Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine, USA; UC Irvine Center for Addiction Neuroscience, School of Biological Sciences, University of California, Irvine, USA; Center for the Neurobiology of Learning and Memory, School of Biological Sciences, University of California, Irvine, USA.
Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine, USA; Center for the Neurobiology of Learning and Memory, School of Biological Sciences, University of California, Irvine, USA.
Neuropharmacology. 2019 Jul 15;153:13-19. doi: 10.1016/j.neuropharm.2019.04.016. Epub 2019 Apr 15.
Propensity to relapse following long periods of abstinence is a key feature of substance use disorder. Drugs of abuse, such as cocaine, cause long-term changes in the neural circuitry regulating reward, motivation, and memory processes through dysregulation of various molecular mechanisms, including epigenetic regulation of activity-dependent gene expression. Underlying drug-induced changes to neural circuit function are the molecular mechanisms regulating activity-dependent gene expression. Of note, histone acetyltransferases and histone deacetylases (HDACs), powerful epigenetic regulators of gene expression, are dysregulated following both acute and chronic cocaine exposure and are linked to cocaine-induced changes in neural circuit function. To better understand the effect of drug-induced changes on epigenetic function and behavior, we investigated HDAC3-mediated regulation of Nr4a2/Nurr1 in the medial habenula, an understudied pathway in cocaine-associated behaviors. Nr4a2, a transcription factor critical in cocaine-associated behaviors and necessary for MHb development, is enriched in the cholinergic cell-population of the MHb; yet, the role of NR4A2 within the MHb in the adult brain remains elusive. Here, we evaluated whether epigenetic regulation of Nr4a2 in the MHb has a role in reinstatement of cocaine-associated behaviors. We found that HDAC3 disengages from Nr4a2 in the MHb in response to cocaine-primed reinstatement. Whereas enhancing HDAC3 function in the MHb had no effect on reinstatement, we found, using a dominant-negative splice variant (NURR2C), that loss of NR4A2 function in the MHb blocked reinstatement behaviors. These results show for the first time that regulation of NR4A2 function in the MHb is critical in relapse-like behaviors.
长期戒断后复发的倾向是物质使用障碍的一个关键特征。可卡因等滥用药物通过各种分子机制的失调，包括对活性依赖性基因表达的表观遗传调控，导致调节奖励、动机和记忆过程的神经回路发生长期变化。调节活性依赖性基因表达的分子机制是导致神经回路功能改变的基础。值得注意的是，组蛋白乙酰转移酶和组蛋白去乙酰化酶（HDACs）是基因表达的强大表观遗传调控因子，在急性和慢性可卡因暴露后都会失调，并与可卡因引起的神经回路功能改变有关。为了更好地了解药物诱导的变化对表观遗传功能和行为的影响，我们研究了 HDAC3 介导的中脑缰核中 Nr4a2/Nurr1 的调节作用，这是可卡因相关行为中研究较少的途径。Nr4a2 是一种在可卡因相关行为中至关重要的转录因子，也是 MHb 发育所必需的，在 MHb 的胆碱能细胞群体中丰富；然而，NR4A2 在成年大脑中的 MHb 中的作用仍不清楚。在这里，我们评估了 MHb 中 Nr4a2 的表观遗传调控是否在可卡因相关行为的复发起作用。我们发现，可卡因引发的复发起始后，HDAC3 与 MHb 中的 Nr4a2 脱离。虽然增强 MHb 中的 HDAC3 功能对复发起作用，但我们发现，使用显性负性剪接变异体（NURR2C），MHb 中 NR4A2 功能的丧失阻断了复发起作用。这些结果首次表明，MHb 中 NR4A2 功能的调节在类复发行为中是至关重要的。
