HDAC3 Activity within the Nucleus Accumbens Regulates Cocaine-Induced Plasticity and Behavior in a Cell-Type-Specific Manner.
HDAC3 Activity within the Nucleus Accumbens Regulates Cocaine-Induced Plasticity and Behavior in a Cell-Type-Specific Manner.
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DOI：
10.1523/jneurosci.2829-20.2021
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发表时间：
2021-03-31
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影响因子：
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通讯作者：
Wood MA
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文献类型：
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作者：
Campbell RR;Kramár EA;Pham L;Beardwood JH;Augustynski AS;López AJ;Chitnis OS;Delima G;Banihani J;Matheos DP;Wood MA
表观遗传机制调节对可卡因诱导行为至关重要的神经可塑性过程。其中包括 I 类组蛋白脱乙酰酶 (HDAC) HDAC3，已知其可作为伏隔核 (NAc) 内可卡因相关记忆形成的负调节因子。尽管如此，可卡因如何改变 HDAC3 依赖性机制仍不清楚。在这里，我们分析了可卡因暴露后总 NAc 小鼠组织中 HDAC3 的表达和活性。尽管长期可卡因不影响 NAc 内 Hdac3 的表达，但长期可卡因确实影响 HDAC3 和 H4K8Ac 占用的启动子特异性变化。启动子占据的这些变化与可卡因诱导的可塑性相关基因表达的变化相关。为了因果地确定可卡因诱导的可塑性是否由 HDAC3 的脱乙酰酶活性介导，我们在成年雄性小鼠的 NAc 中过度表达了脱乙酰酶死亡的 HDAC3 点突变体 (HDAC3-Y298H-v5)。我们发现，破坏 HDAC3 的酶活性会改变可卡因暴露后基因表达和突触可塑性的选择性变化，尽管对可卡因诱导的行为没有影响。在进一步评估 HDAC3 在 NAc 中的作用时，我们观察到长期可卡因会增加 NAc 的 Drd1 细胞中的 Hdac3 表达，但不会增加 Drd2 细胞中的 Hdac3 表达。此外，我们发现 HDAC3 在 D1R 细胞类型中选择性地发挥作用，调节可卡因相关的记忆形成和可卡因寻求。总的来说，这些结果表明可卡因会诱导表观遗传机制中细胞类型特异性的变化，从而促进可卡因相关行为的重要可塑性。意义声明 滥用药物会改变整个奖赏回路的分子机制，从而导致持续的药物相关行为。表观遗传调节因子是药物诱导的基因表达变化的关键驱动因素。在这里，我们证明表观遗传酶的活性可促进伏隔核（NAc）内的神经可塑性，这对于可卡因的作用至关重要。此外，我们证明表观遗传活性的这些变化以细胞类型特异性的方式驱动可卡因寻求行为。这些发现对于理解和针对可卡因对神经回路和行为的影响至关重要。
Epigenetic mechanisms regulate processes of neuroplasticity critical to cocaine-induced behaviors. This includes the Class I histone deacetylase (HDAC) HDAC3, known to act as a negative regulator of cocaine-associated memory formation within the nucleus accumbens (NAc). Despite this, it remains unknown how cocaine alters HDAC3-dependent mechanisms. Here, we profiled HDAC3 expression and activity in total NAc mouse tissue following cocaine exposure. Although chronic cocaine did not affect expression of Hdac3 within the NAc, chronic cocaine did affect promoter-specific changes in HDAC3 and H4K8Ac occupancy. These changes in promoter occupancy correlated with cocaine-induced changes in expression of plasticity-related genes. To causally determine whether cocaine-induced plasticity is mediated by HDAC3's deacetylase activity, we overexpressed a deacetylase-dead HDAC3 point mutant (HDAC3-Y298H-v5) within the NAc of adult male mice. We found that disrupting HDAC3's enzymatic activity altered selective changes in gene expression and synaptic plasticity following cocaine exposure, despite having no effects on cocaine-induced behaviors. In further assessing HDAC3's role within the NAc, we observed that chronic cocaine increases Hdac3 expression in Drd1 but not Drd2-cells of the NAc. Moreover, we discovered that HDAC3 acts selectively within D1R cell-types to regulate cocaine-associated memory formation and cocaine-seeking. Overall, these results suggest that cocaine induces cell-type-specific changes in epigenetic mechanisms to promote plasticity important for driving cocaine-related behaviors. SIGNIFICANCE STATEMENT Drugs of abuse alter molecular mechanisms throughout the reward circuitry that can lead to persistent drug-associated behaviors. Epigenetic regulators are critical drivers of drug-induced changes in gene expression. Here, we demonstrate that the activity of an epigenetic enzyme promotes neuroplasticity within the nucleus accumbens (NAc) critical to cocaine action. In addition, we demonstrate that these changes in epigenetic activity drive cocaine-seeking behaviors in a cell-type-specific manner. These findings are key in understanding and targeting cocaine's impact of neural circuitry and behavior.