Reward induces activity-dependant gene expression and synaptic plasticity-related changes. Lysine-specific histone demethylase 1 (LSD1), a key enzyme driving histone modifications, regulates transcription in neural circuits of memory and emotional behavior. Herein, we focus on the role of LSD1 in modulating the expression of brain derived neurotrophic factor (BDNF), the master regulator of synaptic plasticity, in the lateral hypothalamus-medial forebrain bundle (LH-MFB) circuit during positive reinforcement. Rats, trained for intracranial self-stimulation (ICSS) via an electrode-cannula assembly in the LH-MFB area, were assayed for lever press activity, epigenetic parameters and dendritic sprouting. LSD1 expression and markers of synaptic plasticity like BDNF and dendritic arborization in the LH, showed distinct increase in conditioned animals. H3K4me2 levels at Bdnf IV and Bdnf IX promoters were increased in ICSS-conditioned rats, but H3K9me2 was decreased. While intra LH-MFB treatment with pan Lsd1 siRNA inhibited lever press activity, analyses of LH tissue showed reduction in BDNF expression and levels of H3K4me2 and H3K9me2. However, co-administration of BDNF peptide restored lever press activity mitigated by Lsd1 siRNA. BDNF expression in LH, driven by LSD1 via histone demethylation, may play an important role in reshaping the reward pathway and hold the key to decode the molecular basis of addiction.

奖励诱导活动依赖性基因表达和突触可塑性相关的变化。赖氨酸特异性组蛋白去甲基化酶 1 (LSD1) 是一种驱动组蛋白修饰的关键酶，可调节记忆和情绪行为的神经回路中的转录。在这里，我们关注 LSD1 在正强化期间调节下丘脑外侧 - 前脑内侧束 (LH-MFB) 回路中脑源性神经营养因子 (BDNF) 的表达中的作用，BDNF 是突触可塑性的主要调节因子。经颅内自我刺激 (ICSS) 训练的大鼠对 LH-MFB 区域中的电极-套管组件进行了杠杆按压活动、表观遗传参数和树突萌发的分析。LSD1 表达和突触可塑性标志物，如 LH 中的 BDNF 和树突树枝状结构，在条件性动物中显示出明显的增加。Bdnf IV和Bdnf IX启动子的H3K4me2 水平在 ICSS 条件大鼠中增加，但 H3K9me2 降低。虽然用 pan Lsd1 siRNA 进行的LH-MFB 内处理抑制了杠杆按压活动，但对 LH 组织的分析显示 BDNF 表达和 H3K4me2 和 H3K9me2 水平降低。然而，BDNF 肽的共同给药恢复了Lsd1 siRNA 减轻的杠杆按压活动。LH 中的 BDNF 表达，由 LSD1通过组蛋白去甲基化，可能在重塑奖赏途径中发挥重要作用，是破译成瘾分子基础的关键。