"Mechanisms underlying nicotine induced neuronal toxicity in zebrafish"

描述（由申请方提供）：胚胎暴露于尼古丁对人类发育具有不同程度的有害影响。这种暴露可导致与学习和记忆相关的认知能力和行为的长期变化。许多哺乳动物模型已被用来了解尼古丁如何发挥这种作用，但这是困难的，因为大多数哺乳动物的行为和神经系统是复杂的。我们正在研究尼古丁暴露在模型脊椎动物斑马鱼中的影响，目的是将尼古丁暴露造成的行为异常与脊髓神经元和相关脊髓肌肉组织的发育改变联系起来。斑马鱼胚胎对尼古丁暴露敏感（Svoboda et.等人，2002）。急性暴露于尼古丁的胚胎在通常不游泳的时候表现出游泳样行为。另一方面，长期将胚胎暴露在尼古丁中会导致瘫痪。这两种行为表型为我们指出了斑马鱼胚胎尼古丁暴露可能改变的候选细胞类型。在这个提议中，胚胎尼古丁暴露对脊髓神经元和相关肌肉组织的影响将被确定。据我们所知，这是首次尝试利用斑马鱼模型来了解胚胎尼古丁暴露的后果。其目标是：1）系统地鉴定和表征所有的斑马鱼nAChR，2）确定尼古丁暴露对运动神经元和肌肉发育的机制水平的后果，3）确定尼古丁暴露对胚胎感觉神经元发育的机制水平的后果，4）确定由短暂胚胎尼古丁暴露引起的表型是否持续到成年。这些目标中的每一个都解决了与外源性尼古丁如何在脊椎动物发育期间潜在地发挥其作用有关的基本问题。首先，他们描述了早期胚胎暴露于尼古丁导致的行为和神经解剖学表型。其次，它们提供了这些表型如何产生的机制性见解。这项工作是发育神经毒理学的基础研究。它有助于建立一个基础，使斑马鱼可以在体内利用解开的机制，尼古丁暴露在发展过程中的影响。

DESCRIPTION (provided by applicant): Embryonic exposure to nicotine has deleterious consequences on human development at various levels. Such exposure can lead to long term changes in the cognitive abilities and behaviors related to learning and memory. Many mammalian models have been employed to understand how nicotine can exert such effects, but this is difficult because most mammalian behaviors and the nervous system underlying them are complex. We are studying the effects of nicotine exposure in a model vertebrate, the zebrafish, with the goal of linking behavioral abnormalities created by nicotine exposure to developmental alterations in spinal neurons and associated spinal musculature. Zebrafish embryos are sensitive to nicotine exposure (Svoboda et. al, 2002). Embryos acutely exposed to nicotine exhibit a swimming-like behavior at time when they typically do not swim. On the other hand, chronically exposing embryos to nicotine, results in paralysis. These two behavioral phenotypes point us toward candidate cell types that may be altered in zebrafish by embryonic nicotine exposure. In this proposal the consequences of embryonic nicotine exposure on spinal neurons and associated musculature will be determined. To our knowledge, this is the first attempt at utilizing the zebrafish model to understand the consequences of embryonic nicotine exposure. The aims are: 1) To systematically identify and characterize all of the zebrafish nAChRs, 2) to determine the consequences of nicotine exposure on motoneuron and muscle development at the mechanistic level, 3) to determine the consequences of nicotine exposure on embryonic sensory neuron development at the mechanistic level, 4) To determine if phenotypes that arise form transient embryonic nicotine exposure persist into adulthood. Each of these aims addresses a fundamental issue relating to how exogenous nicotine potentially exerts its effects during vertebrate development. First, they describe behavioral and neuroanatomical phenotypes that result from early embryonic exposure to nicotine. Secondly, they provide mechanistic insight into how those phenotypes could arise. The work is basic research in developmental neurotoxicology. It serves to establish a foundation whereby zebrafish can be utilized in vivo to unravel the mechanisms that underlie the effects of nicotine exposure during development.