National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
J Neurosci. 2021 Aug 4;41(31):6753-6774. doi: 10.1523/JNEUROSCI.2848-20.2021. Epub 2021 Jun 7.
The development, persistence and relapse of drug addiction require drug memory that generally develops with drug administration-paired contextual stimuli. Adult hippocampal neurogenesis (AHN) contributes to cocaine memory formation; however, the underlying mechanism remains unclear. Male mice hippocampal expression of Tau was significantly decreased during the cocaine-associated memory formation. Genetic overexpression of four microtubule-binding repeats Tau (4R Tau) in the mice hippocampus disrupted cocaine memory by suppressing AHN. Furthermore, 4R Tau directly interacted with phosphoinositide 3-kinase (PI3K)-p85 and impaired its nuclear translocation and PI3K-AKT signaling, processes required for hippocampal neuron proliferation. Collectively, 4R Tau modulates cocaine memory formation by disrupting AHN, suggesting a novel mechanism underlying cocaine memory formation and provide a new strategy for the treatment of cocaine addiction. Drug memory that generally develops with drug-paired contextual stimuli and drug administration is critical for the development, persistence and relapse of drug addiction. Previous studies have suggested that adult hippocampal neurogenesis (AHN) plays a role in cocaine memory formation. Here, we showed that Tau was significantly downregulated in the hippocampus in the cocaine memory formation. Tau knock-out (KO) promoted AHN in the hippocampal dentate gyrus (DG), resulting in the enhanced memory formation evoked by cocaine-cue stimuli. In contrast, genetically overexpressed 4R Tau in the hippocampus disrupted cocaine-cue memory by suppressing AHN. In addition, 4R Tau interacted directly with phosphoinositide 3-kinase (PI3K)-p85 and hindered its nuclear translocation, eventually repressing PI3K-AKT signaling, which is essential for hippocampal neuronal proliferation.
药物成瘾的发展、持续和复发需要药物记忆，而药物记忆通常随着药物给药与环境刺激的结合而发展。成人海马神经发生（AHN）有助于可卡因记忆的形成；然而，其潜在机制仍不清楚。在可卡因相关记忆形成过程中，雄性小鼠海马 Tau 的表达明显减少。在小鼠海马中过表达四个微管结合重复 Tau（4R Tau）会通过抑制 AHN 破坏可卡因记忆。此外，4R Tau 直接与磷酸肌醇 3-激酶（PI3K）-p85 相互作用，并抑制其核转位和 PI3K-AKT 信号转导，这是海马神经元增殖所必需的过程。总之，4R Tau 通过破坏 AHN 调节可卡因记忆的形成，表明了可卡因记忆形成的新机制，并为可卡因成瘾的治疗提供了新策略。与药物相关的环境刺激和药物给药共同发展的药物记忆对于药物成瘾的发展、持续和复发至关重要。先前的研究表明，成人海马神经发生（AHN）在可卡因记忆形成中起作用。在这里，我们发现在可卡因记忆形成过程中，海马中的 Tau 明显下调。Tau 敲除（KO）促进了海马齿状回（DG）中的 AHN，导致可卡因线索刺激引起的记忆形成增强。相比之下，在海马中过表达 4R Tau 会通过抑制 AHN 破坏可卡因线索记忆。此外，4R Tau 直接与磷酸肌醇 3-激酶（PI3K）-p85 相互作用，并阻碍其核转位，最终抑制 PI3K-AKT 信号转导，这对于海马神经元增殖至关重要。
