the expertise of the Lee lab in the use optogenetic methods to identify foci and mechanisms of activity-dependent changes in synaptic function. Our model for the regulation of the timing of the critical period refutes many widely-held assumptions regarding developmental changes in synaptic plasticity in the mammalian cortex.

 描述（由申请人提供）：在出生后早期发育的关键时期，双眼视觉输入质量的不对称使眼睛偏好远离较弱的眼睛，并诱导弱视，这是人类单眼视觉缺陷的最常见原因。弱视在成年后很难逆转，这在很大程度上是由于可塑性增强的关键期的终止。了解关键期的可塑性增强是如何在发育过程中启动和终止的，对于开发旨在重新激活可塑性以治疗成人弱视的治疗策略至关重要，这可以转化为临床人群和其他关键期。一个流行的模型， 关键期的调节提出，兴奋性突触处的可塑性的抑制性控制是由介导体周抑制的快速尖峰中间神经元（FS-IN）的输出的成熟介导的。然而，我们已经表明，眼优势可塑性可以诱导几个月后，成熟的体周抑制。相反，我们认为眼优势可塑性受抑制输出“上游”可塑性的调节， 从而影响抑制作用在功能回路中的恢复。此外，我们提出，Pyr->FS突触的功能连接必须保持在一个允许的范围内，以表达眼优势可塑性，因为遗传操作诱导的Pyr->FS连接的较大减少抑制了眼优势可塑性的表达。我们对锥体神经元对FS-INs的兴奋调节（Pyr->FS）的初步分析表明，在关键期单眼剥夺可能通过显着减少对这些神经元的兴奋性输入的数量而在功能上断开FS-INs与皮层网络的连接。因此，我们假设一种新的可塑性机制，剥夺诱导的功能性Pyr->FS连接的丧失1）是MD诱导的眼优势转变的早期和强制性步骤，2）决定了关键期的时间。我们提出了一套多学科的实验来测试这些假设，联合收割机结合：在检查生理变化的昆兰实验室的专业知识在体内的视觉皮层在单眼剥夺的反应，柯克伍德实验室的专业知识在直接评估的贡献，在视觉皮层的活动依赖性可塑性的单突触的变化;以及Lee实验室在使用光遗传学方法识别突触功能中活动依赖性变化的焦点和机制方面的专业知识。我们的模型的关键期的时间调控驳斥了许多广泛持有的假设，在哺乳动物皮层突触可塑性的发展变化。