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，而且因为它已经成为研究可塑性、学习和记忆基础细胞过程的模型系统。在儿童早期所谓的关键时期的视觉体验决定了V1神经元在一生中对视觉刺激的反应方式，任何使一只眼睛处于不利地位的情况（如斜眼或白内障）如果不及时纠正，都可能导致弱视（“懒眼”）。高达4%的人口患有这种疾病。近年来，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。研究已经确定了不同长度和不同年龄的单眼剥夺所涉及的不同机制。其中之一是“内稳态可塑性”，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。这被认为是由一个叫做突触缩放的过程介导的。我们之前已经发现了单眼剥夺在幼鼠而非成年小鼠视觉皮层中运作的证据。我们还发现AMPA受体的GluA1亚基是视觉皮层兴奋传递的主要介质，对稳态可塑性很重要。除了单眼剥夺外，将动物置于完全黑暗的环境中也可以触发稳态可塑性，可能是因为这极大地抑制了大脑皮层的整体活动。最近有研究表明，暴露在黑暗环境中可以促进青春期大鼠和猫从单眼剥夺中恢复过来，因此可能为治疗超过关键时期的弱视提供了机会。我们实验室的最新工作表明，仅仅几天的黑暗暴露就可以恢复单眼剥夺小鼠V1的可塑性，超过了关键时期的结束。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的关键问题，以及黑暗暴露对可塑性的影响。我们将探讨：1)黑暗暴露促进成人视觉皮层可塑性的机制是什么？它是否使GluA1依赖的内稳态可塑性在青少年皮层中运作，或者它只是增强了成人可塑性的现有机制（如长期增强）？2)暗暴露对成年小鼠视觉皮层可塑性的恢复是否具有行为学意义？换句话说，在一段时间的黑暗暴露后，老鼠在使用先前被剥夺的眼睛进行视觉引导任务时表现得更好吗？3) V1中哪些细胞介导了GluA1依赖性的可塑性？利用分子生物学技术，我们将依次抑制3种主要细胞（兴奋性锥体神经元、小白蛋白阳性抑制神经元和星形胶质细胞）中GluA1的产生，以评估年轻小鼠单眼剥夺反应的可塑性是否受到影响。4)在成人视觉皮层中是否存在稳态可塑性，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?