Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.
Department of Neuroscience, Central Clinical School, The Alfred Hospital, Monash University and Department of Neurology, Melbourne, Victoria, Australia.
Epilepsia. 2019 Aug;60(8):1650-1660. doi: 10.1111/epi.16291. Epub 2019 Jul 23.
Cognitive deficits are commonly observed in people with epilepsy, but the biologic causation of these is challenging to identify. Animal models of epilepsy can be used to explore pathophysiologic mechanisms leading to cognitive problems, as well as to test novel therapeutics. We utilized a well-validated animal model of epilepsy to explore cognitive deficits using novel translational assessment tools/automated rodent touchscreen assays.
To induce epilepsy, adult Wistar rats were subjected to kainic acid-induced status epilepticus or sham control (n = 12/group). Two months following induction, animals underwent the Pairwise Discrimination and Reversal learning touchscreen tasks, novel object recognition, and the Y maze test of spatial memory.
In the Pairwise Discrimination paradigm, only 40% of epilepsy animals acquired the discrimination learning criterion, compared to 100% of sham animals (P = 0.003). Epilepsy and sham animals that successfully acquired the discrimination progressed onto the reversal phase, which measures cognitive flexibility. Of interest, there were no differences in the rate of reversal learning; however, on the first reversal session, epilepsy rats committed more perseverative errors than shams (mean ± SEM: 6.3 ± 0.9 vs 1.8 ± 0.5, P < 0.0001). Additional behavioral analysis revealed that epilepsy rats were significantly impaired in novel object recognition and short-term spatial learning and memory.
Using translationally relevant behavioral tools in combination with traditional assays to measure cognition in animal models, here we identify impairments in learning and memory, and enhanced perseverative behaviors in rats with epilepsy. These tools can be used in future research to explore biologic mechanisms and treatments for cognitive deficits associated with epilepsy.
癫痫患者常伴有认知缺陷，但这些缺陷的生物学原因难以确定。癫痫动物模型可用于探索导致认知问题的病理生理机制，并测试新的治疗方法。我们利用一种经过充分验证的癫痫动物模型，使用新的转化评估工具/自动啮齿动物触摸屏检测来探索认知缺陷。
为诱导癫痫，成年 Wistar 大鼠接受海人酸诱导的癫痫持续状态或假手术对照（每组 n=12）。诱导后 2 个月，动物接受成对辨别和反转学习触摸屏任务、新物体识别和 Y 迷宫空间记忆测试。
在成对辨别范式中，只有 40%的癫痫动物获得了辨别学习标准，而假手术动物为 100%（P=0.003）。成功获得辨别学习的癫痫和假手术动物进入反转阶段，该阶段用于测量认知灵活性。有趣的是，反转学习的速度没有差异；然而，在第一次反转测试中，癫痫大鼠比假手术大鼠犯更多的坚持性错误（平均值±SEM：6.3±0.9 比 1.8±0.5，P<0.0001）。进一步的行为分析表明，癫痫大鼠在新物体识别和短期空间学习和记忆方面明显受损。
使用与转化相关的行为工具结合传统的认知测试方法，我们在癫痫大鼠中发现了学习和记忆缺陷，以及增强的坚持性行为。这些工具可用于未来的研究，以探索与癫痫相关的认知缺陷的生物学机制和治疗方法。
