Taylor Jeremy A, Rodgers Krista M, Bercum Florencia M, Booth Carmen J, Dudek F Edward, Barth Daniel S
Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado 80309.
Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, and.
J Neurosci. 2017 Jun 14;37(24):5861-5869. doi: 10.1523/JNEUROSCI.3235-16.2017. Epub 2017 May 18.
Genetically inherited absence epilepsy in humans is typically characterized by brief (seconds) spontaneous seizures, which involve spike-wave discharges (SWDs) in the EEG and interruption of consciousness and ongoing behavior. Genetic (inbred) models of this disorder in rats have been used to examine mechanisms, comorbidities, and antiabsence drugs. SWDs have also been proposed as models of complex partial seizures (CPSs) following traumatic brain injury (post-traumatic epilepsy). However, the ictal characteristics of these rat models, including SWDs and associated immobility, are also prevalent in healthy outbred laboratory rats. We therefore hypothesized that SWDs are not always associated with classically defined absence seizures or CPSs. To test this hypothesis, we used operant conditioning in male rats to determine whether outbred strains, Sprague Dawley and Long-Evans, and/or the inbred strain (a rat model of heritable human absence epilepsy) could exercise voluntary control over these epileptiform events. We discovered that both inbred and outbred rats could shorten the duration of SWDs to obtain a reward. These results indicate that SWD and associated immobility in rats may not reflect the obvious cognitive/behavioral interruption classically associated with absence seizures or CPSs in humans. One interpretation of these results is that human absence seizures and perhaps CPSs could permit a far greater degree of cognitive capacity than often assumed and might be brought under voluntary control in some cases. However, these results also suggest that SWDs and associated immobility may be nonepileptic in healthy outbred rats and reflect instead voluntary rodent behavior unrelated to genetic manipulation or to brain trauma. Our evidence that inbred and outbred rats learn to control the duration of spike-wave discharges (SWDs) suggests a voluntary behavior with maintenance of consciousness. If SWDs model mild absence seizures and/or complex partial seizures in humans, then an opportunity may exist for operant control complementing or in some cases replacing medication. Their equal occurrence in outbred rats also implies a major potential confound for behavioral neuroscience experiments, at least in adult rats where SWDs are prevalent. Alternatively, the presence and voluntary control of SWDs in healthy outbred rats could indicate that these phenomena do not always model heritable absence epilepsy or post-traumatic epilepsy in humans, and may instead reflect typical rodent behavior.
人类遗传性失神癫痫的典型特征是短暂（数秒）的自发性发作，包括脑电图中的棘波 - 慢波放电（SWD）以及意识和正在进行的行为中断。大鼠这种疾病的遗传（近交）模型已被用于研究发病机制、合并症和抗失神药物。SWD也被提议作为创伤性脑损伤后（创伤后癫痫）复杂部分性发作（CPS）的模型。然而，这些大鼠模型的发作特征，包括SWD和相关的不动状态，在健康的远交系实验大鼠中也很常见。因此，我们假设SWD并不总是与经典定义的失神发作或CPS相关。为了验证这一假设，我们在雄性大鼠中使用操作性条件反射来确定远交系Sprague Dawley和Long - Evans以及/或者近交系（遗传性人类失神癫痫的大鼠模型）是否能够对这些癫痫样事件进行自主控制。我们发现近交系和远交系大鼠都可以缩短SWD的持续时间以获得奖励。这些结果表明，大鼠中的SWD和相关的不动状态可能并不反映与人类失神发作或CPS经典相关的明显认知/行为中断。对这些结果的一种解释是，人类失神发作以及或许CPS可能允许比通常假设的更大程度的认知能力，并且在某些情况下可能受到自主控制。然而，这些结果也表明，在健康的远交系大鼠中，SWD和相关的不动状态可能是非癫痫性的，而是反映了与基因操作或脑外伤无关的自主啮齿动物行为。我们的证据表明近交系和远交系大鼠学会控制棘波 - 慢波放电（SWD）的持续时间，这表明存在一种保持意识的自主行为。如果SWD模拟人类的轻度失神发作和/或复杂部分性发作，那么可能存在通过操作性控制来补充或在某些情况下替代药物治疗的机会。它们在远交系大鼠中同样出现也意味着行为神经科学实验存在一个主要的潜在混淆因素，至少在成年大鼠中SWD很普遍的情况下是这样。或者，健康远交系大鼠中SWD的存在和自主控制可能表明这些现象并不总是模拟人类的遗传性失神癫痫或创伤后癫痫，而可能反而反映了典型的啮齿动物行为。
