Aging and regenerative capacity of the rat serotonergic system. A morphological, neurochemical and behavioral analysis after transplantation of fetal raphe cells.
Morphological dissimilarities between the brains of young (3 months) and aged (28 months and older) rats were demonstrated using serotonin-immunocytochemistry. A degeneration of the serotonergic system, noted as a decreased innervation and the appearance of enlarged or swollen varicosities, was observed particularly in the frontoparietal cortex, and the neostriatum of the aged rat brain. No direct relationship between this aberrant morphology and decrease in density of serotonin-innervation was found as we demonstrated a decline in fiber density without the appearance of aberrant serotonergic fibers in the hippocampus. HPLC analysis revealed that serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels in the frontoparietal cortex, hippocampus and raphe area were increased in the aged rat, while the 5-HT level in the caudate-putamen complex was not different from the young adult rat. The ratio 5-HIAA/5-HT, indicative of 5-HT turnover, appeared increased in the frontoparietal cortex, sensoric part, the caudate-putamen and the raphe area, while this ration in the frontoparietal cortex, motoric part and the hippocampus was not altered in the aged rat. Behavioral screening revealed a decrease spatial performance of aged males in a Morris Water-Maze task. To investigate whether the age of the host recipient was of influence on the regenerative capacity, a fetal raphe cell suspension of embryonic day E 15 was implanted in the caudate-putamen of young adult as well as aged rats. Neither differences in survival of the serotonergic cells nor in fiber outgrowth between both groups appeared five weeks after transplantation. Subsequently, transplantation of raphe cells in the hippocampus of young adult rats, after lesioning the hippocampal serotonergic innervation with 5,7-DHT, was performed to compare behavioral, morphological and neurochemical effects of the implants. It appeared that 11 months after transplantation the serotonergic innervation of the previously denervated hippocampus was greatly restored. There was a striking resemblance between the immunohistochemical and neurochemical data with respect to the increase in the amount of newly formed serotonergic fibers, the increase in uptake of [3H]-5-HT and in 5-HT and 5-HIAA levels. Also the behavior of lesioned and lesioned + transplanted males was rather similar to controls. In the behavioral tests we were mainly interested in hippocampal functioning, therefore orientation was of our prime interest. The other behavioral tests were only to confirm that the possible changes were linked to hypothalamic or extra-hypothalamic functions.(ABSTRACT TRUNCATED AT 400 WORDS)
Steinbusch
H W
HW
Department of Pharmacology, Faculty of Medicine, Free University, Amsterdam, The Netherlands.
Van Luijtelaar
M G
MG
Dijkstra
H
H
Nijssen
A
A
Tonnaer
J A
JA
D000375:Aging; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000254:growth & development / Q000502:physiology*; D016380:Brain Tissue Transplantation / Q000502:physiology*; D003714:Denervation; D016332:Fetal Tissue Transplantation / Q000502:physiology*; D006624:Hippocampus / Q000254:growth & development / Q000502:physiology; D008297:Male; D009416:Nerve Regeneration; D011903:Raphe Nuclei; D051381:Rats; D012701:Serotonin / Q000502:physiology*
D012701:Serotonin