The risk of developing drug addiction is strongly influenced by the epigenetic landscape and chromatin remodeling. While histone modifications such as methylation and acetylation have been studied in the ventral tegmental area and nucleus accumbens (NAc), the role of H2A monoubiquitination remains unknown. Our investigations, initially focused on the scaffold protein melanoma-associated antigen D1 (Maged1), reveal that H2A monoubiquitination in the paraventricular thalamus (PVT) significantly contributes to cocaine-adaptive behaviors and transcriptional repression induced by cocaine. Chronic cocaine use increases H2A monoubiquitination, regulated by Maged1 and its partner USP7. Accordingly, Maged1 specific inactivation in thalamic Vglut2 neurons, or USP7 inhibition, blocks cocaine-evoked H2A monoubiquitination and cocaine locomotor sensitization. Additionally, genetic variations in MAGED1 and USP7 are linked to altered susceptibility to cocaine addiction and cocaine-associated symptoms in humans. These findings unveil an epigenetic modification in a non-canonical reward pathway of the brain and a potent marker of epigenetic risk factors for drug addiction in humans.

吸毒成瘾的风险很大程度上受到表观遗传景观和染色质重塑的影响。虽然组蛋白修饰（例如甲基化和乙酰化）已在腹侧被盖区和伏核 (NAc) 中进行了研究，但 H2A 单泛素化的作用仍然未知。我们的研究最初集中在支架蛋白黑色素瘤相关抗原 D1 (Mged1) 上，结果表明室旁丘脑 (PVT) 中的 H2A 单泛素化显着促进可卡因适应性行为和可卡因诱导的转录抑制。长期使用可卡因会增加 H2A 单泛素化，受 Maged1 及其伙伴 USP7 调节。因此，丘脑 Vglut2 神经元中的 Maged1 特异性失活或 USP7 抑制可阻断可卡因诱发的 H2A 单泛素化和可卡因运动敏化。此外，MAGED1 和 USP7 的遗传变异与人类对可卡因成瘾和可卡因相关症状的易感性改变有关。这些发现揭示了大脑非典型奖赏通路的表观遗传修饰，以及人类毒瘾表观遗传风险因素的有效标志。