Time-of-day effects have been noted in a wide variety of cognitive behavioral tests, and perturbation of the circadian system, either at the level of the master clock in the SCN or downstream, impairs hippocampus-dependent learning and memory. A number of kinases, including the serine-threonine casein kinase 1 (CK1) isoforms CK1δ/ε, regulate the timing of the circadian period through post-translational modification of clock proteins. Modulation of these circadian kinases presents a novel treatment direction for cognitive deficits through circadian modulation. Here, we tested the potential for PF-670462, a small molecule inhibitor of CK1δ/ε, to improve cognitive performance in C57BL/6J mice in an array of behavioral tests. Compared to vehicle-treated mice tested at the same time of the circadian day, mice treated with PF-670462 displayed better recall of contextual fear conditioning, made fewer working memory errors in the radial arm water maze, and trained more efficiently in the Morris Water Maze. These benefits were accompanied by increased expression of activity-regulated cytoskeleton-associated protein (Arc) in the amygdala in response to an acute learning paradigm. Our results suggest the potential utility of CK1δ/ε inhibition in improving time-of-day cognitive performance.

在各种认知行为测试中都注意到了一天中时间的影响，而昼夜节律系统的扰动，无论是在视交叉上核的主时钟水平还是下游，都会损害海马体依赖性的学习和记忆。许多激酶，包括丝氨酸-苏氨酸酪蛋白激酶 1 (CK1) 亚型 CK1δ/ε，通过时钟蛋白的翻译后修饰来调节昼夜节律。这些昼夜节律激酶的调节为通过昼夜节律调节来治疗认知缺陷提供了新的方向。在这里，我们在一系列行为测试中测试了 PF-670462（一种 CK1δ/ε 的小分子抑制剂）改善 C57BL/6J 小鼠认知表现的潜力。与在昼夜节律的同一时间测试的媒介物处理小鼠相比，使用 PF-670462 处理的小鼠对情境恐惧条件反射表现出更好的回忆，在桡臂水迷宫中产生的工作记忆错误更少，并且在莫里斯水迷宫中训练更有效迷宫。这些好处伴随着杏仁核中活性调节细胞骨架相关蛋白（Arc）表达的增加，以响应急性学习范式。我们的结果表明 CK1δ/ε 抑制在改善每日认知表现方面的潜在效用。