Noda epileptic rat (NER) is a genetic rat model of epilepsy that exhibit spontaneous generalized tonic-clonic (GTC) seizures with paroxysmal discharges. We analyzed the regional expression of Fos-like immunoreactivity (Fos-IR) following GTC seizures in NER to clarify the brain regions involved in the seizure generation. GTC seizures in NER elicited a marked increase in Fos expression in the piriform cortex, perirhinal-entorhinal cortex, insular cortex and other cortices including the motor cortex. In the limbic regions, Fos-IR was highest in the amygdalar nuclei (e.g., basomedial amygdaloid nucleus), followed by the cingulate cortex and hippocampus (i.e., dentate gyrus and CA3). As compared to the above forebrain regions, NER either with or without GTC seizures exhibited only marginal Fos expression in the basal ganglia (e.g., accumbens, striatum and globus pallidus), diencephalon (e.g., thalamus and hypothalamus) and lower brain stem structures (e.g., pons-medulla oblongata). These results suggest that GTC seizures in NER are of forebrain origin and are evoked primarily by activation of the limbic and/or cortical seizure circuits.