Epigenetic factors translate environmental signals into stable outcomes, but how they are influenced by regulators of plasticity remain unclear. We previously showed that androgen receptor overexpression inhibited fear memory in male mice and increased expression of the histone variant H2A.Z, a novel epigenetic regulator of memory. Here, we used conditional-inducible H2A.Z knockout mice to investigate how H2A.Z deletion influences androgenic regulation of fear memory. We showed that conditional inducible H2A.Z deletion blocked memory-enhancing effects of androgen depletion (induced by gonadectomy), and of pharmacological inhibition of the androgen receptor with flutamide. Similarly, H2A.Z deletion blocked the memory-reducing effects of DHT, and DHT treatment in cultured hippocampal neurons altered H2A.Z binding, suggesting that AR is an H2A.Z regulator in neurons. Overall, these data show that fear memory formation is regulated by interactions between sex hormones and epigenetic factors, which has implications for sex differences in fear-related disorders.

表观遗传因素将环境信号转化为稳定的结果，但它们如何受到可塑性调节剂的影响尚不清楚。我们之前表明雄激素受体过表达抑制了雄性小鼠的恐惧记忆，并增加了组蛋白变体 H2A.Z 的表达，H2A.Z 是一种新型的记忆表观遗传调节剂。在这里，我们使用条件诱导的 H2A.Z 基因敲除小鼠来研究 H2A.Z 缺失如何影响恐惧记忆的雄激素调节。我们表明，条件诱导的 H2A.Z 缺失阻断了雄激素耗竭（由性腺切除术诱导）的记忆增强作用，以及氟他胺对雄激素受体的药理抑制作用。类似地，H2A.Z 缺失阻断了 DHT 的记忆减少作用，培养的海马神经元中的 DHT 治疗改变了 H2A.Z 的结合，表明 AR 是一种 H2A。神经元中的 Z 调节器。总的来说，这些数据表明恐惧记忆的形成受性激素和表观遗传因素之间的相互作用的调节，这对恐惧相关疾病的性别差异有影响。