Fos, Jun & synaptic plasticity

描述（由申请人提供）： 药物成瘾，长期记忆和其他持久的行为变化源于潜在的神经回路的可塑性，由活性调节的基因表达驱动。最近的行为分析表明，两个转录因子，CREB和AP 1（通常是Fos和Jun的二聚体）在调节可卡因成瘾中的关键作用。在啮齿类动物的丘脑核中，FosB（一种显性负性Fos亚型）的诱导导致长期的行为敏感化和对可卡因的渴望;相反，CREB的诱导通过诱导对更高水平可卡因的适应来减少药物奖励。尽管AP 1和CREB对行为可塑性具有明显的重要性，但对其作用机制知之甚少。我们最近的观察结果与一个意想不到的重要假设相一致，即AP 1在CREB的上游作用，位于已知可塑性相关转录因子的层次结构的顶部。在测试这一假设的同时，该提议旨在：a）更完整地阐述AP 1的细胞功能;和B）鉴定AP 1上游和下游操作的分子机制。在短期内，这项工作将提供对AP 1操纵的细胞生物学后果的描述，并概述调控蛋白之间的层次结构和关系，如启动可塑性过程的AP 1，CREB和MAP激酶。从长远来看，介导突触变化过程的效应分子将被识别并分析其功能。黑腹果蝇是这些分析的一个很好的模式生物。哺乳动物和昆虫中几乎所有已知的可塑性调节因子的功能保守性表明了哺乳动物和昆虫中涉及可塑性调节的潜在机制的共同性。然而，在果蝇中提出的分析的进展速度要快得多，不仅由于其短的世代时间和遗传学设施，而且还由于果蝇基因组计划，微阵列技术和新开发的体内基因破坏，干扰和替换程序的新资源。所提出的实验解决了行为变化背后的突触重塑事件中具有根本重要性的一个领域。这项工作特别重要，因为它解决了Fos和Jun的功能，这两个药物成瘾的关键调节器。此外，通过识别活动调节的神经元蛋白质，该计划可能有助于新的，可塑性过程的分子标记物，成瘾的基础。最后，这些实验的结果可以识别和验证新的分子，以靶向药物治疗。

DESCRIPTION (provided by applicant): Drug addiction, long-term memory and other lasting behavioral changes derive from plasticity of underlying neural circuits, driven by activity-regulated gene expression. Recent behavioral analyses demonstrate critical roles for two transcription factors, CREB and AP1 (usually a dimer of Fos and Jun) in regulating cocaine addiction. Induction of FosB, a dominant-negative Fos isoform, in rodent nucleus accumbens causes long-term behavioral sensitization and craving for cocaine; in contrast, induction of CREB reduces drug-reward by inducing adaptation to higher levels of cocaine. Despite the obvious importance of AP1 and CREB for behavioral plasticity, little is known about the mechanism of their action. Our recent observations are consistent with the unexpected, important hypothesis that AP1 acts upstream of CREB at the top of the hierarchy of known plasticity-associated transcription factors. While testing this hypotheses, this proposal aims to: a) more completely elaborate cellular functions of AP1; and b) identify molecular mechanisms that operate upstream and downstream of AP1. In the short term, the work will provide a description of cellular biological consequences of AP1 manipulations, and outline the hierarchies and relationships among regulatory proteins, like AP1, CREB and MAP kinases that initiate plasticity processes. In the longer term, effector molecules that mediate the processes of synaptic change will be identified and their functions analyzed. Drosophila melanogaster is an excellent model organism for these analyses. The commonality of underlying mechanisms involved in plasticity regulation in mammals and insects is indicated by the functional conservation of almost all known regulators of plasticity in both phyla. However, the rate of progress of the proposed analyses in Drosophila is much faster, facilitated not only by its short generation time and facility for genetics, but also by novel resources from Drosophila genome projects, microarray technologies and newly developed procedures for gene disruption, perturbation and replacement in vivo. The proposed experiments address an area of fundamental importance in synaptic remodeling events that underlie behavioral change. The work is particularly significant because it addresses the function of Fos and Jun, two critical regulators of drug addiction. In addition, by identifying activity-regulated neuronal proteins the program may contribute new, molecular markers of plasticity processes that underlie addiction. Finally, results from these experiments may identify and validate new molecules to target for pharmacological therapy.