Global synaptic plasticity mechanisms in visual cortex

视觉皮层的整体突触可塑性机制

• 批准号: 7687356
• 负责人: Hey-Kyoung Lee
• 金额: $ 37.06万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687356
• 关键词: AMPA Receptors; Address; Adult; Affect; Animals; Architecture; Auditory area; Biochemical; Biological Neural Networks; Blindness; Brain; Brain region; Cells; Clinical; Coupled; Cyclic AMP-Dependent Protein Kinases; Environment; Esthesia; Genes; Hand; Homeostasis; Human; Individual; Intervention; Knowledge; Measures; Mediating; Modality; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Neuromodulator; Patch-Clamp Techniques; Pattern; Process; Property; Prosthesis; Proteins; Recovery; Regulation; Research; Rodent; Sensory; Synapses; Synaptic Transmission; Synaptic plasticity; System; Vision; Visual; Visual Cortex; Visually Impaired Persons; Work; area striata; blind; dark rearing; design; effective therapy; experience; in vivo; insight; neural circuit; neural prosthesis; public health relevance; relating to nervous system; research study; restoration; scale up; sensory cortex; sensory system; somatosensory; visual deprivation; visual information

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.

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“跨模式”可塑性已在盲人中观察到，并被认为提供了一种补偿机制，可以在没有视力的情况下更好地利用剩余的感觉模式。虽然跨模式变化对盲人有益，但在设计临床干预措施以克服视力丧失时却构成了挑战，因为神经回路的广泛跨模式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式变化的系统水平分析上，然而，细胞和分子机制尚未得到探索。该应用的长期目标是了解视觉体验变化后皮质可塑性的细胞和分子机制。最近我们发现，剥夺啮齿类动物的视力（通过黑暗饲养）不仅会增加视觉皮层浅层的兴奋性突触传递，还会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处 AMPA 受体亚基组成的相关变化。我们假设，通过视觉剥夺在其他感觉皮层中跨模式观察到的稳态可塑性可能与在盲人中观察到的跨模式可塑性的细胞相关性。有趣的是，视觉剥夺导致的视觉皮层以及其他感觉皮层功能的稳态变化发生得相当快（一周内），并且很容易通过恢复视力（通过将动物重新暴露在光照环境中）来逆转。在本提案中，我们将确定初级感觉皮层全局稳态跨模式可塑性的细胞机制和功能。具体来说，我们的目标是从（1）诱导机制、（2）分子机制和（3）皮质回路水平的功能后果方面研究视觉体验诱导的全局稳态可塑性。为此，我们将使用全细胞膜片钳技术结合兴奋性突触传递的电生理学测量、突触蛋白的生化和免疫组织化学分析，并利用各种基因改造小鼠和体内基因敲除。拟议实验的结果将为开发针对各种视觉缺陷的更好的治疗方案提供见解，这些方案可能会根据视力受影响的程度和引起的跨模式变化的程度而有所不同。公共卫生相关性 众所周知，与视力正常的人相比，盲人的剩余感觉表现出代偿性增强。这些变化被称为“跨模式可塑性”，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，因为广泛的跨模式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针对各种形式的视觉缺陷开发更好的疗法提供见解，这可能需要根据视力受影响的程度和引起的跨模式变化的程度采取不同的治疗选择。