Department of Physiology, Michigan State University, East Lansing, Michigan 48824.
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
J Neurosci. 2019 Oct 16;39(42):8305-8314. doi: 10.1523/JNEUROSCI.0800-19.2019. Epub 2019 Sep 2.
Drug addiction results in part from maladaptive learning, including the formation of strong associations between the drug and the circumstances of consumption. However, drug-induced changes in gene expression underlying the saliency of these associations remain understudied. Consolidation of explicit memories occurs within the hippocampus, and we have shown that spatial learning induces expression of the transcription factor ΔFosB in hippocampus and that this induction is critical for learning. Drugs of abuse also upregulate ΔFosB in hippocampus, but the mechanism of its induction by cocaine and its role in hippocampus-dependent cocaine responses is unknown. We investigated differences in mouse dorsal and ventral hippocampal ΔFosB expression in response to chronic cocaine, because these regions appear to regulate distinct cocaine-related behaviors. We found that cocaine-mediated induction of ΔFosB was subregion-specific, and that ΔFosB transcriptional activity in both the dorsal and ventral hippocampus is necessary for cocaine conditioned place preference. Further, we characterize changes in histone modifications at the promoter in hippocampus in response to chronic cocaine and found that locus-specific epigenetic modification is essential for induction and multiple hippocampus-dependent behaviors, including cocaine place preference. Collectively, these findings suggest that exposure to cocaine induces histone modification at the hippocampal gene promoter to cause ΔFosB induction critical for cocaine-related learning. Although cocaine addiction is driven in part by the formation of indelible associations between the drug and the environment, paraphernalia, and circumstances of use, and although this type of associative learning is dependent upon changes in gene expression in a brain region called the hippocampus, the mechanisms by which cocaine alters hippocampal gene expression to drive formation of these associations is poorly understood. Here, we demonstrate that chronic cocaine engages locus-specific changes in the epigenetic profile of the gene in the hippocampus, and that these alterations are required for cocaine-dependent gene expression and cocaine-environment associations. This work provides novel insight into addiction etiology and potential inroads for therapeutic intervention in cocaine addiction.
药物成瘾部分源于适应性学习，包括药物与消费环境之间形成强烈关联。然而，这些关联显著性背后的药物诱导基因表达变化仍研究不足。外显记忆的巩固发生在海马体中，我们已经表明，空间学习会诱导海马体中转录因子 ΔFosB 的表达，而这种诱导对于学习至关重要。滥用药物也会在上调海马体中的 ΔFosB，但可卡因诱导其表达的机制及其在海马体依赖可卡因反应中的作用尚不清楚。我们研究了慢性可卡因对小鼠背侧和腹侧海马体 ΔFosB 表达的影响，因为这两个区域似乎调节着不同的与可卡因相关的行为。我们发现，可卡因介导的 ΔFosB 诱导具有亚区特异性，并且背侧和腹侧海马体中的 ΔFosB 转录活性对于可卡因条件性位置偏好都是必需的。此外，我们还研究了慢性可卡因处理后海马体中 启动子处组蛋白修饰的变化，发现该基因启动子处的局部表观遗传修饰对于 的诱导和多种海马体依赖行为，包括可卡因位置偏好，都是必需的。总之，这些发现表明，暴露于可卡因会导致海马体 基因启动子处的组蛋白修饰，从而引起 ΔFosB 诱导，这对于可卡因相关学习至关重要。尽管可卡因成瘾部分是由药物与环境、药物使用的器具和环境之间不可磨灭的关联，以及这种类型的联想学习依赖于大脑中称为海马体的区域中的基因表达变化所驱动的，但可卡因改变海马体基因表达以驱动这些关联形成的机制知之甚少。在这里，我们证明慢性可卡因会导致海马体中 基因的表观遗传特征发生特定于基因座的变化，并且这些变化对于可卡因依赖基因表达和可卡因-环境关联是必需的。这项工作为成瘾病因学提供了新的见解，并为可卡因成瘾的治疗干预提供了潜在的途径。
