Role of Nogo receptor in addiction

描述（由申请人提供）：物质滥用导致长期（如果不是永久性的话）脑功能改变，这被认为至少部分存在于皮质区和皮质下脑奖励通路的结构重组中。Nogo信号传导系统在结合到由Nogo受体（NgR 1）与存在于神经细胞膜中的辅助受体组成的受体复合物时将引起神经纤维生长的抑制。NgR也被增加的神经元活动有效地下调，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诱导型NgR转基因（“MemoFlex”）的小鼠在转基因活跃时不能形成持久的记忆（参见Karl n 2009 et al.）。在这些“MemoFlex”小鼠中，LTP和1天记忆是正常的。我们建议使用NgR无效突变体和过表达“MemoFlex”小鼠在需要长期（>4周）记忆的药物反应行为模型中表征NgR的作用。将分析先前与接受成瘾药物配对的环境的条件性位置偏好（CPP）的恢复，以及NgR如何影响对药物诱导的运动反应的敏感性。两种模型都使用4周的无药物期，然后用低引发剂量的药物恢复动物的行为。结构变化，如树突棘改变大脑奖励途径后，成瘾药物或自然奖励，车轮运行，将在同一小鼠进行分析。最后，将分析对结构可塑性和神经营养因子BDNF和β-FosB水平重要的代谢途径中的活性，这两种因子在成瘾性药物和车轮运行后在神经元中均上调。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。我们将测试的假设，在皮质和皮质下端脑区的结构重组的基础长期相关的药物暴露和成瘾之间的过渡在独特的小鼠模型。据我们所知，Nogo系统从未在成瘾模型中进行过分析。这项研究还将有助于确定NgR信号通路是否可以为药物成瘾治疗的发展提供新的靶点。 公共卫生相关性：成瘾性药物的消费形成非常稳定的药物相关记忆，这可能是非常重要的发展和维持的强迫性药物消费行为。在这个项目中，我们的目标是表征Nogo受体的作用，它在长期记忆和大脑结构重排中具有关键功能。如果成功的话，这个项目可以为开发针对Nogo受体信号传导的药物成瘾者的新疗法开辟道路。

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