Regulation of Synaptic Plastiticy in Visual Cortex

描述（由申请人提供）：长期以来，人们一直认为早期关键时期的视觉体验对视觉皮层的正常成熟至关重要。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，视觉皮层连接可以以一种活动依赖的方式进行修改。这些研究还表明，视觉皮层的可塑性取决于传递动物行为状态信息的神经模块输入，以及皮质内抑制的强度。该项目的长期目标是阐明年龄、神经调节剂和突触抑制控制视觉皮层突触修饰的细胞机制。这一建议建立在最近两项关于皮层突触可塑性调节的发现之上。首先，我们在体外大鼠视觉皮层切片中发现，神经调节剂控制由模式神经活动引起的突触变化的极性（增加或减少）。因此，我们将研究可塑性的神经调节机制，并将研究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，暴露在完全黑暗的环境中一周可以重新激活成年大鼠的幼年样可塑性，两种形式的突触修饰被认为与自然发生的可塑性有关：长期增强（LTP）和长期抑郁（LTD）。这些研究旨在测试两种假设，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，神经调节剂控制着活动依赖性突触修饰的极性和强度。第二个假说认为，突触抑制强度的发育增加减少或阻止了LTP和LTD的诱导。实验将在不同年龄、不同环境下长大的大鼠和小鼠的视觉皮层切片中进行。LTP和LTD的变化将与报道的自然发生的突触修饰的变化进行比较。了解LTP和LTD是如何被调节的，将有助于深入了解关键时期的机制，并将提供对皮质可塑性综合方面的细胞理解。除了这种神经可塑性与视觉能力发展的明显相关性之外，似乎类似的过程可能形成成人大脑中某些形式的学习和记忆的基础。婴幼儿早期视觉经验异常或不足可导致视觉系统的不适当连接和视觉能力下降。本提案将研究控制视觉系统连接的机制。这些结论将对预防不正确的布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.