Vulnerability to aging in the rat serotonergic system

Abstract

Distributional changes of serotonergic fibers associated with aging were demonstrated immunohistochemically. Old rat brains were morphologically characterized by the presence of peculiar features of serotonergic fibers not found in the young adult brain. In 24-month-old rats, these aberrant serotonergic fibers were subdivided into two groups according to morphological alterations: type 1 fibers consisting of thin fibers with moderately enlarged varicosities, and type 2 fibers consisting of much thicker fibers that have even larger varicosities and a tortuous course. These two types of fibers were distributed differentially in the forebrain. Type 1 fibers were found mainly in the striatum and frontoparietal cortex, whereas type 2 fibers were found in the posterior cingulate cortex and dentate gyrus of the hippocampal formation. Both types of aberrant fibers were seen in amygdala, frontoparietal cortex, hypothalamus, and thalamus. In 36-month-old rats, more highly degenerating arborizations were detected, and these aberrant ramifications were classified as follows based on shape as: type 3 fibers consisting of highly arborized thin fibers with a larger number of larger varicosities, and type 4 fibers consisting of thick fibers with abundant larger varicosities. Distributional difference indicated that type 1 fibers progress into type 3 fibers, whereas type 2 develop into type 4 fibers. These findings suggest the possibility that one set of pathological fibers emanate from the dorsal raphe nucleus and the other from the median raphe. Moreover, both two sets of serotonergic fibers show age-related aberrations in their morphology over same time course.

Recovery and aging of serotonergic fibers after single and intermittent MDMA treatment in dark agouti rat

“…To determine potential differences in the aging of serotonergic system between animals treated with MDMA at a young age and saline controls, we performed the quantitative evaluation of these structures in fairly large brain areas to avoid underestimation. The highest number of single swollen varicosities/intervaricose connections in the caudate putamen, the highest number of clusters in the parietal cortex with no apparent layer preferences, and the least number of both alterations in the hippocampus CA1 are all in accordance with previous studies indicating that these differences in the senescence process of distinct brain areas are hallmarks of the aging rat brain (Nishimura et al, 1998;van Luijtelaar et al, 1992).…”

“…Our investigation of the morphology and distribution of single swollen varicosities/intervaricose connections and clusters of aberrant fibers in 24-25-month-old Dark Agouti rats is in agreement with previous papers using 5-HT antibodies (van Luijtelaar et al, 1988(van Luijtelaar et al, , 1992Davidoff and Lolova, 1991;Nishimura et al, 1998). To determine potential differences in the aging of serotonergic system between animals treated with MDMA at a young age and saline controls, we performed the quantitative evaluation of these structures in fairly large brain areas to avoid underestimation.…”

“…At the same time, the density of serotonergic fibers decreases during senescence (van Luijtelaar et al, 1988Luijtelaar et al, , 1992Davidoff and Lolova, 1991;Nishimura et al, 1998). Swollen varicosities are generated as a result of impaired axonal transport due to the destruction of microtubules; the interrupted axonal flow causes an accumulation of 5-HT in the proximal stump of serotonergic fibers (van Luijtelaar et al, 1992).…”

Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer’s disease

“…Such features have already been reported for serotonergic and cholinergic systems in normal, aging rats [7,110,77,3], as well as in the entire monoaminergic system of Zitter mutant or microenchephalic rats [106,114]. Enlarged/swollen varicosities are generated by accumulations of intra-axonal materials as a result of impaired axonal transport due to destabilization of microtubules.…”

Lack of serotonin1B receptor expression leads to age-related motor dysfunction, early onset of brain molecular aging and reduced longevity

“…[10][11][12][13] However, the mechanisms underlying normal aging of the brain likely differ from those associated with neurodegenerative and pathological conditions and are still poorly understood. 14 Several lines of evidence suggest a role for 5-HT during aging, including structural and functional age-related changes in the 5-HT system in rodents [15][16][17] and in humans, as documented by post-mortem receptor binding studies, [18][19][20] RNA level studies, 21 in vivo imaging studies 22 and neuroendocrine challenges. 10 Depending on the brain region investigated, the 5-HT modulation of cerebral glucose metabolism increases or decreases during normal aging, suggesting a deregulated control of 5-HT 23 (see also 24 ).…”