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Mapping patterns of c-Fos expression in the central nervous system of the marmoset (Callithrix jacchus) after seizure


It is known that often intense neuronal firing triggers the synthesis of proteins that require specific activation of expression of immediate early genes, the best known of these being c-Fos. This gene is related to neuronal activation and is expressed when the animal is exposed to new situations. Several studies with mice and rats showed expression of c-fos in various regions of the central nervous system, such as the dentate gyrus, CA1, CA2, CA3, thalamus, piriform cortex, cingulate gyrus, amygdala, visual cortex, olfactory bulb, cerebellum, striatum, among other brain structures, when the animal is exposed to a wide range of stimuli (water stress, fear, odors, intraparenchymal injection of various substances, etc.). The early works, regarding the pattern of expression of c-fos after a certain stimulus, relied on pentylenetetrazol (PTZ) as stimulating agent. In rats and mice, it is known that after the injection of PTZ expression of c-Fos gene increases gradually reaching a maximum at around 1 hour later. Thereafter the expression progressively diminishes to baseline. There is some controversy regarding the time required for c-fos levels to return to baseline (which may vary according to the stimulus deployed) as indicated by studies that show this return to be at 6h (Chaudihuri et al. 2000), 17h (Morgan et al. 1987), 48 (Bisler et al. 2,002 ) or even only at 5 days after stimulation. All authors state that a second stimulus alone triggers the same increase in gene expression after the level of c-fos reaches the baseline. Before that, the expression is lower or zero, characterizing a period called refractory or semi-refractory.Kindling is a technique in which the application of repetitive subconvulsant stimuli over several days, ultimately results in convulsions, even though at the same original subconvulsant stimulation level. It is well established that it is possible to induce kindling in rodents, but there are questions as to whether it may be induced in primates (both human and non-human). Based on preliminary data obtained in our laboratory, we hypothesized that the stimuli to induce kindling in primates might originate refractory period of c-fos which may largely exceed that described for rodents. Based on this, we believe that the profile of expression of c-fos in primates may be different from that described in rodents. There are only a few studies that address the temporal aspect of c-fos expression in primates. Kazi and colleagues, (2003) showed peak expression of c-fos in the visual cortex at 6h after enucleation of the eye which progressively decreased at 42 and 72 h. However, the levels did not return to baseline values and thus it is unclear what would be the refractory period in that study. More importantly, that work (or any other for that matter) does not discuss the intriguing question of what biochemical differences (not just anatomical differences) between primates and rodents may contribute to differences in memory and learning among these families. The present study aims to evluate the expression of c-fos by stimulation with PTZ in rats (control group for comparison) and monkeys in various regions of the central nervous system, to compare under similar conditions, the similarities and differences of the expression of c-fos. Our experimental hypothesis is that despite the similarly experimental conditions important differences between the temporal expression profiles c-fos between rodents and primates will emerge. We speculate that these biochemical differences may partly contribute to the differences between mechanisms of memory and learning between these two orders of mammals. This study is a first investigation in this matter. If successful, we hope in a short period of time to be undergoing much more ambitious and comprehensive experiments assessing this and other funding agencies. (AU)

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