Homeostatic plasticity in mouse visual cortex

初级视觉皮层（V1）是哺乳动物大脑中研究最广泛的区域之一，不仅因为它对我们理解人类视觉至关重要，而且因为它已成为研究可塑性，学习和记忆的细胞过程的模型系统。在幼儿期所谓的关键时期的视觉体验塑造了V1神经元对整个生命中视觉刺激的反应方式，如果不及时纠正，任何使一只眼睛处于不利地位的情况（如斗鸡眼或白内障）都可能导致弱视（“懒惰的眼睛”）。高达4%的人口患有这种疾病。近年来的研究（包括我们自己的实验室）越来越多地使用小鼠来发现潜在过程的细胞和分子机制，使用单眼眼睑缝合（“单眼剥夺”）作为挑战视觉皮层可塑性的标准范例。研究发现，单眼剥夺的时间长短不同，年龄也不同，涉及的机制也不同。其中之一是“稳态可塑性”，这是神经元调节其兴奋性以维持稳定网络活动的重要能力，平衡长期突触增强和抑制的影响。这被认为是由一种称为突触缩放的过程介导的。我们以前发现的证据表明，这种机制的运作后，单眼剥夺少年，但不是成年小鼠的视觉皮层。我们还发现，AMPA受体的GluA1亚基是视觉皮层兴奋性传递的主要介质，对稳态可塑性非常重要，除了单眼剥夺外，将动物置于完全黑暗中也可以触发稳态可塑性，这可能是因为这会显著抑制整体皮层活动。最近的研究表明，黑暗暴露可以促进青少年大鼠和猫从单眼剥夺中恢复，因此可能为治疗弱视提供了一个机会。我们实验室的最新工作表明，仅仅几天的黑暗暴露就恢复了V1小鼠的可塑性，这些小鼠在关键期结束后被单眼剥夺，在这里，我们解决了关于幼年和成年小鼠体内稳态可塑性的细胞机制以及黑暗暴露对可塑性的影响的关键问题。我们将研究：1）黑暗暴露通过何种机制促进成人视皮层的可塑性？它是否能够实现在幼年皮质中发挥作用的GluA 1依赖性稳态可塑性，或者它只是增强现有的成年可塑性机制（例如长时程增强）？2)通过黑暗暴露恢复成年小鼠的视觉皮层可塑性是否具有行为学意义？换句话说，老鼠在黑暗中暴露一段时间后，使用先前被剥夺的眼睛在视觉引导的任务中表现更好吗？3)V1中哪些细胞介导GluA1依赖的可塑性？利用分子生物学技术，我们将依次抑制3类主要细胞（兴奋性锥体神经元、小白蛋白阳性抑制性神经元和星形胶质细胞）中GluA1的产生，以评估幼年小鼠单眼剥夺后的可塑性是否受到影响。4）稳态可塑性是否发生在成年视皮层中，如果不是通过突触缩放，那么是通过哪种替代机制？

The primary visual cortex (V1) is one of the most extensively studied areas of the mammalian brain, not only because it is crucial for our understanding of human vision but also because it has become a model system for studying cellular processes underlying plasticity, learning and memory. Visual experience during a so-called critical period in early childhood shapes the way neurons in V1 respond to visual stimuli throughout life, and any conditions that put one eye at a disadvantage (such as cross-eyes or a cataract) can cause amblyopia ('lazy eye') if not corrected in time. Up to 4% of the population suffer from this condition. In recent years research (including in our own labs) has increasingly employed mice in an effort to discover the cellular and molecular mechanisms of the underlying processes, using monocular eyelid suture ('monocular deprivation') as the standard paradigm to challenge visual cortex plasticity. Studies have identified the involvement of different mechanisms for different lengths of monocular deprivation and at different ages. One of these is 'homeostatic plasticity', an important ability of neurons to regulate their excitability in order to maintain stable network activity, balancing the effects of long-term synaptic potentiation and depression. This is thought to be mediated by a process called synaptic scaling. We have previously discovered evidence for the operation of this mechanism following monocular deprivation in juvenile but not adult mouse visual cortex. We also showed that the GluA1 subunit of the AMPA receptor which is the main mediator of excitatory transmission in the visual cortex is important for homeostatic plasticity.In addition to monocular deprivation, homeostatic plasticity can be triggered by placing animals in complete darkness, presumably because this depresses overall cortical activity dramatically. Dark exposure has recently been shown to promote recovery from monocular deprivation in adolescent rats and cats and may therefore present an opportunity to treat amblyopia beyond the end of the critical period. The latest work in our lab demonstrates that just a few days of dark exposure restore plasticity in V1 of mice which have been monocular deprived beyond the end of the critical period.Here we address key questions regarding the cellular mechanisms of homeostatic plasticity in juvenile and adult mice, as well as of the effects of dark exposure on plasticity. We shall investigate,1) By which mechanism does dark exposure promote plasticity in the adult visual cortex? Does it enable the GluA1 dependent homeostatic plasticity that operates in the juvenile cortex, or does it simply enhance existing mechanisms of adult plasticity (such as long-term potentiation)? 2) Is the restoration of visual cortex plasticity in adult mice by means of dark exposure behaviourally significant? In other words, do mice perform better on visually guided tasks, using the previously deprived eye, after a period of dark exposure?3) Which of the cells in V1 mediate the GluA1 dependent plasticity? Using molecular biology techniques we shall inhibit the production of GluA1 in each of 3 main classes of cells (excitatory pyramidal neurons, parvalbumin positive inhibitory neurons and astrocytes) in turn to assess whether plasticity in response to monocular deprivation in young mice is affected.4) Does homeostatic plasticity occur at all in adult visual cortex, and if not through synaptic scaling then through which alternative mechanism?