Role of a medial habenula circuit and Nr4a2 in cocaine-induced reinstatement

项目总结/摘要 众所周知，滥用药物会导致奖赏回路突触可塑性的长期变化， 最终，行为的持续变化。了解这些变化背后的机制是 一个关键的未决问题。由于奖赏回路和学习记忆回路共享关键节点， 点，在学习和记忆领域的新发现将有可能阐明方面 寻求毒品的行为。特别是，已经充分确定基因表达是长时间的基因表达所必需的。 突触可塑性和长期记忆形成的持久形式。最近，研究表明， 记忆巩固过程中基因表达的表观遗传调控可以调节基因表达， 表达动力学，对记忆形成产生惊人的影响。例如，抑制或 组蛋白去乙酰化酶3（HDAC 3）在核内的缺失导致维持表达， nr 4a 2（核孤儿受体2），与可卡因相关的记忆形成。NR4a2 是酪氨酸羟化酶和多巴胺转运蛋白的转录因子，定义了 多巴胺能信号内侧缰核（MHb）是一个高度表达HDAC 3和HDAC 4的区域。 NR 4A 2及其预测最近被确定为滥用药物的主要目标。最近的工作 已经表明，MHb与寻求药物行为的获得和恢复有关。 此外，我的初步数据表明，MHb在可卡因的恢复过程中是活跃的- 相关记忆然而，滥用药物对MHb和MHb电路的影响是不确定的。 调节其基因表达的表观遗传机制在很大程度上尚未研究。中的实验 这个建议将解决总体假设，即MHb是必要的和足够的， 以Nr 4a 2依赖性方式恢复可卡因背景记忆（特异性目标1和2） 目标3）。

Project Summary/Abstract Drugs of abuse are known to cause long-term changes in the synaptic plasticity of reward circuitry and, ultimately, persistent changes in behavior. Understanding the mechanisms underlying these changes is a key open question. As the reward circuitry and the learning and memory circuitry share key nodal points, new discoveries in the learning and memory field will have the potential to shed light on aspects of drug-seeking behavior. In particular, it is well established that gene expression is required for long- lasting forms of synaptic plasticity and long-term memory formation. Very recently, studies demonstrated that epigenetic regulation of gene expression during memory consolidation can modulate gene expression dynamics, resulting in surprising effects on memory formation. For example, inhibition or deletion of histone deacetylase 3 (HDAC3) in the nucleus accumbens leads to maintained expression of Nr4a2 (nuclear orphan receptor 2), correlating with cocaine-context associated memory formation. Nr4a2 is a transcription factor for tyrosine hydroxylase and the dopamine transporter, defining enzymes of dopaminergic signaling. The medial habenula (MHb), a region that highly expresses both HDAC3 and NR4A2, and its projections have recently been identified as main targets of drugs of abuse. Recent work has shown that the MHb is implicated in both the acquisition and reinstatement of drug-seeking behavior. Furthermore, my preliminary data has shown that the MHb is active during the reinstatement of cocaine- associated memories. Yet, the effects that drugs of abuse have on the circuitry of the MHb and the epigenetic mechanisms that regulate its gene expression remain largely unstudied. The experiments in this proposal will address the overall hypothesis that the MHb is necessary and sufficient for reinstatement of cocaine-context memory (Specific Aim 1 and 2) in an Nr4a2-dependent manner (Specific Aim 3).