Oxytocin-dependent reopening of a social reward learning critical period with MDMA
Oxytocin-dependent reopening of a social reward learning critical period with MDMA
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DOI：
10.1038/s41586-019-1075-9
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发表时间：
2019-05-02
期刊：
影响因子：
64.8
通讯作者：
Dolen, Gul
中科院分区：
文献类型：
--
作者：
Nardou, Romain;Lewis, Eastman M.;Dolen, Gul
关键期是一个发育时期，在此期间，神经系统对适当的电路组织和学习所需的特定环境刺激非常敏感。关键时期的机制表征揭示了早期发育期间旺盛的大脑可塑性的重要作用，以及随着大脑成熟而对这些机制施加的限制（1）。在疾病状态下，关键期的关闭限制了大脑的适应能力，即使在最佳条件恢复时也是如此。因此，识别重新打开关键时期的操作一直是转化神经科学的优先事项（2）。在这里，我们提供的证据表明，发育调节催产素介导的突触可塑性（长期抑郁症）的核丘脑建立了一个关键时期的社会奖励学习。此外，我们发现，单剂量的（+/-）-3，4-亚甲二氧基甲基苯丙胺（MDMA）重新打开社会奖励学习的关键期，并导致催产素依赖性长期抑郁症的化生上调。MDMA诱导的这一关键时期的重新开放需要激活中脑核中的催产素受体，并通过刺激中脑核中的催产素末梢来重现。这些发现对于理解以社会障碍为特征的神经发育疾病的发病机制以及对社会影响做出反应或因社会伤害而导致的疾病具有重要意义（3）。
A critical period is a developmental epoch during which the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit organization and learning. Mechanistic characterization of critical periods has revealed an important role for exuberant brain plasticity during early development, and for constraints that are imposed on these mechanisms as the brain matures(1). In disease states, closure of critical periods limits the ability of the brain to adapt even when optimal conditions are restored. Thus, identification of manipulations that reopen critical periods has been a priority for translational neuroscience(2). Here we provide evidence that developmental regulation of oxytocin-mediated synaptic plasticity (long-term depression) in the nucleus accumbens establishes a critical period for social reward learning. Furthermore, we show that a single dose of (+/-)-3,4-methylendioxymethamphetamine (MDMA) reopens the critical period for social reward learning and leads to a metaplastic upregulation of oxytocin-dependent long-term depression. MDMA-induced reopening of this critical period requires activation of oxytocin receptors in the nucleus accumbens, and is recapitulated by stimulation of oxytocin terminals in the nucleus accumbens. These findings have important implications for understanding the pathogenesis of neurodevelopmental diseases that are characterized by social impairments and of disorders that respond to social influence or are the result of social injury(3).