Voluntary Control of Epileptiform Spike–Wave Discharges in Awake Rats

摘要

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 WAG/Rij 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.>SIGNIFICANCE STATEMENT 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.