Global synaptic plasticity mechanisms in visual cortex

描述（由申请人提供）：视力丧失不仅会改变大脑处理视觉信息的功能，还会影响其他感觉系统的功能。这种类型的“跨模态”可塑性已经在盲人中观察到，并且被认为提供了一种补偿机制，以在缺乏视觉的情况下更好地利用剩余的感觉模态。虽然跨模态变化对盲人有益，但在设计临床干预措施以克服视力丧失时，它们构成了挑战，因为神经回路中广泛的跨模态变化可能会阻碍正常功能的恢复。迄今为止，大多数研究都集中在跨模态变化的系统水平分析，但尚未探讨细胞和分子机制。本申请的长期目标是了解视觉体验变化后皮层可塑性的细胞和分子机制。最近，我们发现剥夺啮齿动物的视觉（通过黑暗饲养）不仅增加了视觉皮层浅层的兴奋性突触传递，而且在其他初级感觉皮层中产生相反的变化。这些变化遵循稳态可塑性机制的规则，该机制在神经活动长期扰动后为神经网络提供稳定性。这些变化伴随着突触AMPA受体亚单位组成的相关变化。我们假设，在视觉剥夺的其他感觉皮层中观察到的跨模态稳态可塑性可能是在盲人中观察到的跨模态可塑性的细胞相关性。有趣的是，视觉皮层以及其他感觉皮层功能的自稳态变化发生得非常迅速（在一周内），并且很容易通过恢复视力（通过将动物重新暴露于光照环境）来逆转。在这个建议中，我们将确定初级感觉皮层的整体稳态跨模态可塑性的细胞机制和功能。具体而言，我们的目标是研究视觉经验诱导的全球稳态可塑性方面的（1）诱导机制，（2）分子机制，（3）功能后果在皮层回路水平。为此，我们将结合联合收割机电生理测量兴奋性突触传递使用全细胞膜片钳技术，突触蛋白的生化和免疫组织化学分析，并利用各种遗传改变的小鼠和体内基因敲除。从拟议的实验结果将提供深入了解开发更好的治疗方案，为各种视觉缺陷，这可能会有所不同，这取决于视力受影响的程度和跨模态的变化引起的程度。公共卫生相关性众所周知，与正常视力的人相比，盲人在其余感觉方面表现出补偿性增强。这些变化被称为“跨模态可塑性”，虽然对盲人有益，但对开发有效的视力丧失治疗方法提出了挑战，因为广泛的跨模态变化阻碍了正常功能的恢复。从我们的工作中获得的知识将为开发更好的治疗各种形式的视觉缺陷提供见解，这可能需要不同的治疗方案，具体取决于受影响的视力程度和引起的跨模态变化的程度。

DESCRIPTION (provided by applicant): Loss of vision not only alters the function of the brain processing visual information, but also affects the function of other sensory systems. This type of "cross-modal" plasticity has been observed in blind humans, and is thought to provide a compensatory mechanism to better utilize the remaining sensory modalities in the absence of vision. While the cross-modal changes are beneficial to blind individuals, they pose a challenge when devising clinical interventions to overcome the loss of vision because extensive cross-modal changes in neural circuitry may hinder restoration of normal function. So far most research has focused on the systems level analyses of cross-modal changes, however, the cellular and molecular mechanisms have not been explored. The long-term objective of this application is to understand the cellular and molecular mechanisms underlying cortical plasticity following changes in visual experience. Recently we found that depriving vision (by dark-rearing) of rodents not only increases excitatory synaptic transmission in the superficial layers of the visual cortex, but also produces opposite changes in other primary sensory cortices. These changes followed the rules of a homeostatic plasticity mechanism, which provides stability to neural networks following prolonged perturbation in neural activity. These changes were accompanied by correlative changes in AMPA receptor subunit composition at synapses. We hypothesize that the homeostatic plasticity observed cross-modally in other sensory cortices by visual deprivation may be a cellular correlate of cross-modal plasticity observed in blind individuals. Interestingly, the homeostatic changes in the function of visual cortex, as well as other sensory cortices, by visual deprivation occurred quite rapidly (within a week) and were readily reversed by restoring vision (by re-exposing the animals to a lighted environment). In this proposal we will determine the cellular mechanisms and functions of global homeostatic cross-modal plasticity in primary sensory cortices. Specifically, we aim to investigate visual experience-induced global homeostatic plasticity in terms of its (1) induction mechanisms, (2) molecular mechanisms, and (3) functional consequences at a cortical circuit level. To do this, we will combine electrophysiological measure of excitatory synaptic transmission using whole-cell patch clamp techniques, biochemical and immunohistochemical analyses of synaptic proteins, and utilize various genetically altered mice and in vivo gene knockdown. Results from the proposed experiments will provide insights into developing better treatment options for various visual deficits, which may differ depending on the degree of vision affected and the extent of cross-modal changes elicited. PUBLIC HEALTH RELEVANCE It is known that blind individuals display a compensatory enhancement in the remaining sensations when compared to normal sighted individuals. These changes, termed "cross-modal plasticity", while beneficial to the blind individual, poses a challenge in developing effective treatments for vision loss because extensive cross-modal changes hinder restoration of normal function. Knowledge gained from our work will provide insights into developing better therapies for various forms of visual deficits, which may require distinct treatment options depending on the degree of vision affected and the extent of cross-modal changes elicited.