BACKGROUND Optimal behavior and decision making result from a balance of control between two strategies, one cognitive/goal-directed and one habitual. These systems are known to rely on the anatomically distinct dorsomedial and dorsolateral striatum, respectively. However, the transcriptional regulatory mechanisms required to learn and transition between these strategies are unknown. Here we examined the role of one chromatin-based transcriptional regulator, histone modification via histone deacetylases (HDACs), in this process. METHODS We combined procedures that diagnose behavioral strategy in rats with pharmacological and viral-mediated HDAC manipulations, chromatin immunoprecipitation, and messenger RNA quantification. RESULTS The results indicate that dorsal striatal HDAC3 activity constrains habit formation. Systemic HDAC inhibition following instrumental (lever press → reward) conditioning increased histone acetylation throughout the dorsal striatum and accelerated habitual control of behavior. HDAC3 was removed from the promoters of key learning-related genes in the dorsal striatum as habits formed with overtraining and with posttraining HDAC inhibition. Decreasing HDAC3 function, either by selective pharmacological inhibition or by expression of dominant-negative mutated HDAC3, in either the dorsolateral striatum or the dorsomedial striatum accelerated habit formation, while HDAC3 overexpression in either region prevented habit. CONCLUSIONS These results challenge the strict dissociation between dorsomedial striatum and dorsolateral striatum function in goal-directed versus habitual behavioral control and identify dorsostriatal HDAC3 as a critical molecular directive of the transition to habit. Because this transition is disrupted in many neurodegenerative and psychiatric diseases, these data suggest a potential molecular mechanism for the negative behavioral symptoms of these conditions and a target for therapeutic intervention.

中文翻译：

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背侧纹状体中的组蛋白脱乙酰酶 3 负向调节习惯

背景技术最佳行为和决策是由两种策略之间的控制平衡产生的，一种是认知/目标导向的，另一种是习惯的。已知这些系统分别依赖于解剖学上不同的背内侧和背外侧纹状体。然而，学习和这些策略之间转换所需的转录调控机制尚不清楚。在这里，我们研究了一种基于染色质的转录调节因子，即通过组蛋白脱乙酰酶 (HDAC) 进行的组蛋白修饰在此过程中的作用。方法 我们将诊断大鼠行为策略的程序与药理学和病毒介导的 HDAC 操作、染色质免疫沉淀和信使 RNA 定量相结合。结果 结果表明背侧纹状体 HDAC3 活性限制习惯形成。工具性（杠杆按下 → 奖励）调节后的系统性 HDAC 抑制增加了整个背侧纹状体的组蛋白乙酰化，并加速了行为的习惯性控制。由于过度训练和训练后 HDAC 抑制而形成的习惯，HDAC3 从背侧纹状体中关键学习相关基因的启动子中被移除。通过选择性药理学抑制或显性失活突变 HDAC3 的表达，在背外侧纹状体或背内侧纹状体中降低 HDAC3 功能会加速习惯的形成，而任一区域的 HDAC3 过度表达都会阻止习惯的形成。结论 这些结果挑战了背内侧纹状体和背外侧纹状体功能在目标导向与习惯行为控制中的严格分离，并将背纹状体 HDAC3 确定为习惯过渡的关键分子指令。由于这种转变在许多神经退行性疾病和精神疾病中被破坏，因此这些数据表明了这些疾病的负面行为症状的潜在分子机制以及治疗干预的目标。