Role of NPAS2 in the nucleus accumbens in drug addiction

 描述（由申请人提供）：昼夜节律紊乱在精神疾病（包括成瘾和情绪障碍）患者中很突出。此外，与节律和睡眠有关的问题增加了滥用药物的脆弱性，并在个人停止滥用药物后很长一段时间内导致复发。然而，昼夜节律基因破坏导致药物滥用奖励价值变化的分子机制仍不清楚。我们实验室和其他人的研究发现，组成分子钟的基因通过直接调节腹侧被盖区（VTA）-丘脑核（NAc）多巴胺能奖励回路中的基因表达来调节情绪和奖励相关行为。CLOCK和NPAS 2是两种重要的分子节律调节因子，它们在结构和功能上非常相似。然而，虽然Clock突变小鼠对可卡因的偏好增加，但NPAS 2突变小鼠的偏好降低。CLOCK在VTA和NAc中表达，而NPAS 2在VTA中不表达，并且我们最近发现其在NAc中的表达几乎仅在表达D1多巴胺受体的神经元中表达。我们还发现，NAc中NPAS 2的局部敲低足以降低可卡因偏好。在这里，我们将集中在NPAS 2在D1神经元的NAc的作用。我们的目标是将NPAS 2调节基因、神经元兴奋性和成瘾相关行为之间的联系联系起来。我们将确定NPAS 2的直接转录目标，特别是在D1神经元，并确定其模式的基因表达。我们特别感兴趣的基因是重要的调节神经元的活动。我们还将确定D1神经元中NPAS 2的敲低如何影响这些神经元中的mEPSC和AMPA/NMDA比率。这些是神经元活动的重要指标，这些神经元活动参与对滥用药物的反应。最后，我们将确定NPAS 2选择性在奖励相关行为和可卡因自我管理的NAc中的D1神经元中的作用。这种“从基因到生理再到行为”的方法将引导我们找到成瘾脆弱性的明确机制，并帮助我们为未来开发有针对性的治疗方法。

 DESCRIPTION (provided by applicant): Circadian rhythm disruptions are prominent in individuals with psychiatric disorders including addiction and mood disorders. Furthermore, rhythm and sleep-related problems increase the vulnerability for substance abuse and contribute to relapse long after an individual stops abusing drugs. However, the molecular mechanisms by which circadian gene disruption leads to changes in reward value for drugs of abuse has remained unclear. Studies from our lab and others have found that the genes that make up the molecular clock regulate mood and reward related-behavior via direct regulation of gene expression in the ventral tegmental area (VTA)- nucleus accumbens (NAc) dopaminergic reward circuit. CLOCK and NPAS2 are two of the central regulators of molecular rhythms and they are very similar in structure and function. However, while Clock mutant mice have an increase in preference for cocaine, NPAS2 mutant mice have a decreased preference. CLOCK is expressed in both the VTA and NAc while NPAS2 is not expressed in the VTA, and we have recently found that its expression in the NAc is almost exclusively in neurons expressing D1 dopamine receptors. We have also found that local knock-down of NPAS2 in the NAc is sufficient to reduce cocaine preference. Here we will focus on the role of NPAS2 in D1 neurons of the NAc. Our goal in this proposal is to connect the dots between NPAS2 regulated genes, neuronal excitability and addiction-related behavior. We will identify direct transcriptional targes of NPAS2 specifically in D1 neurons and determine their patterns in gene expression. We are particularly interested in genes that are important in regulating neuronal activity. We will also determine how a knock-down of NPAS2 in D1 neurons impacts mEPSCs and AMPA/NMDA ratios in these neurons. These are important indicators of neuronal activity which are involved in the responses to drugs of abuse. Finally, we will determine the role of NPAS2 selectively in D1 neurons in the NAc in reward-related behavior and cocaine self-administration. This "gene to physiology to behavior" approach will lead us to defined mechanisms that underlie the vulnerability for addiction and help us to develop targeted treatments for the future.