The State Key Laboratory of Medical Neurobiology and Pharmacology Research Center, School of Basic Medical Sciences and Institutes of Brain Science, and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China.
Int J Neuropsychopharmacol. 2018 Mar 1;21(3):255-266. doi: 10.1093/ijnp/pyx099.
Memory retrieval refers to reexposure to information previously encoded and stored in the brain. Following retrieval, a once-consolidated memory destabilizes and undergoes reconsolidation, during which gene expression changes to restabilize memory. Investigating epigenetic regulation during reconsolidation could provide insights into normal memory formation and pathological memory associated with psychiatric disorders.
We used cocaine-induced conditioned place preference to assess the cocaine-associated memory of mice and used chemogenetic methods to manipulate the activity of the pyramidal neurons in the dorsal hippocampus. We isolated the ribosome-associated transcripts from the excitatory neurons in the dorsal hippocampus by RiboTag purification to identify the potential epigenetic regulators, and we specifically knocked down gene expression in pyramidal neurons with a Cre-dependent lentivirus.
Chemogenetically silencing the activity of the pyramidal neurons in the dorsal hippocampus immediately after memory retrieval markedly impaired memory reconsolidation, and the ribosome-associated mRNA level of the ten-eleven translocation (Tet) family methylcytosine dioxygenase Tet3, but not Tet1 or Tet2, was dramatically upregulated 10 minutes after memory retrieval. The protein level of Tet3 in the dorsal hippocampus but not in the anterior cingulate cortex was dramatically increased 1 hour after memory retrieval. Specifically, knockdown of Tet3 in pyramidal neurons in the dorsal hippocampus decreased the activation of pyramidal neurons and impaired the reconsolidation of cocaine-associated memory.
Our findings highlight the new function of the DNA demethylation regulator Tet3 in pyramidal neurons of the dorsal hippocampus in regulating the reconsolidation of cocaine-associated memory.
记忆检索是指重新暴露于先前编码并存储在大脑中的信息。检索后，曾经巩固的记忆会变得不稳定，并经历再巩固，在此期间基因表达会发生变化以重新稳定记忆。研究再巩固过程中的表观遗传调控可以深入了解正常记忆形成和与精神障碍相关的病理性记忆。
我们使用可卡因诱导的条件性位置偏好来评估小鼠与可卡因相关的记忆，并使用化学遗传学方法来操纵背侧海马体中的锥体神经元的活性。我们通过 RiboTag 纯化从背侧海马体中的兴奋性神经元中分离核糖体相关转录物，以鉴定潜在的表观遗传调节剂，并且我们使用 Cre 依赖性慢病毒特异性敲低锥体神经元中的基因表达。
记忆检索后立即化学遗传学沉默背侧海马体中的锥体神经元的活性，显著损害了记忆再巩固，并且十-十一易位（Tet）家族甲基胞嘧啶双加氧酶 Tet3 的核糖体相关 mRNA 水平在记忆检索后 10 分钟显著上调，而 Tet1 或 Tet2 则没有上调。记忆检索后 1 小时，背侧海马体中的 Tet3 蛋白水平而非前扣带皮层中的 Tet3 蛋白水平显著增加。具体而言，背侧海马体中的锥体神经元中的 Tet3 敲低降低了锥体神经元的激活，并损害了可卡因相关记忆的再巩固。
我们的研究结果强调了 DNA 去甲基化调节剂 Tet3 在背侧海马体中的锥体神经元中调节可卡因相关记忆再巩固的新功能。
