Abstracts

Rationale: Genetically epilepsy-prone rats (GEPR-9s) respond to intense acoustic stimuli with audiogenic seizures (AGS) that consist of wild running (WR), and tonic hind-limb extension (TE), followed by post-ictal depression (PID). The neuronal network subserving AGS is known to be localized within specific brainstem nuclei, including the periaqueductal gray (PAG). Repetitive induction of AGS results in AGS kindling, consisting of a major increase in seizure duration and induction of an additional convulsive behavior, generalized clonus, following TE, termed post-tonic clonus (PTC). AGS kindling also results in expansion of the AGS network to the amygdala. The present study examined the changes in PAG neuronal firing during seizures in AGS-kindled GEPR-9s. Methods: AGS in 6 GEPR-9s (200-450 g) were induced by an acoustic stimulus (electric bell 122dB SPL Re: 0.0002 dyn/cm2). The rats were subjected to AGS kindling, which consisted of induction of AGS twice daily until 14 seizures were evoked. Microwires were then chronically implanted stereotaxically into the ventrolateral PAG of these AGS-kindled GEPR-9s under ketamine/xylazine anesthesia. At least one week after surgery, PAG neuronal activity was recorded in behaving rats in response to 12 kHz tone burst stimuli (80-100 dB SPL), which at highest intensity and increased repetition rates ultimately triggered AGS. Neuronal responses were displayed on an oscilloscope and recorded digitally. Seizure behavior and neuronal firing were recorded simultaneously using split screen video. The neuronal responses were analyzed off-line, and peristimulus time histograms were generated (1 ms bin width, 200 ms scan length). Single unit neuronal activity was analyzed, and the split screen data were evaluated to determine the temporal correlation of neuronal activity with seizure behaviors. Histological localization of the electrode tips was subsequently confirmed.Results: PAG neurons in the kindled GEPR-9s displayed tonic firing during WR and TE. This firing pattern was similar to that seen in non-kindled GEPR-9s. PAG neuronal activity was silent during PID in both kindled and non-kindled GEPR-9s. During the AGS kindling-induced PTC, PAG neurons displayed epochs of burst firing activity, which occurred during the entire duration of PTC. Burst firing was characterized by ~30 msec periods of very rapid neuronal firing, alternating with variable length quiescent periods temporally related to the clonic movements.Conclusions: The current study showed that burst firing in PAG neurons coincided temporally with the emergence of PTC, suggesting a causal relationship between this neuronal activity and this behavior. A similar burst firing pattern during PTC in AGS-kindled GEPR-9s was previously seen in the amygdala. Burst firing is considered to be a very intense form of elevated neuronal excitability. Since extensive projections from the amygdala to PAG are known, the current findings suggest a role for this pathway in the generation of PTC induced by AGS kindling in GEPR-9s. (Support SIUSM EAM grant)