Reversible activation on critical plasticity in visual cortex

 描述(申请人提供)：在出生后早期发育的关键时期，双眼视觉输入的质量不对称会使弱视的视觉偏好从较弱的眼睛转移，并导致弱视，这是人类单眼视觉缺陷的最常见原因。弱视在成年后高度抵抗逆转，这在很大程度上是由于高度可塑性的关键期的终止。了解关键期增强的可塑性是如何在发育过程中开始和终止的，这对于开发旨在重新激活可塑性来治疗成人弱视的治疗策略是至关重要的，这可以转化为临床人群和其他关键期。一种流行的型号 关键期的调节表明，兴奋性突触可塑性的抑制控制是由介导周围抑制的快脉冲中间神经元(FS-INS)的输出成熟所介导的。然而，我们已经证明，眼球优势可塑性可以在成熟的颧骨周围抑制几个月后诱导。相反，我们提出，眼睛优势可塑性可能是由抑制输出的可塑性“上游”调节的 影响抑制作用在功能回路中的募集。此外，我们认为，为了表达眼优势可塑性，必须将PYR-&>FS突触的功能连接性保持在允许的范围内，因为遗传操作导致的PYR-&>FS连接性的较大降低抑制了眼优势可塑性的表达。我们对锥体神经元兴奋对FS-ins(PYR-&GT；FS)的调节的初步分析表明，关键期的单眼剥夺可能通过显著减少对这些神经元的兴奋性输入而从功能上切断FS-IN与皮质网络的连接。因此，我们假设，一种新的可塑性、剥夺导致功能性PYR-&GT；FS连接性丧失的机制1)是MD引起的眼优势转移的早期和必需的步骤，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说，这些实验结合了以下几个方面：昆兰实验室在检查单眼剥夺后活体视觉皮质的生理变化方面的专业知识；柯克伍德实验室在直接评估单个突触变化对视皮层活动依赖可塑性的贡献方面的专业知识；以及Lee实验室在使用光遗传学方法确定突触功能活动依赖变化的焦点和机制方面的专业知识。我们的关键期时间调控模型驳斥了许多关于哺乳动物皮质突触可塑性发育变化的广泛持有的假设。

 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.