Regulation of Synaptic Plastiticy in Visual Cortex

描述(由申请人提供)：长期以来，人们一直认识到，在早期关键期的视觉体验对于视觉皮质的正常成熟是必不可少的。对在不同环境中饲养的动物的研究已经证实，在这一关键时期，视觉皮质连接可以依赖于活动的方式进行修改。这些研究还表明，视觉皮质的可塑性取决于传达动物行为状态信息的神经调节输入，以及皮质内抑制的强度。该项目的长期目标是阐明AGE、神经调节剂和突触抑制控制视皮层突触修饰的细胞机制。这一建议建立在最近关于皮层突触可塑性调节的两项发现的基础上。首先，我们发现神经调节剂控制由体外模式神经活动引起的大鼠视皮层脑片突触变化的极性(增加或减少)。因此，我们将研究可塑性的神经调节机制，并将检查这些机制是否也在体内和灵长类动物中起作用。其次，根据最近的观察，暴露在完全黑暗中一周会重新激活成年大鼠的幼年样可塑性，对两种形式的突触修饰的调节被认为与自然发生的可塑性有关：长期增强(LTP)和长期抑制(LTD)。这项研究的目的是检验两种假说，即神经调节剂和突触抑制如何调节这些形式的可塑性的诱导。第一种假说认为，神经调节剂控制着依赖活性的突触修饰的极性和幅度。第二个假设指出，突触抑制强度的发育增加减少或阻止了LTP和LTD的诱导。这些实验将在不同年龄、在不同环境中饲养的大鼠和小鼠的视皮层切片上进行。LTP和LTD的变化将与报道的自然发生的突触修改的变化进行比较。了解LTP和LTD是如何调控的，将有助于深入了解关键期的潜在机制，并将提供细胞对皮质可塑性的综合方面的理解。除了这种神经可塑性与视觉能力的发展明显相关外，似乎类似的过程可能形成了成人大脑中某些形式的学习和记忆的基础。公共卫生相关性婴儿早期的异常或不足的视觉体验可能导致视觉系统的不适当连接，并削弱视觉能力。这项建议将研究控制视觉系统连接的机制。这些结论将对防止错误接线和恢复正常视力具有重要意义。

DESCRIPTION (provided by applicant): It has long been appreciated that visual experience during an early critical period is essential for the normal maturation of visual cortex. Studies on animals reared in different environments have established that during this critical period, visual cortical connections can be modified in an activity dependent manner. Those studies have also shown that visual cortical plasticity depends on neuromodulary inputs that convey information on the behavioral state of the animals, and on the strength of intracortical inhibition. The long-term goal of this project is to elucidate the cellular mechanisms by which age, neuromodulators and synaptic inhibition control synaptic modification in visual cortex. This proposal builds upon two recent findings on the regulation of synaptic plasticity in cortex. First, we have found that neuromodulators control the polarity (increase or decrease) of synaptic changes induced by patterned neural activity in vitro, in slices of rat visual cortex. Therefore we will investigate the mechanisms of the neuromodulation of plasticity, and will examine whether these mechanism also operate in vivo and in primates. Second, prompted by the recent observation that exposure to complete darkness for a week reactivates juvenile-like plasticity in adults rats, the regulation of two forms of synaptic modification are believed to be involved in natural occurring plasticity: long-term potentiation (LTP) and long-term depression (LTD). The studies are aimed to test two hypotheses concerning how neuromodulators and synaptic inhibition might regulate the induction of these forms of plasticity. The first hypothesis states that neuromodulators control the polarity and magnitude of activity- dependent synaptic modification. The second hypothesis states that developmental increases in the strength of synaptic inhibition reduces or prevents the induction of LTP and LTD. The experiments will be performed in slices made from the visual cortex of rats and mice of different ages and raised in different environments. Changes in LTP and LTD will be compared with reported changes in naturally-occurring synaptic modifications. Understanding how LTP and LTD are regulated will yield insights into the mechanisms underlying the critical period and will provide a cellular understanding of the integrative aspects of cortical plasticity. Besides the obvious relevance of this neural plasticity to the development of visual capabilities, it seems likely that similar processes may form the basis for some forms of learning and memory in the adult brain. PUBLIC HEALTH RELEVANCE Abnormal or insufficient visual experience during early infancy can result in inappropriate wiring of the visual system, and in diminished visual capabilities. This proposal will investigate the mechanisms that control the wiring of the visual system. The conclusions will be relevant for preventing incorrect wiring, and for restoring normal vision.