Exposure to sedative/hypnotic and anesthetic drugs, such as ketamine, during the critical period of synaptogenesis, causes profound neurotoxicity in the developing rodent and primate brains and is associated with poor cognitive outcomes later in life. The subiculum is especially vulnerable to acute neurotoxicity after neonatal exposure to sedative/hypnotic and anesthetic drugs. The subiculum acts as a relay center between the hippocampal complex and various cortical and subcortical brain regions and is also an independent generator of gamma oscillations. Gamma oscillations are vital in neuronal synchronization and play a role in learning and memory during wake and sleep. However, there has been little research examining long-term changes in subicular neurophysiology after neonatal exposure to ketamine. Here we explore the lasting effects of neonatal ketamine exposure on sleep macrostructure as well as subicular neuronal oscillations and synaptic plasticity in rats. During the peak of rodent synaptogenesis at postnatal day 7, rat pups were exposed to either 40 mg/kg of ketamine over 12 h or to volume matched saline vehicle. At weaning age, a subset of rats were implanted with a cortical and subicular electroencephalogram electrode, and at postnatal day 31, we performed in vivo experiments that included sleep macrostructure (divided into the wake, non-rapid eye movement, and rapid eye movement sleep) and electroencephalogram power spectra in cortex and subiculum. In a second subset of ketamine exposed animals, we conducted ex vivo studies of long-term potentiation (LTP) experiments in adolescent rats. Overall, we found that neonatal exposure to ketamine increased subicular gamma oscillations during non-rapid eye movement sleep but it did not alter sleep macrostructure. Also, we observed a significant decrease in subicular LTP. Gamma oscillations during non-rapid eye movement sleep are implicated in memory formation and consolidation, while LTP serves as a surrogate for learning and memory. Together these results suggest that lasting functional changes in subiculum circuitry may underlie neurocognitive impairments associated with neonatal exposure to anesthetic agents.

中文翻译：

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新生儿氯胺酮改变下叶的高频振荡和突触可塑性，但不影响青春期大鼠的睡眠宏观结构

在突触形成的关键时期暴露于镇静/催眠和麻醉药物（如氯胺酮）会导致正在发育的啮齿动物和灵长类动物的大脑产生严重的神经毒性，并与以后生活中的不良认知结果有关。新生儿暴露于镇静/催眠和麻醉药物后，下丘特别容易受到急性神经毒性的影响。下丘作为海马复合体和各种皮层和皮层下大脑区域之间的中继中心，也是伽马振荡的独立发生器。伽马振荡对神经元同步至关重要，并在清醒和睡眠期间的学习和记忆中发挥作用。然而，很少有研究检查新生儿暴露于氯胺酮后皮下神经生理学的长期变化。在这里，我们探讨了新生儿氯胺酮暴露对大鼠睡眠宏观结构以及下皮神经元振荡和突触可塑性的持久影响。在出生后第 7 天的啮齿动物突触形成高峰期间，大鼠幼崽在 12 小时内暴露于 40 毫克/公斤的氯胺酮或体积匹配的盐水载体。在断奶年龄，一部分大鼠被植入皮质和皮下脑电图电极，在出生后第 31 天，我们进行了体内实验，包括睡眠宏观结构（分为清醒、非快速眼动睡眠和快速眼动睡眠） ) 和皮层和下叶的脑电图功率谱。在氯胺酮暴露动物的第二个子集中，我们对青春期大鼠进行了长期增强 (LTP) 实验的离体研究。全面的，我们发现，在非快速眼动睡眠期间，新生儿暴露于氯胺酮会增加眼底伽马振荡，但不会改变睡眠宏观结构。此外，我们观察到皮下 LTP 显着降低。非快速眼动睡眠期间的伽马振荡与记忆形成和巩固有关，而 LTP 则作为学习和记忆的替代品。这些结果共同表明，下丘脑回路的持续功能变化可能是与新生儿暴露于麻醉剂相关的神经认知障碍的基础。非快速眼动睡眠期间的伽马振荡与记忆形成和巩固有关，而 LTP 则作为学习和记忆的替代品。这些结果共同表明，下丘脑回路的持续功能变化可能是与新生儿暴露于麻醉剂相关的神经认知障碍的基础。非快速眼动睡眠期间的伽马振荡与记忆形成和巩固有关，而 LTP 则作为学习和记忆的替代品。这些结果共同表明，下丘脑回路的持续功能变化可能是与新生儿暴露于麻醉剂相关的神经认知障碍的基础。