Date(s) - 07/01/2013
For over a century epileptic seizures have been known to cluster at specific times of the day. Recent studies have suggested that the circadian regulatory system may become permanently altered in epilepsy, but little is known about how this affects neural activity and the daily patterns of seizure recurrence. To investigate, we tracked long-term changes in the rate of spontaneous hippocampal EEG spikes (SPKs) in a rat model of temporal lobe epilepsy. In healthy animals, SPKs oscillated with near 24-hour period; however, following injury by status epilepticus (SE), a persistent phase shift of ~12 hours emerged in animals that later went on to develop chronic spontaneous seizures. Additional measurements showed that this phase shift affected other features of hippocampal activity, including 24-hour modulation of gamma and beta-frequency rhythms, but did not affect global 24-hour rhythms, including core body temperature and theta state transitions. Based on this, we hypothesized that the phase shift might be due to locally impaired circadian input to the hippocampus. This was investigated using a biophysical computer model in which we showed that subtle changes in the relative strengths of circadian inputs could produce a phase shift in hippocampal neural activity. Additional EEG analysis provided evidence that circadian input strengths may be altered by showing that the amplitude of 24-hour modulation of certain EEG rhythms, particularly theta, was attenuated following SE injury. Furthermore, MRI provided evidence that the medial septum, a putative circadian relay center, exhibited signs of damage and therefore could contribute to local circadian impairment. Our results suggest that balanced circadian input is critical to maintaining natural circadian phase in the hippocampus, and that damage to the medial septum may disrupt this balance.