Role of Nogo receptor in addiction

描述(申请人提供)：物质滥用导致长期的，如果不是永久性的大脑功能改变，被认为至少部分存在于皮质区域和皮质下大脑奖励通路的结构重组中。Nogo信号系统一旦与由Nogo受体(NgR1)组成的受体复合体与驻留在神经细胞膜上的辅助受体结合，将导致神经纤维生长受到抑制。神经元活性的增加也有效地下调了NGR的表达，我们推测这是形成持久(一个月)记忆所需可塑性的关键因素。为了支持我们的假设，在前脑神经元中携带可诱导的NGR转基因(“MemoFlex”)的小鼠在转基因活跃时不能形成持久的记忆(见Karl？n 2009等人)。在这些“MemoFlex”小鼠中，LTP和1天的记忆是正常的。我们建议使用NGR缺失突变和过度表达“MemoFlex”小鼠来表征NGR在药物反应需要长时间(4周)记忆的行为模型中的作用。恢复先前与接受成瘾药物配对的环境的条件性位置偏好(CPP)，以及NGR如何影响对药物诱导的运动反应的敏化将被分析。这两种模型都使用了4周的无药期，然后用低剂量的药物恢复动物的行为。在同一组小鼠中，将分析结构变化，如上瘾药物或自然奖励、滚轮跑步后大脑奖励路径中树突棘的变化。最后，将分析对结构可塑性重要的代谢途径的活性以及神经营养因子BDNF和(FosB)的水平，这两种因子在成瘾药物和车轮跑步后都在伏隔核上调。该项目旨在揭示Nogo系统在成瘾发展和维持所需的大脑通路中的结构可塑性、学习和记忆事件中的作用。我们将检验这一假设，即在独特的小鼠模型中，皮质和皮质下对头区的结构重组是药物暴露和成瘾转变的长期相关性的基础。据我们所知，从未在成瘾模型中分析过Nogo系统。这项研究还将有助于确定NGR信号通路是否可能为药物成瘾治疗的发展提供新的靶点。 公共卫生相关性：吸食成瘾药物形成非常稳定的药物相关记忆，这可能对强迫性药物消费行为的发展和维持非常重要。在这个项目中，我们的目标是描述Nogo受体的作用，它在大脑的长期记忆和结构重排中具有关键功能。如果成功，这个项目可以为开发针对Nogo受体信号的吸毒者的新疗法打开大门。

DESCRIPTION (provided by applicant): Substance abuse causes long-term, if not permanent alterations of brain function, which are thought to at least partly reside in structural reorganization in cortical areas and subcortical brain reward pathways. The Nogo signaling system that upon binding to receptor complexes comprised of the Nogo receptor (NgR1) in conjunction with coreceptors residing in nerve cell membranes will cause inhibition of nerve fiber growth. NgR is also effectively down-regulated by increased neuronal activity and we postulated this to be a key factor in the plasticity needed to form lasting (one month) memories. In support of our hypothesis mice carrying an inducible NgR transgene ("MemoFlex") in forebrain neurons, cannot form lasting memories when the transgene is active (See Karl¿n 2009 et al.). In these "MemoFlex" mice LTP and 1 day memories are normal. We propose to characterize the role of NgR using NgR null mutant and overexpressing "MemoFlex" mice in behavioral models for drug responses that require long term (>4 weeks) memory. Reinstatement of conditioned place preference (CPP) for environments previously paired with receipt of addictive drugs, and how NgR affects sensitization to drug induced locomotor responses will be analyzed. Both models use a drug free period of 4 weeks before the animal's behaviors are reinstated with a low priming dose of the drug. Structural changes such as dendritic spine alterations in brain reward pathways after addictive drugs or a natural reward, wheel running, will be analyzed in the same mice. Finally, activity in metabolic pathways that are important for structural plasticity and levels of the neurotrophic factor BDNF and (FosB which are both upregulated in accumbens after addictive drugs and wheel running will be analyzed. The project aims at revealing the roles of the Nogo system for the structural plasticity, learning and memory events in brain pathways needed for development and maintenance of addiction. We will test the hypothesis that structural reorganization in cortical and subcortical telenecephalic areas underlie long term correlates of the transition between drug exposure and addiction in unique mouse models. To our knowledge the Nogo system has never been analyzed in models of addiction. This research will also help determine if the NgR signaling pathways may offer new targets for the development of treatments for drug addiction. PUBLIC HEALTH RELEVANCE: Consumption of addictive drugs form very stable drug associated memories, which are likely to be very important for the development and maintenance of compulsive drug consuming behaviors. In this project we aim to characterize the role of the Nogo receptor, which has a key function in long- term memory and structural rearrangement of the brain. If successful this program can open up for the development of new treatments for drug addicts, which targets Nogo receptor signaling