Ketamine-Induced Alteration of Working Memory Utility during Oculomotor Foraging Task in Monkeys
Ketamine-Induced Alteration of Working Memory Utility during Oculomotor Foraging Task in Monkeys
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DOI：
10.1523/eneuro.0403-20.2021
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发表时间：
2021-03
期刊：
影响因子：
3.4
通讯作者：
Ryo Sawagashira;Masaki Tanaka
中科院分区：
文献类型：
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作者：
Ryo Sawagashira;Masaki Tanaka
摘要 工作记忆损伤（WM）常见于多种神经退行性疾病，但在临床病例中很难定量评估。最近对实验动物的研究使用低剂量氯胺酮（一种 NMDA 受体拮抗剂）来破坏 WM，部分模仿了精神分裂症的病理生理学。在这里，我们开发了一种新的行为范例来评估 WM 的多个组成部分，并将其应用于服用和未服用氯胺酮的猴子。在动眼神经觅食任务中，动物在屏幕上看到 15 个相同的物体。其中一个物体与液体奖励相关，猴子被训练在时间限制下通过产生连续的扫视来搜索目标。我们假设对同一对象的递归运动的发生可能反映了 WM 功能障碍。我们构建了一个“觅食模型”，其中包含（1）记忆容量、（2）记忆衰减和（3）利用率；该模型能够解释从三只猴子获得的行为数据中超过 92% 的变化。全身给予低剂量氯胺酮后，记忆容量和利用率分别急剧下降15%和57%，而记忆衰退基本没有变化。这些结果表明，NMDA 受体阻断期间的行为缺陷主要是由于短期记忆使用减少所致。我们的动眼神经范式和觅食模型似乎对于量化 WM 的多个组成部分很有用，并且可以适用于未来研究中的临床病例。
Abstract Impairments of working memory (WM) are commonly observed in a variety of neurodegenerative disorders but they are difficult to quantitatively assess in clinical cases. Recent studies in experimental animals have used low-dose ketamine (an NMDA receptor antagonist) to disrupt WM, partly mimicking the pathophysiology of schizophrenia. Here, we developed a novel behavioral paradigm to assess multiple components of WM and applied it to monkeys with and without ketamine administration. In an oculomotor foraging task, the animals were presented with 15 identical objects on the screen. One of the objects was associated with a liquid reward, and monkeys were trained to search for the target by generating sequential saccades under a time constraint. We assumed that the occurrence of recursive movements to the same object might reflect WM dysfunction. We constructed a “foraging model” that incorporated (1) memory capacity, (2) memory decay, and (3) utility rate; this model was able to explain more than 92% of the variations in behavioral data obtained from three monkeys. Following systemic administration of low dosages of ketamine, the memory capacity and utility rate were dramatically reduced by 15% and 57%, respectively, while memory decay remained largely unchanged. These results suggested that the behavioral deficits during the blockade of NMDA receptors were mostly due to the decreased usage of short-term memory. Our oculomotor paradigm and foraging model appear to be useful for quantifying multiple components of WM and could be applicable to clinical cases in future studies.