Role of Nogo receptor in addiction

描述（由申请人提供）：药物滥用导致长期的，如果不是永久性的脑功能改变，这被认为至少部分存在于皮层区域和皮层下脑奖励通路的结构重组中。Nogo信号系统与由Nogo受体（NgR1）和位于神经细胞膜上的辅受体组成的受体复合物结合后，会抑制神经纤维的生长。神经元活动的增加也有效地下调了NgR，我们假设这是形成持久（一个月）记忆所需的可塑性的关键因素。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”）的小鼠在转基因激活时不能形成持久的记忆（见Karl¿n 2009 et al.）。在这些“MemoFlex”小鼠中，LTP和1天记忆正常。我们建议在行为模型中使用NgR零突变体和过表达“MemoFlex”小鼠来表征NgR的作用，这些小鼠需要长期（bb0 - 4周）记忆的药物反应。本研究将分析条件位置偏好（CPP）的恢复，以及NgR如何影响对药物诱导的运动反应的敏化。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。在同样的老鼠身上，研究人员将分析上瘾药物或自然奖励（滚轮跑步）后大脑奖励通路中的树突棘改变等结构变化。最后，我们将分析对结构可塑性至关重要的代谢途径的活性，以及成瘾药物和轮式跑步后伏隔核上调的神经营养因子BDNF和（FosB）水平。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。我们将在独特的小鼠模型中验证皮层和皮层下的脑端区结构重组是药物暴露和成瘾之间过渡的长期相关因素的假设。据我们所知，Nogo系统从未在成瘾模型中被分析过。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。

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