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（由适用提供）：在产后早期发育的关键时期，视觉输入质量到两只眼睛的不对称性使眼部偏好从弱眼中转移，并引起弱视，这是人类中最常见的单眼视觉性缺陷的原因。弱视在成年期高度抗性，这在很大程度上是由于终止量增强的终止。了解如何启动和终止关键时期的增强可塑性，这是旨在重新激活可塑性以治疗成年人的弱视的治疗策略的基础，这些策略可以转化为临床人群和其他关键时期。一个流行的模型 对兴奋性突触抑制可塑性控制的关键时期建议的调节是通过介导的抑制周围抑制的快速尖刺中间神经元（FS-INS）的成熟来介导的。但是，我们已经表明，可以在围par抑制成熟后几个月诱导眼部优势可塑性。相反，我们建议眼部优势可塑性受抑制输出的“上游”的可塑性调节，很可能 影响将抑制作用募集到功能电路中。此外，我们建议必须将PYR-> FS突触的功能连通性保留在宽敞的范围内，以表达眼部优势可塑性，因为遗传操纵诱导的PYR-> FS连通性的较大降低抑制了Oripary优势可塑性的表达。我们对从锥体神经元对FS-INS（PYR-> FS）调节兴奋的初步分析表明，在关键时期，单眼剥夺可以通过功能性地从皮质网络中脱离皮质网络，从而显着减少对这些神经元的激发投入的数量。因此，我们假设一种新颖的可塑性机制，剥夺引起的功能性pyr-> fs连接性的丧失1）是MD引起的眼部优势转移的早期和强制性步骤，2）确定关键时期的时间。我们提出了一组多学科的实验，以测试结合结合的假设：昆兰实验室的专业知识，以检查体内视觉皮层的物理变化，以响应单眼剥夺；柯克伍德实验室的专业知识在直接评估单个突触变化对视觉皮层中活性依赖性可塑性的贡献的直接评估中； Lee Lab在使用光遗传学方法中的专业知识来识别突触功能的活性依赖性变化的焦点和机制。我们调节关键时期时间安排的模型反驳了许多关于哺乳动物皮质突触可塑性发展的广泛假设。